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Evaluating occupational health risks associated with substitution of high-level disinfectants in hospitals Rideout, Karen L. 2003

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EVALUATING OCCUPATIONAL HEALTH RISKS ASSOCIATED WITH SUBSTITUTION OF HIGH-LEVEL DISINFECTANTS IN HOSPITALS by  K A R E N L. R I D E O U T B.A., Wilfrid Laurier University, 1999 B . S c . (Hons.), Mount Saint V i n c e n t University, 1999  A T H E S I S S U B M I T T E D IN P A R T I A L F U L F I L L M E N T O F THE REQUIREMENTS FOR THE DEGREE OF MASTER OF SCIENCE in THE FACULTY OF GRADUATE STUDIES ( S c h o o l of O c c u p a t i o n a l and Environmental H y g i e n e )  W e accept this thesis a s conforming to the required standard  T H E UNIVERSITY OF BRITISH C O L U M B I A April 2 0 0 3 © K a r e n L. Rideout, 2 0 0 3  Page 1 of 1  In  In p r e s e n t i n g t h i s t h e s i s i n p a r t i a l f u l f i l m e n t o f t h e r e q u i r e m e n t s f o r an a d v a n c e d d e g r e e a t t h e U n i v e r s i t y o f B r i t i s h C o l u m b i a , I a g r e e t h a t t h e L i b r a r y s h a l l make i t f r e e l y a v a i l a b l e f o r r e f e r e n c e and s t u d y . I f u r t h e r a g r e e t h a t p e r m i s s i o n f o r e x t e n s i v e c o p y i n g o f t h i s t h e s i s f o r s c h o l a r l y p u r p o s e s may be g r a n t e d b y t h e h e a d o f my department o r by h i s o r h e r r e p r e s e n t a t i v e s . I t i s understood that copying or p u b l i c a t i o n of t h i s thesis f o r f i n a n c i a l gain s h a l l not be a l l o w e d w i t h o u t my w r i t t e n p e r m i s s i o n .  Department The U n i v e r s i t y o f B r i t i s h Vancouver, Canada  Printed for Karen Rideout  Columbia  <krideout@interchange.ubc.ca>  4/23/2003  ABSTRACT  Glutaraldehyde, a c h e m i c a l a s s o c i a t e d with respiratory illness, h a s b e e n u s e d for high-level disinfection in hospitals for 40 years. T w o substitutes have recently been introduced—ortho-phthalaldehyde and a mixture of hydrogen peroxide and peracetic a c i d — d e s p i t e limited health effects information about the products. T h i s project u s e d a two-tiered a p p r o a c h to evaluate the risks a s s o c i a t e d with substitution of high-level disinfectants. It involved predicting the relative toxic effects of all the products and a s s e s s i n g the current practices regarding the u s e of high-level disinfectants in British C o l u m b i a hospitals. Relative potential toxicities were e x a m i n e d b a s e d on regulatory data, a review of the published literature, and a qualitative structure-activity relationship analysis. T h e r e w a s no published literature and little regulatory data available for orthophthalaldehyde and there is no history of using ortho-phthalaldehyde solutions in any industry. Structure-activity results s u g g e s t ortho-phthalaldehyde h a s dermal and respiratory sensitizing potential. Although little epidemiological data w a s available for hydrogen peroxide or peracetic acid, structure-activity a n a l y s i s results s u g g e s t little risk of sensitization. Current practices in industry were a s s e s s e d using a c o m p r e h e n s i v e survey of current practices and d e c i s i o n p r o c e s s e s in all hospitals in British C o l u m b i a . Of 95 hospitals, 64 returned surveys; 8 0 % of these u s e d high-level disinfection. A m o n g user hospitals, 4 9 % u s e d glutaraldehyde only and 5 1 % had introduced alternatives. C o n c e r n about e m p l o y e e health w a s the most c o m m o n r e a s o n for substituting but w a s frequently not c o n s i d e r e d w h e n c h o o s i n g specific alternatives. Although occupational health a n d safety staff w e r e available to 6 7 % of u s e r hospitals, they were involved in the d e c i s i o n p r o c e s s about the u s e of c h e m i c a l high-level disinfectants in only 4 1 % . Hospitals that involved o c c u p a t i o n a l health, infection control, or regional staff in high-level disinfectant d e c i s i o n s u s e d glutaraldehyde alternatives l e s s frequently. In most hospitals it w a s difficult to find any o n e person knowledgeable about the u s e of disinfectants at the site. Despite the fact that little is known about the risks to e m p l o y e e s from glutaraldehyde alternatives, their u s e is w i d e s p r e a d . T h e potential risks of all high-level disinfectants are serious; thus, regulators are f a c e d with important risk m a n a g e m e n t d e c i s i o n s not only before introducing new c h e m i c a l s , but also after they h a v e b e e n introduced into the workplace.  TABLE OF CONTENTS Abstract  ii  T a b l e of C o n t e n t s  iii  List of T a b l e s  ix  List of Figures  xii  List of Abbreviations  xiii  Acknowledgements  xiv  CHAPTER I. Introduction  1  1.1 Chemical Substitution for High-Level Disinfection  1  1.1.1 Project D e v e l o p m e n t  1  1.1.2 C h e m i c a l Substitution  1  1.1.3 C h e m i c a l High-Level Disinfection  2  1.1.4 C h e m i c a l s U s e d for High-Level Disinfection  3  1.1.4.1 G l u t a r a l d e h y d e  4  1.1.4.2 Ortho-phthalaldehyde ( O P A )  5  1.1.4.3 P e r a c e t i c A c i d - H y d r o g e n P e r o x i d e  5  1.2 Strategies to Evaluate the Problem  7  1.2.1 Predicting T o x i c Effects  7  1.2.2 A s s e s s i n g Current Patterns of U s e in the H e a l t h c a r e Industry  8  1.3 Objectives CHAPTER 2. Predicting Toxic Effects 2.1 Regulatory Processes  9 10 10  2.1.1 Objectives: Regulatory P r o c e s s e s R e v i e w  10  2.1.2 B a c k g r o u n d : C a n a d i a n and A m e r i c a n R e g u l a t o r y P r o c e s s e s  10  2.1.2.1 C a n a d a : Therapeutic Products Directorate  10  2.1.2.2 C a n a d a : P e s t M a n a g e m e n t Regulatory A g e n c y  11  2.1.2.3 U S : C e n t e r for D e v i c e s a n d R a d i o l o g i c a l Health  13  2.1.2.4 U S : Environmental Protection A g e n c y  14  2.1.3 M e t h o d s : Obtaining Regulatory T e s t i n g Information  15  2.1.3.1 Access to Information in Canada,,,,,,,,,  15  2.1.3.1.1 Access to Information R e q u e s t s to Health C a n a d a for C i d e x OPA® a n d C o m p l i a n c e ™ 15 2.1.3.2 Freedom of Information in the United S t a t e s  17  2.1.3.2.1 Freedom of Information Act R e q u e s t s to the F o o d a n d Drug Administration for C i d e x OPA® 18 2.1.3.2.2 Freedom of Information R e q u e s t s to the F o o d a n d Drug Administration for C o m p l i a n c e ™ 19 2.1.3.2.3 Freedom of Information R e q u e s t s to the Environmental Protection A g e n c y for C i d e x OPA® 2.1.3.3 Regulatory Information from Manufacturers  19 20  2.1.3.3.1 A d v a n c e d Sterilization P r o d u c t s Data  20  2.1.3.3.2 Metrex Data  21  2.1.4 Results: Regulatory Toxicology Data O b t a i n e d 2.1.4.1 C i d e x OPA® Data  22 22  2.1.4.1.1 Data from Regulatory A g e n c i e s  22  2.1.4.1.2 Data from Manufacturer  23  2.1.4.2 C o m p l i a n c e ™ Data 2.1.4.2.1 D a t a from Regulatory A g e n c i e s 2.1.4.2.2 Data from Manufacturer  27 27 29  2.2 Comprehensive Literature Review  30  2.2.1 Literature R e v i e w Objectives  30  2.2.2 Literature R e v i e w M e t h o d s  30  2.2.3 R e s u l t s of Literature R e v i e w  31  2.2.3.1 G l u t a r a l d e h y d e  31  iv  2.2.3.1.1 D e r m a l Effects of G l u t a r a l d e h y d e E x p o s u r e  31  2.2.3.1.2 Respiratory Effects of G l u t a r a l d e h y d e E x p o s u r e  32  2.2.3.1.3 Glutaraldehyde Toxicology S t u d i e s  34  2.2.3.2 Ortho-phthalaldehyde ( O P A )  35  2.2.3.3 H y d r o g e n Peroxide  36  2.2.3.3.1 Effects of Hydrogen P e r o x i d e Ingestion  36  2.2.3.3.2 D e r m a l Effects of H y d r o g e n P e r o x i d e E x p o s u r e  36  2.2.3.3.3 Respiratory Effects of H y d r o g e n P e r o x i d e E x p o s u r e . 3 7 2.2.3.4 P e r a c e t i c A c i d  37  2.2.3.4.1 D e r m a l Effects of P e r a c e t i c A c i d E x p o s u r e  38  2.2.3.4.2 Respiratory Effects of P e r a c e t i c A c i d E x p o s u r e  38  40  2.3 Structure-Activity Relationship Analysis (SAR) 2.3.1 U s e of S A R to Predict Respiratory Sensitization  40  2.3.2 S A R Objectives  42  2.3.3 S A R M e t h o d s  42  2.3.3.1 Respiratory Sensitizing Predictors 2.3.3.2 C h e m i c a l A s t h m a H a z a r d A s s e s s m e n t P r o g r a m :  42 Hazassess..45  2.3.4 R e s u l t s of S A R A n a l y s i s  46  2.3.4.1 G l u t a r a l d e h y d e  46  2.3.4.2 Ortho-phthalaldehyde ( O P A )  47  2.3.4.3 H y d r o g e n Peroxide  48  2.3.4.4 P e r a c e t i c A c i d  49  2.3.4.5 S A R A n a l y s i s S u m m a r y  49  2.4 Discussion of Predicted Toxic Effects  51  2.4.1 G l u t a r a l d e h y d e Toxicity and Prediction of Respiratory Sensitization... 51 2.4.1.1 G l u t a r a l d e h y d e Toxicity  51  2.4.1.2 Limitations of A n i m a l M o d e l s for Predicting Respiratory Sensitization 2.4.2 O P A Toxicity  54 54  2.4.2.1 Production of O P A V a p o u r  54  2.4.2.2 O P A Toxicity Data  56  2.4.2.3 Structure-Activity Relationships for O P A  56  v  2.4.2.4 Tier A p p r o a c h to Predicting Respiratory Sensitization Potential of O P A 58 2.4.3 P e r a c e t i c A c i d and H y d r o g e n P e r o x i d e  CHAPTER 3. Assessing High-Level Disinfection Practices in the Healthcare Industry 3.1 Current Practices Survey Objectives 3.2 Current Practices Survey Methods 3.2.1 Preliminary N o t i c e s 3.2.2 D a t a b a s e D e v e l o p m e n t 3.2.3 Q u e s t i o n n a i r e D e v e l o p m e n t 3.2.4 S u r v e y Implementation and Follow-up 3.2.5 Data M a n a g e m e n t and A n a l y s i s 3.2.5.1 Hospital Characteristics 3.2.5.2 Exploratory Statistical A n a l y s i s  3.3 Current Practices Survey Results 3.3.1 S u r v e y R e s p o n s e and Hospital Characteristics 3.3.2 C h e m i c a l s U s e d for H i g h - L e v e l Disinfection 3.3.3 R e l a t i o n s h i p s B e t w e e n Hospital Characteristics a n d C h o i c e of H i g h - L e v e l Disinfection C h e m i c a l s 3.3.4 Hospitals U s i n g O n l y Glutaraldehyde for H i g h - L e v e l Disinfection 3.3.5 Hospitals U s i n g G l u t a r a l d e h y d e Alternatives 3.3.6 D e c i s i o n M a k i n g for High-Level Disinfection 3.3.6.1 Why: R e a s o n s for C h o o s i n g Disinfectants 3.3.6.2 How: Criteria for C h o o s i n g S p e c i f i c Alternatives 3.3.6.3. Who: D e c i s i o n M a k e r s for High-Level Disinfection 3.3.7 F a c t o r s A s s o c i a t e d with the U s e of A n y Alternatives  3.4 Discussion of Current Practices Survey 3.4.1 D i s c u s s i o n of S u r v e y Results 3.4.2 Strengths a n d Limitations of the S u r v e y T o o l  CHAPTER 4. Conclusions and Recommendations 4.1 Synthesis of Predictive Toxicology and Industry Data  98  98  4.2 Recommendations for Policy Makers and Hospital Decision Makers.. 100 4.2.1 H e a l t h - B a s e d Product R e c o m m e n d a t i o n s  100  4.2.2 R e c o m m e n d a t i o n s for D e c i s i o n M a k e r s  100  4.2.3 R e c o m m e n d a t i o n s for Policy M a k e r s  102  4.3 Future Work  105  References Appendix I.  103  C o r r e s p o n d e n c e with Health C a n a d a A c c e s s to Information Office  116  Appendix II.  C o r r e s p o n d e n c e with the Information C o m m i s s i o n e r of C a n a d a . . 1 3 7  Appendix III.  C o r r e s p o n d e n c e with the United States F o o d a n d Drug Administration R e g a r d i n g F r e e d o m of Information R e q u e s t s for C i d e x OPA® 141 Toxicity C o m p a r i s o n T a b l e s : G l u t a r a l d e h y d e (Cidex®) vs. Orthophthalaldehyde (Cidex OPA®), Obtained from Freedom of Information R e q u e s t to the United S t a t e s F o o d and Drug Administration 150  Appendix IV.  Appendix V.  C o r r e s p o n d e n c e with the United States F o o d a n d Drug Administration R e g a r d i n g Freedom of Information R e q u e s t for Compliance™ 153  Appendix VI.  C o m p l i a n c e ™ Toxicity S u m m a r i e s O b t a i n e d from Freedom of Information R e q u e s t to the United S t a t e s F o o d and Drug Administration  161  C o r r e s p o n d e n c e with National T e c h n i c a l Information S e r v i c e R e g a r d i n g R e q u e s t for E P A Fact S h e e t on 1,2benzenedicarboxaldehyde (OPA)  165  Appendix VII.  Appendix VIII. Affirmation of Non-multinational Status F o r m Appendix IX.  C o r r e s p o n d e n c e with United States Environmental Protection A g e n c y R e g a r d i n g F r e e d o m of Information R e q u e s t for C i d e x O P A Antimicrobial  172  174  Appendix X.  F a x from A d v a n c e d Sterilization P r o d u c t s R e g a r d i n g Air Monitoring of Cidex® O P A Solution 179  Appendix XI.  C o r r e s p o n d e n c e with A d v a n c e d Sterilization P r o d u c t s R e g a r d i n g R e q u e s t s for C i d e x OPA® Data 181  VII  Appendix XII.  Toxicity S u m m a r i e s for C o m p l i a n c e ™ O b t a i n e d from Metrex  184  Appendix XIII. C o r r e s p o n d e n c e with MetrexVSybron Dental S p e c i a l t i e s R e g a r d i n g R e q u e s t s for C o m p l i a n c e ™ Data  186  Appendix XIV.  M S D S for O P A R a w Material  194  Appendix XV.  M S D S for C i d e x OPA®  200  Appendix XVI.  M S D S for C o m p l i a n c e ™  206  Appendix XVII. Letter M a i l e d to C h i e f Executive Officers of Health Authorities and Healthcare Unions  Appendix XVIII. Q u e s t i o n n a i r e C o v e r Letter  211 214  Appendix XIX.  Current P r a c t i c e s S u r v e y Q u e s t i o n n a i r e  217  Appendix XX.  T e l e p h o n e Follow-up G u i d e for Current P r a c t i c e s S u r v e y  229  Appendix XXI.  C o m p l e t e T a b l e s of R e a s o n s for C h o o s i n g Disinfectants 231 A s s o c i a t i o n s B e t w e e n C a n d i d a t e V a r i a b l e s for Multivariable Logistic Regression 233  Appendix XXII.  viii  LIST O F T A B L E S  T A B L E 2.1.  Non-active ingredients in C i d e x O P A  T A B L E 2.2.  Structural and c h e m i c a l predictors of respiratory sensitization potential identified from published S A R reports 45  T A B L E 2.3.  R e s u l t s of qualitative S A R  50  T A B L E 2.4.  Toxicity and health effects c o m p a r i s o n of c h e m i c a l s u s e d for high-level disinfection  52  S u m m a r y of d e r m a l and respiratory toxicity d a t a for high-level disinfection c h e m i c a l s at concentrations approximating in use conditions  53  T A B L E 2.6.  S u m m a r y of qualitative S A R results  57  T A B L E 3.1.  Hospital s i z e categories  64  T A B L E 3.2.  Municipality s i z e categories  65  T A B L E 3.3.  C a n d i d a t e variables for logistic regression  67  T A B L E 3.4.  S u r v e y r e s p o n s e rates  69  T A B L E 3.5.  Descriptive characteristics of respondent hospitals  70  T A B L E 3.6.  High-level disinfectant u s a g e characteristics of respondent  T A B L E 2.5.  22  hospitals  71  T A B L E 3.7.  D e p a r t m e n t s using c h e m i c a l s for high-level disinfection  72  T A B L E 3.8.  C h e m i c a l s u s e d for high-level disinfection  73  T A B L E 3.9.  T y p e s of c h e m i c a l s u s e d for high-level disinfection a c c o r d i n g to department  73  T A B L E 3.10. U s e of high-level disinfection c h e m i c a l s a c c o r d i n g to hospital size... 74 T A B L E 3.11. U s e of high-level disinfection c h e m i c a l s a c c o r d i n g to municipality size T A B L E 3.12. U s e of high-level disinfection c h e m i c a l s a c c o r d i n g to occupational health staff availability  74 75  T A B L E 3.13. T y p e s of c h e m i c a l s u s e d for high-level disinfection a c c o r d i n g to hospital s i z e  75  T A B L E 3.14. T y p e s of c h e m i c a l s u s e d for high-level disinfection a c c o r d i n g to municipality s i z e  76  T A B L E 3.15. T y p e s of c h e m i c a l s u s e d for high-level disinfection a c c o r d i n g to health authority 76  ix  T A B L E 3.16. T y p e s of c h e m i c a l s u s e d for high-level disinfection a c c o r d i n g to o c c u p a t i o n a l health staff availability T A B L E 3.17. A m o u n t of c h e m i c a l high-level disinfectants u s e d in hospitals  76 77  T A B L E 3.18. Full-time e m p l o y e e s reported to be working in d e p a r t m e n t s that use high-level disinfectants ('exposed' e m p l o y e e s ) 77 T A B L E 3.19. Hospitals using only glutaraldehyde for c h e m i c a l high-level disinfection  78  T A B L E 3.20. C h a r a c t e r i s t i c s of hospitals using only glutaraldehyde  78  T A B L E 3.21. C h a r a c t e r i s t i c s of departments using only glutaraldehyde  79  T A B L E 3.22. High-level disinfectant u s a g e characteristics a m o n g hospitals using only glutaraldehyde  80  T A B L E 3.23. P r o d u c t s planned to replace glutaraldehyde in future  81  T A B L E 3.24. P l a n s to continue using alternatives for high-level disinfection  81  T A B L E 3.25. R e a s o n s for not introducing glutaraldehyde substitutes  82  T A B L E 3.26. R e a s o n s for considering substitution  82  T A B L E 3.27. R e a s o n s for introducing glutaraldehyde substitutes  83  T A B L E 3.28. R e a s o n s for continuing to use alternatives  83  T A B L E 3.29. Criteria for c h o o s i n g specific alternatives  84  T A B L E 3.30. D e c i s i o n m a k e r s in hospitals using high-level disinfection  86  T A B L E 3.31. D e c i s i o n m a k e r s in hospitals using only glutaraldehyde 87 T A B L E 3.32. R e l a t i o n s h i p between availability of occupational health staff and the u s e of glutaraldehyde alternatives 87 T A B L E 3.33. Relationship between availability of o c c u p a t i o n a l health staff and their involvement in high-level disinfection d e c i s i o n s  87  T A B L E 3.34. Relationship between involvement of o c c u p a t i o n a l health staff in high-level disinfection d e c i s i o n s and the u s e of glutaraldehyde alternatives  88  T A B L E 3.35. Relationship between c h o i c e of high-level disinfection c h e m i c a l and u s e of s a l e s representative information 88 T A B L E 3.36. Relationship between occupational health involvement in d e c i s i o n s and u s e of s a l e s representative information 88 T A B L E 3.37. Highly correlated candidate variables  89  T A B L E 3.38. Univariate logistic regression m o d e l s of the relationship between individual hospital characteristics and the u s e of glutaraldehyde alternatives  90  x  T A B L E 3.39. Multivariable logistic regression model of the relationship between hospital characteristics and the use of glutaraldehyde alternatives...91 T A B L E 3.40. Effect of removing a s s o c i a t e d variables o n o d d s ratio estimates in the multivariable logistic regression m o d e l 92 T A B L E A 1 . R e a s o n s for not introducing glutaraldehyde substitutes  231  T A B L E A 2 . R e a s o n s for considering glutaraldehyde substitution  231  T A B L E A 3 . R e a s o n s for introducing glutaraldehyde substitutes  231  T A B L E A 4 . R e a s o n s for continuing to use alternatives  232  T A B L E A 5 . Criteria for c h o o s i n g specific alternatives  232  T A B L E A6. Variable codes  233  T A B L E A 7 . A s s o c i a t i o n s (p-value, chi-square analysis) b e t w e e n candidate variables  234  T A B L E A 8 . P e a r s o n correlation coefficients for candidate variables  235  xi  LIST O F F I G U R E S  F I G U R E 2.1. G l u t a r a l d e h y d e  46  F I G U R E 2.2. Ortho-phthalaldehyde ( O P A )  47  F I G U R E 2.3. Phthalic anhydride  48  F I G U R E 2.4. H y d r o g e n peroxide  48  F I G U R E 2.5. P e r a c e t i c acid  49  F I G U R E 3.1. U s e of high-level disinfection c h e m i c a l s a c c o r d i n g to hospital s i z e . . . 7 4 F I G U R E 3.2. U s e of high-level disinfection c h e m i c a l s a c c o r d i n g to municipality size  74  F I G U R E 3.3. U s e of high-level disinfection c h e m i c a l s a c c o r d i n g to occupational health staff availability  75  F I G U R E 3.4. R e a s o n s for not introducing glutaraldehyde substitutes  85  F I G U R E 3.5. R e a s o n s for introducing glutaraldehyde substitutes  85  F I G U R E 3.6. Criteria for c h o o s i n g specific alternatives  85  F I G U R E 3.7. U s e of high-level disinfection c h e m i c a l s a c c o r d i n g to d e c i s i o n makers  86  LIST O F A B B R E V I A T I O N S  ACGIH ALARA ASP ATI CASE CDRH CFR DIN DNPH EPA FDA GC/MS HLD HPLC HSDB igE LD MW LOEL MSDS MultiCASE NIOSH NOEL OHS OHSAH OPA OR PCP PMRA ppm QSAR 5 0  RD RADS RTECS® SAR SENSOR SPME 5 0  TC50  TLV TPD UBC WCB w/v  A m e r i c a n C o n f e r e n c e of G o v e r n m e n t a l Industrial Hygienists a s low a s reasonably a c h i e v a b l e A d v a n c e d Sterilization P r o d u c t s A c c e s s to Information C o m p u t e r A u t o m a t e d Structure Evaluation C e n t e r for D e v i c e s and Radiological Health  Code of Federal Regulations ( U S ) Drug Identification N u m b e r 1,2-dinitrophenylhydrazine Environmental Protection A g e n c y F o o d and Drug Administration g a s c h r o m a t o g r a p h y / m a s s spectrometry high-level disinfection high performance liquid c h r o m a t o g r a p h y H a z a r d o u s S u b s t a n c e s Data B a n k immunoglobulin E m e d i a n lethal d o s e molecular weight lowest o b s e r v e d effect level material safety data sheet Multiple C o m p u t e r A u t o m a t e d Structure Evaluation National Institute of O c c u p a t i o n a l Safety a n d Health no o b s e r v e d effect level o c c u p a t i o n a l health staff O c c u p a t i o n a l Health and Safety A g e n c y for H e a l t h c a r e ortho-phthalaldehyde O d d s ratio P e s t Control Product P e s t M a n a g e m e n t Regulatory A g e n c y parts per million qualitative structure-activity relationship concentration resulting in 5 0 % d e c r e a s e in respiratory rate reactive airways dysfunction s y n d r o m e Registry of T o x i c Effects of C h e m i c a l S u b s t a n c e s structure-activity relationship Sentinel Event Notification S y s t e m for O c c u p a t i o n a l R i s k s solid p h a s e microextraction m e d i a n toxic concentration threshold limit value T h e r a p e u t i c Products Directorate University of British C o l u m b i a W o r k e r s ' C o m p e n s a t i o n Board weight per v o l u m e  xi  ACKNOWLEDGEMENTS  First, I would like to thank my supervisor, Dr. S u s a n K e n n e d y , w h o s e e m e d to have confidence in my abilities e v e n w h e n I did not. I could not h a v e d o n e this without her ongoing support a n d e n c o u r a g e m e n t . T h a n k you to my c o m m i t t e e m e m b e r s , Dr. K a y T e s c h k e and Dr. H e l e n W a r d , for their invaluable support a n d g u i d a n c e throughout this p r o c e s s , and to all the professors w h o helped m e to d e v e l o p the knowledge and skills required to complete this project. I would like to thank the C a n a d i a n Institutes of Health R e s e a r c h for funding this project and the Natural S c i e n c e and Engineering R e s e a r c h C o u n c i l a n d the M i c h a e l Smith Foundation for Health R e s e a r c h for scholarship support during my studies. I would also like to thank A n n a l e e Y a s s i and the O c c u p a t i o n a l Health and Safety A g e n c y for H e a l t h c a r e ( O H S A H ) for supporting this project. My sincere gratitude to all the hospital e m p l o y e e s w h o c o m p l e t e d surveys, a n s w e r e d my questions about high-level disinfection, and g a v e m e tours of their w o r k p l a c e s . T h a n k s to e v e r y o n e at Health C a n a d a and the U S F o o d a n d Drug Administration w h o helped m e obtain regulatory information, a n d to the B C W o r k e r s ' C o m p e n s a t i o n B o a r d for helping to obtain information from manufacturers. T h a n k s to all the faculty and staff in the S c h o o l of O c c u p a t i o n a l and Environmental Hygiene, and to my fellow students and friends from the p r o g r a m . A n d a special thanks g o e s to R i c k for always being there.  xiv  CHAPTER I. introduction 1.1 Chemical Substitution for High-Level Disinfection 1.1.1 Project  Development  C o n c e r n s about e m p l o y e e health impact and c h e m i c a l substitution w e r e raised at a British C o l u m b i a hospital in 2 0 0 0 w h e n a new c h e m i c a l high-level disinfectant product w a s introduced. All high-level disinfectant products available previously had contained the s a m e primary active ingredient, glutaraldehyde, w h i c h is a s s o c i a t e d with a n u m b e r of serious health problems. In r e s p o n s e to t h e s e health concerns, a new product b e c a m e available in 1999 that w a s purported to result in fewer e m p l o y e e health effects than the traditional products. T h e active ingredient in the new product w a s a c h e m i c a l that had not previously b e e n u s e d in solution form and its potential health effects w e r e not known. This situation raised a n u m b e r of questions about how to deal with i s s u e s of c h e m i c a l substitution and unknown e m p l o y e e health risks. This thesis u s e s the e x a m p l e of high-level disinfection to e x a m i n e i s s u e s surrounding c h e m i c a l substitution and e m p l o y e e health, particularly in the acute care sector of the healthcare industry. W h e n a product called C i d e x OPA® w a s introduced to the market, s o m e British C o l u m b i a hospitals b e g a n using it a s a substitute for glutaraldehyde despite having little k n o w l e d g e of its potential e m p l o y e e health impact. T h e occupational health department at N a n a i m o G e n e r a l Hospital on V a n c o u v e r Island b e c a m e interested in the i s s u e w h e n this product w a s c o n s i d e r e d a s a p o s s i b l e high-level disinfectant there. B e c a u s e of c o n c e r n about the lack of available health information, a proposal for funding w a s submitted by the Central V a n c o u v e r Island Health R e g i o n ( C V I H R ) to the O c c u p a t i o n a l Health and Safety A g e n c y for H e a l t h c a r e in B C ( O H S A H ) . T h e project w a s later adopted by researchers in the S c h o o l of O c c u p a t i o n a l and Environmental H y g i e n e at the University of British C o l u m b i a , in collaboration with O H S A H a n d C V I H R . A s the research protocol w a s being d e v e l o p e d , a s e c o n d glutaraldehyde alternative, C o m p l i a n c e ™ , w a s introduced. T h e current study w a s then e x p a n d e d to a s s e s s the e m p l o y e e health impacts of both products. This project is a preliminary study that will be u s e d to plan future r e s e a r c h , i.e., an epidemiological study of the e x p o s u r e - r e s p o n s e relationships of glutaraldehyde and glutaraldehyde alternatives.  1.1.2 Chemical  Substitution  A c c o r d i n g to b a s i c industrial hygiene practice, the best w a y to protect e m p l o y e e s w h o are e x p o s e d to a h a z a r d o u s chemical is to remove that c h e m i c a l from the work  1  environment and substitute it with either another less h a z a r d o u s c h e m i c a l , or to c h a n g e the p r o c e s s s o that the h a z a r d o u s c h e m i c a l is no longer n e c e s s a r y (Ellenbecker 1996). W h e n a substitute c h e m i c a l with a long history of industrial use and with fewer or l e s s s e v e r e health effects than the original c h e m i c a l is u s e d , substitution is a n effective m e a n s to reduce or r e m o v e risks to e m p l o y e e health. W h e n the health impacts of a new c h e m i c a l are not fully u n d e r s t o o d , substitution may not n e c e s s a r i l y be the ideal w a y to protect health. B a s i c toxicology data may not be sufficient to determine the potential health effects of new c h e m i c a l s and unknown p r o b l e m s m a y surface later. B e c a u s e of this unknown potential for harm, the c o n s e q u e n c e s of any substitution program need to be systematically evaluated before the program is implemented and control m e a s u r e s are better put in place w h e n the substitute is introduced rather than waiting for u n f o r e s e e n problems to arise ( A n t o n s s o n 1995). T h e r e c a n be m a n y risks w h e n substituting new or unknown c h e m i c a l s . Despite this, it is e a s y to a s s u m e that a s u b s t a n c e is not h a z a r d o u s just b e c a u s e it is not known to have serious health effects. A s A n t o n s s o n said, "Lack of knowledge should be treated a s a warning sign, not a s a sign of immunity from problems" ( A n t o n s s o n 1995, p. 396).  1.1.3 Chemical High-Level Disinfection  (HLD)  High-level disinfection ( H L D ) is a cleaning p r o c e s s that kills all m i c r o o r g a n i s m s except large n u m b e r s of bacterial s p o r e s (Rutala 1996). Health C a n a d a , the a g e n c y that regulates high-level disinfection products in C a n a d a , defines a high-level disinfectant a s "a disinfectant that kills all microbial pathogens, e x c e p t large numbers of bacterial e n d o s p o r e s w h e n u s e d in a c c o r d a n c e with labelling" (Therapeutic P r o d u c t s P r o g r a m m e [TPP] 1999). High-level disinfection is the first level of disinfection below sterilization, which kills all m i c r o o r g a n i s m s including bacterial and fungal s p o r e s . B e c a u s e they are not rendered sterile, medical instruments c l e a n e d using high-level disinfection are c o n s i d e r e d "semicritical" items; they may contact broken skin or m u c o u s m e m b r a n e s , w h i c h are usually resistant to c o m m o n spores, but they should not contact v a s c u l a r or other sterile body tissue (Rutala 1996; W h i t e h o u s e et al. 1998). Instruments that require high-level disinfection are t h o s e that are not d i s p o s a b l e and are fragile or sensitive to normal heat or s t e a m sterilization procedures. T h e y must therefore be disinfected by lowtemperature c h e m i c a l m e t h o d s . T h i s type of equipment usually contains electronic and fibre-optic c o m p o n e n t s , heat-sensitive glues, or flexible tubing. Instruments that require high-level disinfection include flexible e n d o s c o p e s , l a r y n g o s c o p e s , respiratory therapy equipment, a n a e s t h e s i a equipment, rectal and vaginal probes, endotrachial tubes, nebulizer cups, nasal s p e c u l a , and other similar instruments (Health C a n a d a 1998). T r a n s - o e s o p h a g e a l ( T E E ) probes and ultrasound probes are also c o m m o n l y c l e a n e d using high-level disinfection (personal c o m m u n i c a t i o n , R. Kilty, Safety Consultant, R o y a l C o l u m b i a n Hospital, J u n e 19, 2 0 0 1 ; personal communication, D. Buhr, Safety Coordinator, E a g l e R i d g e Hospital, J u n e 20, 2001).  2  High-level disinfection is c o n d u c t e d a s part of the infection control program within a hospital. Infection control b e c a m e recognized as a discipline in the 1950's after a series of n o s o c o m i a l s t a p h y l o c o c c u s infections occurred in A m e r i c a n hospitals. S i n c e that time, n u m e r o u s different c h e m i c a l s have b e e n u s e d to disinfect semicritical instruments that are not stable to heat, including h y d r o g e n peroxide, quaternary a m m o n i u m c o m p o u n d s , alcohol, s o d i u m hypochlorite (chlorine bleach), phenolic c o m p o u n d s , peracetic acid, and glutaraldehyde ( W h i t e h o u s e et al. 1998). Hydrogen peroxide and f o r m a l d e h y d e were first u s e d a s liquid c h e m i c a l disinfectants in the 1880's; quaternary a m m o n i u m c o m p o u n d s w e r e introduced in 1916. Chlorhexidine, peracetic acid, and glutaraldehyde w e r e introduced m u c h later in 1954, 1955, and 1957, respectively (Hugo 1991). G l u t a r a l d e h y d e has been the most c o m m o n l y u s e d c h e m i c a l for high-level disinfection s i n c e its introduction. It is effective against a broad range of microorganisms, is compatible with most equipment (non-damaging), and is relatively e a s y to use. Unfortunately, glutaraldehyde v a p o u r is highly irritating to the eyes, m u c o u s m e m b r a n e s , and the respiratory s y s t e m , and it c a n c a u s e allergic contact dermatitis and a s t h m a (Russell 1994; Rutala & W e b e r 1999). B e c a u s e of these e m p l o y e e health issues, there has been an ongoing s e a r c h for a feasible substitute for glutaraldehyde. T h e ideal highlevel disinfectant w o u l d be highly biocidal, e a s y to use, easily monitored for biocidal activity, cost-effective, fast acting, compatible with equipment, non-toxic to the environment, non-staining to skin or equipment, free of u n p l e a s a n t odours, have a long shelf life and r e u s e life, and would not present a health hazard to e m p l o y e e s who work with or around the disinfectant (Fraise 1999; R u t a l a & W e b e r 1999).  1.1.4 Chemicals Used for High-Level  Disinfection  C h e m i c a l s currently u s e d for high-level disinfection are sold in a q u e o u s solution form. T h e instruments to be c l e a n e d are s o a k e d for a specific period of time, depending on the active ingredient and concentration. S o a k i n g m a y be d o n e by using a "soaker boat," w h i c h is a container similar to a d i s h p a n that is filled with a high-level disinfection solution, or s o m e other small o p e n container that can be filled with liquid for s o a k i n g instruments. Certain types of instruments s u c h as e n d o s c o p e s are often c l e a n e d in a n automatic e n d o s c o p e reprocessor. T h e s e are m a c h i n e s d e s i g n e d specifically for high-level disinfection of e n d o s c o p e s . T h e y are filled with the high-level disinfection solution; w h e n instruments are p l a c e d inside, the m a c h i n e runs through a p r e - p r o g r a m m e d cycle of pre-rinsing, w a s h i n g , disinfecting (which allows the solution to flush through the inner lumens of the e n d o s c o p e tubing), and final rinsing. All high-level disinfectant products currently on the market c a n be re-used; that is, a series of instruments m a y be s o a k e d and r e m o v e d , and more c a n then be disinfected using the s a m e solution. T h e length of time and n u m b e r of u s e s possible before disinfection capability b e c o m e s c o m p r o m i s e d d e p e n d s o n the type of highlevel disinfection solution and on the degree of contamination of the instruments.  3  1.1.4.1 G l u t a r a l d e h y d e Glutaraldehyde ( C A S registry no. 111-30-8) solutions h a v e b e e n the industry standard for high-level disinfection of medical d e v i c e s for approximately 4 0 years (Russell 1994). It is a linear dialdehyde with a c h e m i c a l formula of C H 0 and a molecular weight of 100.11. Glutaraldehyde is also known a s 1,5-pentanedial, 1,5pentanedione, glutaral, a n d glutaric dialdehyde a m o n g others. It is normally u s e d as a saturated solution containing approximately 2% glutaraldehyde (Rutala & W e b e r 1999). T h e v a p o u r p r e s s u r e of one c o m m o n g l u t a r a l d e h y d e - b a s e d disinfectant is 0.0012 m m H g at 20 °C ( A S P 1999); the vapour p r e s s u r e of a 7 0 % solution of glutaraldehyde is 17 m m Hg at 20 °C (Ladd R e s e a r c h Industries 2002). Glutaraldehyde is more stable in its natural acidic form (pH 3.0-4.6) but is more biologically active at alkaline p H . Until recently, most glutaraldehyde products were sold as an acidic solution that had to be "activated" to p H 7 . 5 - 8 . 5 prior to use by adding a n alkalizing agent. T h e r e w e r e s o m e products a v a i l a b l e that d o not require activation but t h e s e had a shelf life of only 1 to 2 w e e k s ( R u s s e l l 1994). Buffered solutions are n o w available that do not require activation yet h a v e a longer shelf life ( A S P 1999). 5  8  2  There are m a n y g l u t a r a l d e h y d e - b a s e d high-level disinfection products available. S o m e of the more c o m m o n brands available in C a n a d a include Cidex® ( A d v a n c e d Sterilization Products), Glutacide® ( P h a r m a x Limited), Metricide® (Metrex R e s e a r c h , Inc.), Wavicide® ( W a v e E n e r g y S y s t e m s ) , and Asepti-Steryl ( E c o l a b , Inc.). Shelf life of the c l o s e d bottle product is about 2 years. R e u s e life for glutaraldehyde solutions is normally about 2 to 4 w e e k s , although the solutions must be tested regularly to e n s u r e sufficient activity. S o a k i n g times for high-level disinfection are approximately 20 to 90 minutes (Rutala & W e b e r 1999). T h e m e c h a n i s m of the biocidal activity of glutaraldehyde is fairly well understood. Glutaraldehyde h a s a bifunctional reactivity b e c a u s e of the two a l d e h y d e groups at either end of the molecule. T h e s e functional groups c a u s e cross-linking reactions with primary a n d then s e c o n d a r y amino groups on the cell s u r f a c e of microorganisms. T h i s kills them by preventing the cellular functions n e c e s s a r y for life (Walsh et al. 1999). G l u t a r a l d e h y d e also disrupts R N A , D N A , a n d protein synthesis of m i c r o o r g a n i s m s through alkylation of sulfhydryl, hydroxyl, carboxyl, and amino groups (Rutala 1996), but its biocidal activity is not related to direct interactions with R N A or D N A ( W a l s h et al. 1999). T h e extent to w h i c h glutaraldehyde is active against microorganisms d e p e n d s partly on the type of organism and the amount of organic matter present, a s well a s on the concentration of the active ingredient, contact time, and temperature (Rutala & W e b e r 1999). pH influences efficacy not by a direct effect on glutaraldehyde but by c a u s i n g a m i n e s on the s u r f a c e of o r g a n i s m s to b e c o m e unprotonated a n d therefore free to react with a l d e h y d e g r o u p s on the glutaraldehyde m o l e c u l e ( W a l s h et al. 1999).  4  1.1.4.2 Ortho-phthalaldehyde ( O P A ) Ortho-phthalaldehyde ( O P A ) ( C A S registry no. 643-79-8) h a s b e e n available for u s e as a high-level disinfectant since 1999 (personal c o m m u n i c a t i o n , H. P a c e , Director of Marketing and S a l e s , A d v a n c e d Sterilization Products, M a r c h 10, 2003). Like glutaraldehyde, O P A is a dialdehyde, but it has a b e n z e n e ring rather than a linear structure. T h e m o l e c u l a r formula of O P A is C H 0 2 a n d its m o l e c u l a r weight is 134.14. Alternative n a m e s for O P A include 1,2-benzenedicarboxaldehyde, phthalic dialdehyde, and phthalic d i c a r b o x a l d e h y d e . O P A forms an alkaline solution with a pH of 7.2-7.8. Currently there is only o n e high-level disinfection product available with O P A a s the active ingredient. C i d e x OPA® ( A d v a n c e d Sterilization Products [ASP]) is formulated at a low concentration (0.55%) and is stable o v e r a wide p H range ( 3 - 9 ) (Rutala & W e b e r 1999). T h e v a p o u r p r e s s u r e of C i d e x OPA® is not available. T h i s product h a s a 14-day reuse life and a 2-year c l o s e d bottle shelf life. Like glutaraldehyde solutions, O P A must be c h e c k e d regularly for efficacy w h e n being r e u s e d . S o a k i n g time for high-level disinfection is 12 minutes ( A S P 2000). 8  6  T h e m e c h a n i s m by w h i c h O P A acts a s a disinfectant is not well u n d e r s t o o d . It is believed to react with primary a m i n o groups within the cells of m i c r o o r g a n i s m s , thus making them inactive. It is involved in fewer cross-linking reactions than glutaraldehyde, but like glutaraldehyde, higher pH m a y m a k e the c h e m i c a l more active against m i c r o o r g a n i s m s by unprotonating a m i n o groups. It h a s also been s u g g e s t e d that protein coagulation or other protein interactions might also be a factor in the efficacy of O P A (Walsh et al. 1999). 1.1.4.3 P e r a c e t i c A c i d - H y d r o g e n P e r o x i d e Peracetic acid and hydrogen peroxide are u s e d in a c o m b i n e d solution for high-level disinfection. P e r a c e t i c acid ( C A S registry no. 79-21-0) h a s the c h e m i c a l formula C H 0 and a m o l e c u l a r weight of 76.05. It is also known a s acetic peroxide, peroxyacetic acid, and e t h a n e p e r o x o i c acid. H y d r o g e n peroxide ( H 0 ; C A S registry no. 7722-84-1) h a s a m o l e c u l a r weight of 34.01. T h e only currently marketed peracetic a c i d - h y d r o g e n peroxide solution for high-level disinfection contains 0.23% peracetic acid a n d 7.35% hydrogen peroxide. C o m p l i a n c e ™ (Metrex R e s e a r c h , Inc.) has been available s i n c e 2 0 0 0 (personal communication, C. B o s w e l l , Director of Corporate C o m p l i a n c e , Metrex R e s e a r c h , Inc., M a r c h 6, 2003). It has a p H range of 1.8 to 2.2 and a v a p o u r p r e s s u r e of 21 m m H g at 2 5 °C. C o m p l i a n c e h a s a shelf life of 2 years, and m a y be r e u s e d for up to 31 days. T h e manufacturer claims that testing for efficacy of reused solutions is not n e c e s s a r y . S o a k i n g time for high-level disinfection is 10 minutes (Metrex n.d.). A similar product known a s PeraSafe® (Antec Intl.) is available in E u r o p e . T h e Steris System® (Steris Corporation) sterilizer also u s e s a mixture of peracetic acid and hydrogen peroxide, but the solution is supplied in s i n g l e - u s e canisters that are put into a completely e n c l o s e d s y s t e m . 2  4  3  2  2  Hydrogen peroxide acts a s an oxidizing agent, producing hydroxyl free radicals, which in turn d a m a g e the lipid m e m b r a n e , D N A , and other cell c o m p o n e n t s (Rutala  5  & W e b e r 1999). P e r a c e t i c acid is believed to act similarly to h y d r o g e n peroxide. Its action is most likely a function of its oxidizing capacity: it c a n denature proteins, alter sulfur and sulfhydryl b o n d s , and disrupt cell wall permeability (Rutala 1996). B e c a u s e of its highly corrosive nature, peracetic acid c a n a l s o d a m a g e m a n y metals, the extent of w h i c h d e p e n d s on the pH of the solution (Rutala & W e b e r 1999).  6  1 . 2 Strategies to E v a l u a t e the  Problem  T h e issue of substituting n e w high-level disinfection products for o n e already in u s e c a n be quite c o m p l e x . T h i s is particularly true in the current situation; first, the existing product is highly effective a n d h a s c o m e to be a c c e p t e d a s the industry "norm" despite its serious impact on e m p l o y e e health, a n d s e c o n d , the n e w products marketed a s safer alternatives contain c o m p o u n d s that h a v e not b e e n fully evaluated for their impact on e m p l o y e e health. A n attempt to evaluate this i s s u e h a s involved two major c o m p o n e n t s : (1) a c o m p a r i s o n of the potential health effects of e a c h product a n d (2) an a s s e s s m e n t of the current u s a g e patterns in industry.  1.2.1 Predicting Toxic Effects P e r h a p s the most a c c u r a t e method to evaluate the acute toxic effects of e x p o s u r e to any c o m p o u n d is to purposefully e x p o s e people to the c o m p o u n d under controlled laboratory conditions a n d m e a s u r e the resulting effects on their health. Of course, it would be unethical to intentionally e x p o s e human subjects to a s u b s t a n c e that m a y c a u s e s e v e r e or irreversible health effects. C h r o n i c effects w o u l d best be determined by randomly e x p o s i n g people to a s u b s t a n c e for m a n y y e a r s a n d conducting a study of their health o u t c o m e s . A g a i n , this is neither ethical nor practical. A more realistic option for examining h u m a n health effects is to a s s e s s e x p o s u r e a n d s y m p t o m s a m o n g people w h o are already e x p o s e d , s u c h a s in an occupational setting w h e r e the c o m p o u n d is being u s e d . Ideally, s o m e method of predicting health effects before e x p o s i n g workers to a potentially harmful s u b s t a n c e could be found. If o n e is to predict health effects in time to prevent t h e m , accurate models that d o not involve h u m a n s must be u s e d . T h e first step in a n y predictive toxicology a s s e s s m e n t is to review all existing information by thoroughly e x a m i n i n g the published, peer-reviewed literature. Unfortunately, there is generally little or no published information about n e w c h e m i c a l s . F o r products s u c h a s disinfectants, however, there is an extensive regulatory review p r o c e s s that must be undertaken prior to marketing of any n e w product. Part of this a s s e s s m e n t often includes a review of toxicological data submitted by the manufacturers to the applicable regulatory body. G a i n i n g a c c e s s to these toxicology s t u d i e s — w h e t h e r from the regulatory a g e n c i e s or directly from the m a n u f a c t u r e r s — c a n be a s o u r c e of valuable information, particularly w h e n there are limited data available from other s o u r c e s . Early prediction of health effects is often d o n e using animal toxicology r e s e a r c h . F o r certain health effects s u c h a s respiratory sensitization, animal r e s e a r c h m a y be less reliable or difficult to perform. T h e r e are several predictive tests for respiratory sensitization, including several g u i n e a pig sensitization tests, the m o u s e IgE test, and cytokine fingerprinting; however, they all have limitations a n d most only predict respiratory effects c a u s e d by a specific immune r e s p o n s e or formation of IgE antibodies ( P a u l u h n 1996; K i m b e r e t al. 1998). B e c a u s e a s t h m a a s s o c i a t e d with low  7  molecular weight c h e m i c a l s s u c h a s a l d e h y d e s is not a l w a y s a s s o c i a t e d with atopy or IgE antibodies, different m o d e l s may be n e e d e d to a s s e s s this type of hypersensitivity. B e c a u s e the g u i n e a pig c a n exhibit the kind of late-onset asthmatic reactions c o m m o n to low molecular weight c h e m i c a l a s t h m a , this m o d e l is most suited to predicting respiratory sensitization to s u c h c o m p o u n d s (Karol 1994). In vitro m o d e l s h a v e b e e n p r o p o s e d that would detect the ability of low molecular weight c o m p o u n d s to react with proteins, thus acting a s h a p t e n s and potentially c a u s i n g respiratory hypersensitivity ( W a s s & Belin 1990; S a r l o & Clark 1992), but these have not b e e n widely u s e d . Despite these issues, however, it is interesting to note that a set of c h e m i c a l s identified by positive results in a n i m a l respiratory sensitivity studies had all b e e n previously identified in clinical reports of h u m a n respiratory sensitivity ( G r a h a m et al. 1997). B e c a u s e of technical difficulties and the high cost of animal r e s e a r c h , other predictive methods, d e s c r i b e d below, are s o m e t i m e s u s e d to a s s e s s potential health impacts. O n e method of predicting toxic effects without using animal or h u m a n subjects in laboratory or field studies is the use of structure-activity relationship a n a l y s i s ( S A R ) . Quantitative S A R ( Q S A R ) u s e s statistical correlations and r e g r e s s i o n analysis to find mathematical relationships between specific structural e l e m e n t s or physicalchemical properties and a given biological activity. T h e biological properties of c h e m i c a l s with known biological activity are extrapolated to a n u n k n o w n c h e m i c a l with similar patterns of molecular structure or reactive capability. T h i s is b a s e d on the premise that m o l e c u l a r structure, reactivity, and toxicity are related (Jurs 1981). Q S A R requires the d e v e l o p m e n t of a d a t a b a s e of c h e m i c a l a n a l o g u e s — a group of c h e m i c a l s with similar structural elements to the "unknown" c o m p o u n d s and with known biological activities. Qualitative S A R is a related p r o c e s s but d o e s not involve the use of a large d a t a b a s e of a n a l o g u e s . C h e m i c a l s with u n k n o w n toxicity are simply c o m p a r e d to c h e m i c a l s that are known to exhibit the health effect in question; the more similar the unknown is to the group of c h e m i c a l s that are known to c a u s e a particular health effect, the more likely it is to exhibit that s a m e effect.  1.2.2 Assessing  Current Patterns of Use in the Healthcare Industry  In order to effectively e v a l u a t e a c h a n g e p r o c e s s in a n y industry, it is essential to know what is currently h a p p e n i n g within that industry with respect to the factors being c h a n g e d . F o r the c a s e of substitution of high-level disinfection c h e m i c a l s , one cannot evaluate the i s s u e without first knowing what c h e m i c a l s are actually being u s e d and what c h a n g e s are planned for the near future. If further study is to be d o n e t o ' e x a m i n e e x p o s u r e s and health s y m p t o m s a s s o c i a t e d with high-level disinfectants, it is helpful to know in a d v a n c e which products are being u s e d in w h i c h hospitals, a n d which products might be introduced in specific hospitals. T h e most systematic w a y to gather detailed information about current and planned practices surrounding high-level disinfection products is to conduct a survey of the u s e r s of t h e s e products.  8  1.3 Objectives T h e overall g o a l of this project w a s to predict a n d e v a l u a t e the relative occupational health impacts of two new high-level disinfection products with respect to the known health impacts of glutaraldehyde, and to explore s o m e of the i s s u e s related to the decision p r o c e s s . T h e following specific objectives w e r e d e s i g n e d to meet this goal. (1) C o m p a r e the methods for risk analysis u s e d by regulatory a g e n c i e s s u c h a s Health C a n a d a a n d the United S t a t e s F o o d a n d D r u g Administration w h e n reviewing new high-level disinfection products for approval. (2) Obtain and a s s e s s all available hazard information regarding new highlevel disinfection products and c h e m i c a l s from regulatory a g e n c i e s and product manufacturers. (3) C o n d u c t a thorough review of the epidemiological literature regarding the health effects a s s o c i a t e d with the high-level disinfection c h e m i c a l s glutaraldehyde, ortho-phthalaldehyde ( O P A ) , h y d r o g e n peroxide, and peracetic acid. (4) R e v i e w the available published in vitro, a n i m a l , a n d h u m a n toxicological data for all available high-level disinfection c o m p o u n d s : glutaraldehyde, O P A , hydrogen peroxide, and peracetic acid. (5) A s s e s s the u s e of structure-activity relationship a n a l y s i s ( S A R ) for prediction of respiratory sensitization and conduct a qualitative S A R analysis of existing high-level disinfection c h e m i c a l s . (6) C o n d u c t a n exploratory survey of all acute care hospitals in British C o l u m b i a to gather descriptive information about current a n d planned practices regarding the u s e of high-level disinfectants and information about how d e c i s i o n s related to the use of high-level disinfectants are m a d e . (7) D e v e l o p r e c o m m e n d a t i o n s regarding the introduction of glutaraldehyde alternatives to British C o l u m b i a hospitals.  9  CHAPTER 2 . Predicting Toxic Effects B e c a u s e limited information is available about the health effects a s s o c i a t e d with c h e m i c a l s u s e d to replace glutaraldehyde for high-level disinfection, the relative toxic effects of t h e s e c h e m i c a l s w a s predicted. This w a s carried out through a combination of s e v e r a l steps. First, government a g e n c i e s w e r e contacted to obtain any available toxicity d a t a that w a s submitted a s part of the regulatory review p r o c e s s for approving the n e w products. S e c o n d , the manufacturers of glutaraldehyde alternatives w e r e contacted a n d a s k e d for all toxicity data that they had compiled about their products. Third, a systematic review of the published literature for all high-level disinfection chemicals, including glutaraldehyde, w a s conducted. Finally, a qualitative structure-activity relationship a n a l y s i s w a s u s e d to predict the potential for respiratory sensitization for all high-level disinfection c h e m i c a l s . T h e information obtained from e a c h of t h e s e steps w a s then synthesized to predict the relative health effects from e x p o s u r e to e a c h of the c h e m i c a l s .  2.1 Regulatory Processes  2.1.1 Objectives: Regulatory Processes  Review  A review of the p r o c e s s e s u s e d to regulate high-level disinfection products in C a n a d a a n d the United States w a s conducted for two primary p u r p o s e s . (1) T h e requirements for premarket approval of n e w high-level disinfection products w e r e reviewed in order to c o m p a r e the risk a n a l y s i s m e t h o d s u s e d by the applicable regulatory a g e n c i e s w h e n making approval d e c i s i o n s . (2) A n attempt w a s m a d e to collect all of the health a n d safety related data submitted to regulatory a g e n c i e s a s part of the approval p r o c e s s . B y combining this data with that available in the published literature, the relative health impacts of currently marketed high-level disinfection products could b e a s s e s s e d and/or predicted.  2.7.2 Background: Canadian and American Regulatory  Processes  2.1.2.1 C a n a d a : T h e r a p e u t i c Products Directorate In C a n a d a , c h e m i c a l high-level disinfectants undergo premarket registration through the Therapeutic P r o d u c t s Directorate ( T P D ) within Health C a n a d a . T h i s a g e n c y regulates all pharmaceutical drugs, medical d e v i c e s a n d other therapeutic products sold in C a n a d a including medical disinfectants. Before a product c a n be approved by the T h e r a p e u t i c P r o d u c t s Directorate, it must be a s s i g n e d a Drug Identification N u m b e r (DIN). A l l disinfectants u s e d "for the sterilization and/or disinfection of medical d e v i c e s , including, but not limited to contact l e n s e s , hospital linens, a n d surgical, m e d i c a l or dental instruments, s u c h a s e n d o s c o p e s , catheters, aspirator  10  tubes a n d thermometers" are classified a s drugs by the Food and Drugs Act a n d thus require a DIN ( T P P 1999). A DIN S u b m i s s i o n includes a Drug S u b m i s s i o n Application, a DIN S u b m i s s i o n Certification, a S u b m i s s i o n F e e Application, p r o p o s e d labelling, a n d efficacy data (Health Protection B r a n c h [ H P B ] 1995). T h e Drug S u b m i s s i o n Application includes information s u c h a s manufacturer contacts, shelf life, medicinal a n d non-medicinal ingredients (name, standard, strength, a n d concentration), d o s a g e , p a c k a g i n g , route of administration, indications, a n d label information. T h e DIN S u b m i s s i o n Certification is a statement that all information submitted is accurate, G o o d Manufacturing P r a c t i c e s will be followed, stability data support the p r o p o s e d shelf life, a n d that the product d o e s not contain certain restricted ingredients. T o x i c o l o g y or health a n d safety data are not required in a n y part of this s u b m i s s i o n . If a drug h a s not b e e n previously marketed in C a n a d a or h a s not b e e n o n the market long e n o u g h to prove its safety, it is considered a "new drug." M a n u f a c t u r e r s of n e w drugs must be i s s u e d a Notice of C o m p l i a n c e in a c c o r d a n c e with Division 8, Part C of the Food and Drugs Act a n d Regulations (C.08.002.(2)(g)), a s well a s a DIN, before they c a n legally market the drug product (Food a n d Drug R e g u l a t i o n s 1985). T h e s u b m i s s i o n p r o c e s s for n e w drugs thus h a s the a d d e d requirement of safety and efficacy data. A l t h o u g h not required in the DIN s u b m i s s i o n , data o n acute a n d chronic toxicity, potential residues, a n d other safety i s s u e s must be available to Health C a n a d a upon request but do not need to be included in the application p a c k a g e ( T P P 1999). A n information letter from the A s s i s t a n t Deputy Minister included in A p p e n d i x V of the Therapeutic Products Programme Guidelines: Disinfectant Drugs ( T P P 1999) s u g g e s t s that the primary c o n c e r n related to highlevel disinfectants is efficacy of the product a n d resulting patient safety. N o mention is m a d e of e m p l o y e e health a n d safety issues. 2.1.2.2 C a n a d a : P e s t M a n a g e m e n t Regulatory A g e n c y T h e P e s t M a n a g e m e n t Regulatory A g e n c y ( P M R A ) is the branch of Health C a n a d a responsible for pest control products. Although C i d e x OPA® a n d C o m p l i a n c e ™ were never registered under the authority of the P e s t M a n a g e m e n t Regulatory A g e n c y , s o m e disinfectants currently under the authority of the T h e r a p e u t i c P r o d u c t s Directorate w e r e o n c e regulated by this agency. Disinfectants w e r e regulated under the Pest Control Products Act b e c a u s e microorganisms are included in the definition of pest. Disinfectants u s e d in healthcare facilities a n d o n m e d i c a l instruments have always b e e n subject to the Food and Drugs Act a n d h a v e required a DIN b e c a u s e they are u s e d to prevent d i s e a s e ( P M R A 1994). If disinfectants h a d "dual uses," i.e., were u s e d in d o m e s t i c , agricultural, institutional, or industrial environments a s well as in hospitals, they w e r e regulated by both acts. A n a m e n d m e n t to the Pest Control Products Act e n a c t e d in A u g u s t 2001 e x e m p t e d all disinfectants u s e d to prevent human or animal d i s e a s e s o that they c a m e under the sole regulatory authority of the Food and Drugs Act ( G o v e r n m e n t of C a n a d a 2001). High-level disinfectants have never b e e n regulated under the Pest Control Products Act, a s disinfectants  11  u s e d for m e d i c a l instruments w e r e e x e m p t from the Pest Control Products Act. Only hard-surface disinfectants fell into the dual u s e category ( G o v e r n m e n t of C a n a d a 2000a; personal c o m m u n i c a t i o n , C . C a m p b e l l , Evaluation Officer, P M R A , M a r c h 13, 2003). Despite this fact, the requirements for P e s t Control P r o d u c t n u m b e r s will be reviewed for c o m p a r i s o n with DIN requirements. T h e P e s t M a n a g e m e n t Regulatory A g e n c y h a s different health a n d toxicology requirements than the T h e r a p e u t i c Products Directorate. T h e r e is a specific Health Evaluation Division to provide expertise on human health h a z a r d s a n d risk a s s e s s m e n t . T h e r e is also a t e a m of scientists w h o conduct toxicology evaluations of pest control products. A n application for a P e s t Control P r o d u c t ( P C P ) n u m b e r requires a variety of supporting data, including toxicology studies o n the e n d - u s e product or the technical g r a d e of the active ingredient ( P M R A 1998). Toxicology test requirements for pest control products are outlined in the T r a d e M e m o r a n d u m T - 1 - 2 4 5 , Guidelines for Developing a Pesticide Toxicology Data Base, and include s p e c i a l reference to the protection of e m p l o y e e a n d bystander health (Agriculture C a n a d a 1984). Applicants for P e s t Control Product n u m b e r s are responsible for proving the safety of a n y n e w pesticide product. T h e following tests types are required for the P e s t Control Product application: • A c u t e toxicity studies, including 24-hour lethal d o s e , d e r m a l irritation, e y e irritation, a n d d e r m a l sensitization. N o o b s e r v e d effect levels ( N O E L ) should also be calculated w h e r e appropriate. • Short term toxicity studies, defined a s continuous or daily repeated administration for one-sixth of the animals' lifetime, including a 90-day oral study a n d at least o n e recovery study. Dermal and/or inhalation studies with the active ingredient a n d the product formulation are s u g g e s t e d to evaluate hazards to workers and bystanders, with the duration a n d d o s e determined by p h a r m a c o k i n e t i c studies. • L o n g term (chronic) studies, which should a s s e s s the tumourigenic potential and the m a x i m u m continuous or daily d o s e given o v e r the lifetime of the animal that p r o d u c e s no a d v e r s e effect. • Additional studies including pharmacokinetic studies o n several s p e c i e s , mutagenicity tests, studies of metabolites a n d environmental b r e a k d o w n products, teratogenicity studies, reproduction studies, a n d e x p o s u r e studies. It is s t r e s s e d that e x p o s u r e studies on h u m a n s should only be c o n d u c t e d  once there is a reasonable level of confidence that the applicator will not be placed at undue risk; it is s u g g e s t e d that t h e s e studies c o i n c i d e with efficacy field trials. W h e n c o m p a r e d with the requirements set by the T h e r a p e u t i c P r o d u c t s Directorate for DIN applications, t h e s e test requirements are m u c h more stringent.  12  2.1.2.3 U S : C e n t e r for D e v i c e s a n d Radiological Health In the United States, high-level disinfectants are regulated a s m e d i c a l d e v i c e s (general hospital a n d personal u s e ) by the C e n t e r for D e v i c e s a n d Radiological Health ( C D R H ) , a division of the F o o d a n d Drug Administration ( F D A ) . G e n e r a l purpose disinfectants are regulated by the Environmental Protection A g e n c y ( E P A ) ( C D R H 2 0 0 0 a ) . T h e United S t a t e s Code of Federal Regulations Part 8 8 0 , G e n e r a l Hospital a n d P e r s o n a l U s e D e v i c e s , 21 C F R S e c . 8 8 0 . 6 8 8 5 (2002), defines a liquid chemical sterilant/high-level disinfectant a s a "germicide that is intended for u s e a s the terminal step in p r o c e s s i n g critical a n d semicritical m e d i c a l d e v i c e s prior to patient u s e . Critical d e v i c e s m a k e contact with normally sterile tissue or body s p a c e s during u s e . Semicritical d e v i c e s m a k e contact during u s e with m u c o u s m e m b r a n e s or nonintact skin." T h e F o o d a n d Drug Administration u s e s three regulatory c l a s s e s for medical devices. C l a s s I d e v i c e s present the least potential for harm a n d are generally simple in d e s i g n . T h e y are subject to "general controls" s u c h a s registration of c o m p a n i e s involved in manufacturing, packaging, a n d distributing, listing of d e v i c e s with the F o o d a n d Drug Administration, G o o d Manufacturing Practices, c o m p l i a n c e with labelling regulations, a n d s u b m i s s i o n of a P r e m a r k e t Notification [510(k)j before marketing. C l a s s II d e v i c e s require greater control to e n s u r e safety a n d effectiveness. Additional "special controls" include additional labelling requirements, g u i d a n c e d o c u m e n t s , performance standards, a n d surveillance of products after introduction to the marketplace. C l a s s III d e v i c e s require the most stringent regulation, a n d must go through a more lengthy P r e m a r k e t A p p r o v a l p r o c e s s . T h e s e d e v i c e s are generally items that "support or sustain h u m a n life, are of substantial importance in preventing impairment of h u m a n health, or w h i c h p o s e a potential, u n r e a s o n a b l e risk of illness or injury." High-level disinfectants are included in C l a s s II with "special controls" ( C D R H 2000b). All C l a s s I a n d II d e v i c e s registered with the C e n t e r for D e v i c e s a n d Radiological Health require a P r e m a r k e t Notification, or 510(k). T h e manufacturer of a n e w device must s h o w that the n e w d e v i c e is "substantially equivalent" to a "predicate device" already on the market. A device is c o n s i d e r e d substantially equivalent if it has the s a m e intended u s e a n d h a s the s a m e technological characteristics a s the predicate device. If there are technological differences, information must be included in the 510(k) that d e m o n s t r a t e s that the n e w device is a s safe a n d effective a s the predicate d e v i c e a n d d o e s not raise additional questions of safety or efficacy. T h e predicate d e v i c e c a n be o n e that w a s legally marketed in the U S before M a y 28, 1976 or is already in C l a s s I or II. If there is no predicate d e v i c e meeting t h e s e criteria, a P r e m a r k e t A p p r o v a l application must be submitted instead of a 510(k) (Rice & L o w e r y 1995). A s part of the 510(k) s u b m i s s i o n , manufacturers are required to a s s e s s the potential health risks a s s o c i a t e d with e x p o s u r e to residues or from handling the product itself. Toxicity is a s s e s s e d by toxicity data provided by the ingredient manufacturers a n d  13  by published toxicity d a t a . If t h e s e data are not available, toxicity studies must be conducted o n the product itself (in its highest u s e concentration) or o n the individual product ingredients. T o a s s e s s health risks to the users a n d handlers of the product, the following toxicity tests are required: • skin irritation test • skin sensitization test • acute d e r m a l toxicity test • s u b c h r o n i c d e r m a l toxicity test • acute oral toxicity test • primary e y e irritation test • acute inhalation toxicity test • genotoxicity tests • chronic toxicity test • reproductive a n d d e v e l o p m e n t a l toxicity tests • possibly carcinogenicity tests ( C D R H 2 0 0 0 a ) . T h e results of the required toxicity tests must indicate that the n e w high-level disinfection d e v i c e is a s safe a s the predicate high-level disinfectant in order for substantial e q u i v a l e n c e to be demonstrated. 2.1.2.4 U S : Environmental Protection A g e n c y Prior to the 1996, liquid c h e m i c a l sterilants/high level disinfectants w e r e c o n s i d e r e d pesticides a n d regulated by the Environmental Protection A g e n c y ( E P A ) . O n A u g u s t 3, 1996, the Food Quality Protection Act a m e n d e d the Federal Insecticide, Fungicide, and Rodenticide Act, transferring responsibility for regulating high-level disinfectants to the C e n t e r for D e v i c e s a n d Radiological Health within the F o o d and Drug Administration ( E P A 1998). T h e approval p r o c e s s for o n e of the n e w glutaraldehyde alternatives, C i d e x OPA®, b e g a n under the old Environmental Protection A g e n c y s y s t e m . A n application for conditional registration of C i d e x O P A Antimicrobial containing 9 9 % O P A w a s submitted in 1993, a n d in M a y 1996, the application w a s a p p r o v e d for u s e in formulating disinfectants a n d sterilants ( E P A 1996). T h e E P A P e s t i c i d e Registration P r o g r a m evaluates applications b a s e d o n h u m a n and occupational health risks a n d environmental risks ( E P A 2002). Toxicity test requirements applicable to high-level disinfectants, a s stated in the Code of Federal Regulations Part 158, Data R e q u i r e m e n t s for Registration, 4 0 C F R S e c . 158.340 (1993), include the following types of tests: • acute toxicity tests: oral (rat), dermal, a n d inhalation (rat) • primary irritation tests: e y e (rabbit) a n d dermal • dermal sensitization test • s u b c h r o n i c toxicity tests: 21-day dermal, 90-day inhalation (rat), possibly 9 0 day neurotoxicity (mammal) • chronic toxicity tests: chronic feeding (rodent a n d non-rodent), oncogenicity (2 s p e c i e s , rat a n d m o u s e preferred), teratogenicity (2 s p e c i e s ) 14  • •  mutagenicity tests: g e n e mutation, structural c h r o m o s o m a l aberration, other genotoxic effects special tests: general metabolism, dermal penetration.  A c o m p a r i s o n of the Environmental Protection A g e n c y test requirements with the C e n t e r for D e v i c e s a n d Radiological Health test requirements indicates that the approval p r o c e s s at both a g e n c i e s is similar with respect to the health a n d safety of end users.  2.1.3 Methods: Obtaining Regulatory Testing Information A n attempt w a s m a d e to obtain all toxicology data submitted to the applicable regulatory a g e n c i e s by the manufacturers of C i d e x OPA® a n d C o m p l i a n c e ™ . C a n a d i a n regulatory information w a s requested from Health C a n a d a using the Access to Information Act. U S regulatory data w a s r e q u e s t e d from both the F o o d and Drug Administration a n d the Environmental Protection A g e n c y through the  Freedom of Information Act. 2.1.3.1 Access to Information in C a n a d a C a n a d i a n g o v e r n m e n t records that a r e not readily available c a n be obtained through the Access to Information Act (1985). A written request mentioning the Act must be submitted to the federal g o v e r n m e n t institution believed to be holding the information. R e q u e s t s c a n be m a d e by writing a letter or by using a n on-line form available through the g o v e r n m e n t of C a n a d a website ( G o v e r n m e n t of C a n a d a 2000b). T h e request must include the n a m e a n d a d d r e s s of the individual making the request, the n a m e of the applicable institution, the details of the information being sought, a n d a statement that the information is being requested under the Access to Information Act. A $5.00 processing fee, p a y a b l e to the R e c e i v e r G e n e r a l of C a n a d a , is a l s o required at the time of request. After a request h a s b e e n p r o c e s s e d , complaints m a y be registered with the A c c e s s to Information C o m m i s s i o n e r if o n e believes that rights to information h a v e b e e n d e n i e d . R e p l i e s to A c c e s s to Information requests must be m a d e within 3 0 d a y s (Treasury B o a r d of C a n a d a Secretariat 1993). 2.1.3.1.1 Access to Information R e q u e s t s to Health C a n a d a for C i d e x OPA® a n d Compliance™ A s e a r c h of the Drug P r o d u c t D a t a b a s e o n the T h e r a p e u t i c P r o d u c t s Directorate website (http://www.hc-sc.gc.ca/hpb-dgps/therapeut/htmleng/dpd.html) found the DIN 0 2 2 4 0 4 6 8 for C o m p l i a n c e ™ a n d the DIN 0 2 2 3 9 7 3 2 for C i d e x OPA® A n initial request w a s submitted to the A c c e s s to Information (ATI) C o o r d i n a t o r at Health C a n a d a o n D e c e m b e r 26, 2001 (Appendix I). T h e letter requested the DIN application, N e w Drug S u b m i s s i o n application, full ingredient listing, a n d all toxicological information for both C i d e x OPA® and C o m p l i a n c e ™ . A r e s p o n s e dated  15  J a n u a r y 9, 2 0 0 2 stated that the request had b e e n received a n d provided a file number for future c o r r e s p o n d e n c e (Appendix I). A s e c o n d letter dated February 1, 2002, indicated that that third party notification w a s n e c e s s a r y before a n y information could be r e l e a s e d (Appendix I). A c c o r d i n g to section 2 7 of the Access to Information Act (1985), the third party—in this c a s e the product m a n u f a c t u r e r s — must be notified before r e l e a s e of information if the institution handling the request, i.e., Health C a n a d a , believes that a n y information related to trade secrets might be involved. A set of records dated M a r c h 13, 2 0 0 2 w a s provided by Health C a n a d a in r e s p o n s e to the initial request. T h e d o c u m e n t s included the Drug S u b m i s s i o n Application, a n evaluation of the DIN application, a n d a Drug Notification F o r m , w h i c h indicates that the product h a s b e e n given a DIN. T h e list of ingredients w a s included, but the concentrations of the ingredients, with the exception of the active ingredient O P A , were deleted. N o toxicological data w a s provided. T h e d o c u m e n t a t i o n relating to C o m p l i a n c e ™ included the Drug S u b m i s s i o n Application, the Drug Notification Form, the DIN Application, a n d s o m e c h a n g e of product n a m e d o c u m e n t s . T h e list of non-active ingredients w a s completely deleted, a n d no toxicological data w a s provided. O n M a y 2, 2 0 0 2 , a s e c o n d request for data related to both high-level disinfection products w a s submitted to Health C a n a d a ' s A c c e s s to Information a n d Privacy Centre (Appendix I). T h i s a p p e a l again requested ingredients a n d toxicology data, and also included a statement indicating w h y the data w a s being requested, that the university h a d no c o m m e r c i a l interest in the information, a n d that the information would be u s e d in the public interest for protection of e m p l o y e e health. T h e r e w a s no r e s p o n s e to the a p p e a l , a n d a reminder letter w a s mailed S e p t e m b e r 18, 2 0 0 2 (Appendix I). A r e s p o n s e w a s received via email a n d fax o n S e p t e m b e r 2 5 , 2002, indicating that a c h a n g e in staffing had resulted in the a p p e a l letter being filed without action (Appendix I). In this letter, I w a s informed that s o m e of the third party information, including the ingredient list for C o m p l i a n c e ™ , w a s c o n s i d e r e d confidential proprietary information (trade secrets) a n d c o u l d be withheld by the third party a c c o r d i n g to S e c t i o n 20(1) of the Access to Information Act (1985). I w a s also informed that most toxicological information w a s e x e m p t from d i s c l o s u r e under Section 20, but s u g g e s t e d that a n e w request be m a d e to e n s u r e that all available records w e r e obtained, including reviewers' c o m m e n t s on a n y submitted toxicology data. T h i s n e w request w a s m a d e in writing S e p t e m b e r 25, a n d w a s a c k n o w l e d g e d on S e p t e m b e r 27, 2 0 0 2 (Appendix I). I w a s notified by Health C a n a d a that no additional records related to toxicology were available. I w a s a l s o informed that s o m e toxicological information a n d reviewers' c o m m e n t s related to C i d e x OPA® had been "severed" by the third party according to Section 2 0 of the Access to Information Act (1985). N o toxicology data w a s submitted for C o m p l i a n c e ™ b e c a u s e the DIN application w a s for a n a m e c h a n g e from E n d o S p o r ™ P l u s to C o m p l i a n c e ™ . It w a s s u g g e s t e d that a n e w request for information included in the original DIN s u b m i s s i o n for E n d o S p o r ™ P l u s could be  16  submitted. T h e third party for C i d e x O P A could be re-notified, but this w a s not likely to result in a n y additional information being r e l e a s e d (personal c o m m u n i c a t i o n , L. Choquette, A s s i s t a n t Coordinator, Health C a n a d a , ATI Division, O c t o b e r 17, 2002). T h i s information w a s provided in writing o n N o v e m b e r 2 2 (Appendix I). A complaint w a s registered with the Information C o m m i s s i o n e r of C a n a d a o n N o v e m b e r 18, 2 0 0 2 (Appendix II) in r e s p o n s e to the s e v e r i n g of toxicological data related to C i d e x OPA®. B e c a u s e of the nature of this r e s e a r c h project a n d its potential to prevent harm to healthcare workers using the product, it w a s felt that releasing this information would be in the public interest a n d therefore should be exempt from third party deletion under section 20 of the Access to Information Act. T h e complaint h a s b e e n a c k n o w l e d g e d , but no r e s p o n s e h a s b e e n received a s of April 2 0 0 3 . A new Access to Information request for information from the original DIN s u b m i s s i o n for E n d o S p o r ™ P l u s w a s initiated on N o v e m b e r 18, 2 0 0 2 . T h e request w a s a c k n o w l e d g e d N o v e m b e r 29, a n d o n D e c e m b e r 2 3 , a statement that a 30-day extension would be required to gather the data w a s i s s u e d (Appendix I). Limited documentation related to efficacy, instructions for use, a n d a brief statement that the product is corrosive w a s r e l e a s e d J a n u a r y 2 1 , 2 0 0 3 . A further e x t e n s i o n of the time limit w a s required to c o m p l e t e third party notification before additional records could be released (Appendix I). T h e final d o c u m e n t s w e r e sent J a n u a r y 2 9 , 2 0 0 3 . T h e s e included the Drug S u b m i s s i o n Application, again with the ingredient listing deleted, and a series of laboratory reports of toxicology studies. 2.1.3.2 Freedom of Information in the United States United States g o v e r n m e n t records not available through the F e d e r a l Register, policy statements, m a n u a l s , or other s u c h s o u r c e s prepared for public distribution c a n be requested using the Freedom of Information Act. Certain types of records, including information related to trade secrets, are exempt from d i s c l o s u r e through the Freedom of Information Act (Code of Federal Regulations Part 2 0 , Public Information, 2 0 C F R S e c . 20.61, 2002). T h e U S Code of Federal Regulations states that safety a n d effectiveness data for C l a s s II medical d e v i c e s , i.e. high-level disinfectants, will be available 30 d a y s after classification unless the third party c o n s i d e r e d the data to be trade secrets or confidential c o m m e r c i a l information a s described in the Code Part 8 6 0 , M e d i c a l D e v i c e Classification P r o c e d u r e s , 21 C F R S e c . 860.5 (2002). Like Access to Information requests in C a n a d a , d e n i e d Freedom of Information Act requests c a n be a p p e a l e d . R e q u e s t s for information through the Freedom of Information Act must be in writing by mail or fax, a n d must include the following information: the n a m e , a d d r e s s a n d phone n u m b e r of the person m a k i n g the request; a detailed description of the specific d o c u m e n t s being requested; a n d a statement of willingness to pay a n y applicable fees. S e p a r a t e requests must be m a d e for documentation related to different products or c o m p a n i e s ( F D A 1997).  17  2.1.3.2.1 Freedom of Information Act R e q u e s t s to the F o o d a n d Drug Administration for C i d e x OPA® A s e a r c h of the F o o d a n d Drug Administration on-line 510(k) d a t a b a s e (http://\AAftA-v.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm) found three different 510(k) n u m b e r s for C i d e x OPA®. K 9 9 1 4 8 7 w a s the original s u b m i s s i o n dated O c t o b e r 3, 1999. T w o "special" 510(k) s u b m i s s i o n s for d e v i c e modifications, K001381 a n d K 0 0 2 4 0 1 , w e r e both dated in 2000. A request w a s m a d e by fax o n D e c e m b e r 2 1 , 2001 for all toxicological data included in the three s u b m i s s i o n s (Appendix III). A n a c k n o w l e d g e m e n t w a s m a d e o n D e c e m b e r 27. D o c u m e n t s from K 9 9 1 4 8 7 w e r e provided o n C D - R O M on February 4, 2 0 0 2 . A n extremely large set of files w a s provided (436 pages); unfortunately, no table of contents w a s provided a n d the d o c u m e n t s w e r e extremely difficult to s e a r c h . A large quantity of data related to labelling, efficacy, materials compatibility, a n d residues, but no ingredient listings and minimal toxicity information, were included o n the C D . L a r g e sections, often several hundred p a g e s , w e r e noted a s having b e e n redacted by the third party. T h e r e were references m a d e to a more than 6 0 0 - p a g e a p p e n d i x titled "Appendix 18: Toxicity Testing;" however, only the title p a g e w a s provided. T w o brief s u m m a r y tables of toxicity t e s t i n g — o n e that c o m p a r e d a >99% O P A solution to a 50% glutaraldehyde solution a n d another that c o m p a r e d C i d e x OPA® (0.55% O P A ) to Cidex® Activated D i a l d e h y d e Solution (2.4% g l u t a r a l d e h y d e ) — w e r e included (Appendix IV). A n appeal for the ingredient listing a n d toxicity testing for C i d e x OPA® w a s initiated on M a y 2 a n d a c k n o w l e d g e d on M a y 14, 2 0 0 2 (Appendix III). A s of April 2 0 0 3 , no official r e s p o n s e h a s b e e n received. I w a s informed that the ingredient listing is a confidential trade secret a n d would not be released without signing a confidentiality agreement. It m a y be p o s s i b l e to obtain toxicity testing, but it would be a considerable period of time before anything additional w a s available (personal c o m m u n i c a t i o n , S . M c G e e h a n , L e a d P a r a l e g a l , C D R H , J u n e 11, 2002). I w a s later informed that the request had b e e n sent to the third party for r e - a s s e s s m e n t (personal c o m m u n i c a t i o n , S. M c G e e h a n , D e c e m b e r 16, 2 0 0 2 ) . A t the time of writing, no further official c o r r e s p o n d e n c e h a s been received. T h e device modification records K 0 0 1 3 8 1 a n d K 0 0 2 4 0 1 w e r e provided o n J a n u a r y 23, 2 0 0 3 . T h e s e s u b m i s s i o n s were for modifications of the p a c k a g e label, indications, a n d instructions for u s e only, a n d therefore no toxicity d a t a w a s required. K 0 0 1 3 8 1 w a s for the removal of a contraindication against the u s e of the product with o n e particular brand of e n d o s c o p e . K 0 0 2 4 0 1 w a s a c h a n g e of the stated o p e n bottle shelf life from 30 to 7 5 d a y s . Neither c h a n g e involved altering the formulation of the product in a n y way.  18  2.1.3.2.2 Freedom of Information Act R e q u e s t s to the F o o d a n d Drug Administration for C o m p l i a n c e ™ A s e a r c h of the F o o d a n d Drug Administration on-line 510(k) d a t a b a s e (http://wvvw.accessdata.fda.gov/scripts/cdrh/cfdocs/cfPMN/pmn.cfm) identified K 9 7 2 7 0 8 a s the 510(k) n u m b e r for C o m p l i a n c e ™ . A request w a s m a d e by fax o n D e c e m b e r 2 1 , 2001 for all toxicological data included in the three s u b m i s s i o n s (Appendix V ) . A n a c k n o w l e d g e m e n t w a s m a d e on D e c e m b e r 2 7 . A large set of d o c u m e n t s (746 p a g e s ) w a s provided o n C D - R O M o n J a n u a r y 2 9 , 2 0 0 2 . A s with the C i d e x OPA® records, no table of contents w a s provided a n d the d o c u m e n t s w e r e extremely difficult to s e a r c h . A large quantity of data related to labelling, efficacy, materials compatibility, a n d residues, but no ingredient listings, w e r e included on the C D . Large sections, often several hundred pages, w e r e noted a s having b e e n redacted by the third party. Brief s u m m a r i e s of toxicity tests w e r e provided (Appendix VI); reference to a set of a p p e n d i c e s (referred to a s A t t a c h m e n t s 24 through 29) related to t h e s e tests w a s made, but they h a d b e e n redacted. A n appeal for the deleted toxicity information w a s submitted M a y 2 a n d a c k n o w l e d g e d o n M a y 14, 2 0 0 2 (Appendix V ) . A s of April 2 0 0 3 , no official r e s p o n s e has been received. I w a s informed that all ingredients or toxicity d a t a are c o n s i d e r e d confidential a c c o r d i n g to the Code of Federal Regulations (21 C F R S e c . 860.5, 2002) a n d c a n therefore be legally withheld by the third party (personal communication, S. Steinberg, P a r a l e g a l , C D R H , S e p t e m b e r 9, 2002). 2.1.3.2.3 Freedom of Information Act R e q u e s t s to the Environmental Protection A g e n c y for C i d e x OPA® A 9 9 % solution of C i d e x O P A Antimicrobial w a s registered with the Environmental Protection A g e n c y in 1996 a s a pesticide product under E P A registration n u m b e r 7078-17. T h e F e d e r a l R e g i s t e r notice of the registration ( E P A 1996) m a k e s reference to a n E P A P e s t i c i d e Fact S h e e t o n the active ingredient 1,2b e n z e n e d i c a r b o x a l d e h y d e , which m a y be obtained through the National T e c h n i c a l Information S e r v i c e . T w o requests were m a d e for this F a c t S h e e t in fall 2 0 0 2 . Both requests received the reply that the information supplied w a s not sufficient for the request to be filled, despite the fact the s e c o n d request included a c o p y of the Federal R e g i s t e r d o c u m e n t that referred to the Fact Sheet, with the applicable statements highlighted (Appendix VII). In order to receive studies or data related to pesticides through the Freedom of Information Act, the requester is required to sign a n "Affirmation of Non-multinational Status F o r m " ( E P A 2 0 0 3 A ) (Appendix VIII). T h i s requirement is in a c c o r d a n c e with Section 10(g) of the Federal Insecticide, Fungicide, and Rodenticide Act, which refers to the protection of trade secrets. B y signing the Affirmation form, the requester states that he or s h e is not involved in the pesticide b u s i n e s s outside of the U S , d o e s not intend to sell a n y information to a n y pesticide b u s i n e s s outside the U S , a n d will not purposefully or negligently allow a n y information to be transferred to  19  any s u c h b u s i n e s s . T h i s is to e n s u r e that entities outside the U S will not be able to use health a n d safety d a t a that w a s submitted for pesticide registration in the U S to obtain pesticide registration in other countries. T h e Affirmation is not intended to prevent publication of excerpts or s u m m a r i e s of data, but if a n y d i s c l o s u r e of data b e c o m e s available to a multinational corporation, the requester could be s u e d by the firm that originally submitted the data to the Environmental Protection A g e n c y . It is r e c o m m e n d e d that legal a d v i c e be retained before publishing anything related to data obtained in this m a n n e r ( E P A 2003a). B e c a u s e of the risk of legal action, a Freedom of Information Act request w a s m a d e for Environmental Protection A g e n c y reviews of toxicity data for C i d e x O P A Antimicrobial a n d a n y other toxicity data available without signing the Affirmation. T h e initial request w a s m a d e N o v e m b e r 27 and a c k n o w l e d g e d N o v e m b e r 29 a n d D e c e m b e r 11, 2 0 0 2 . A n additional letter from the Environmental Protection A g e n c y dated D e c e m b e r 2 3 , 2 0 0 2 stating that more time w a s n e e d e d to locate the d o c u m e n t s a n d review t h e m for confidential information (Appendix IX). A t the time of writing, no further r e s p o n s e h a s b e e n received. 2.1.3.3 Regulatory Information from Manufacturers Prior to initiating Freedom of Information Act a n d Access to Information requests for toxicology data, the manufacturers of C i d e x OPA® a n d C o m p l i a n c e ™ w e r e a s k e d for a n y health a n d safety data they had related to their products. T h i s b e g a n in the s u m m e r of 2 0 0 1 , a n d w h e n both manufacturers s h o w e d reluctance to release a n y data, the regulatory a p p r o a c h w a s initiated. W h e n the regulatory a p p r o a c h failed to produce a n y toxicology data, a s d e s c r i b e d above, further requests w e r e m a d e to the product manufacturers. 2.1.3.3.1 A d v a n c e d Sterilization Products Data C i d e x OPA® is manufactured by A d v a n c e d Sterilization P r o d u c t s ( A S P ) , a division of J o h n s o n & J o h n s o n M e d i c a l Products. A d v a n c e d Sterilization P r o d u c t s claims that C i d e x OPA® is s a f e r than glutaraldehyde-based high-level disinfection products b e c a u s e the active ingredient is u s e d in s u c h a low concentration that inhalation e x p o s u r e is negligible. A f a x received o n J u n e 18, 2001 from David Fraser, Director of Marketing a n d S a l e s for A d v a n c e d Sterilization Products, stated that no O P A vapour could be detected from a g a s c h r o m a t o g r a p h y / m a s s spectrometry ( G C / M S ) head s p a c e a n a l y s i s or from m e a s u r e m e n t s using N I O S H M e t h o d 5 0 0 (Particulates Not Otherwise R e g u l a t e d ) (Appendix X ) . T h e data to support this claim w e r e not provided, a n d it is not clear w h y a particulate a n a l y s i s method w a s u s e d for detecting vapour. A teleconference w a s held O c t o b e r 24, 2001 with representatives from the British C o l u m b i a W o r k e r s ' C o m p e n s a t i o n Board, A d v a n c e d Sterilization P r o d u c t s / J o h n s o n & J o h n s o n , a n d the U B C S c h o o l of O c c u p a t i o n a l a n d E n v i r o n m e n t a l H y g i e n e . S e v e r a l d o c u m e n t s w e r e provided prior to the teleconference: details of the head s p a c e analysis, a s u m m a r y table comparing toxicology results from C i d e x OPA® with  20  regular C i d e x (glutaraldehyde), a n d s u m m a r i e s of the studies included in the table. T h e s e s u m m a r i e s w e r e later found to be part of the a p p e n d i x deleted from the 510(k) s u b m i s s i o n obtained from the F o o d a n d Drug Administration through the Freedom of Information Act. A single value for the v a p o u r p r e s s u r e of C i d e x OPA® w a s also provided during the teleconference. At that time, A d v a n c e d Sterilization Products representatives a g r e e d to provide additional data related to skin a n d respiratory sensitization tests from the O P A raw material, a n d details of rat inhalation tests. O n M a y 9, 2 0 0 2 , additional d o c u m e n t s were provided from A d v a n c e d Sterilization Products. T h e y included s o m e details of vapour p r e s s u r e determination, a brief report of O P A a n d glutaraldehyde monitoring in s e a l e d containers a n d c l o s e d - r o o m environments, a report of a n O P A monitoring study using infrared spectra that w a s conducted in a hospital in the United K i n g d o m , r e s p o n s e s to s o m e of the questions raised at the O c t o b e r teleconference, a n d a laboratory report of a rat o c u l a r a n d upper respiratory irritation study. Following d e n i a l s for toxicology data from both Health C a n a d a a n d the F o o d a n d Drug Administration, a letter w a s mailed to the Director of Marketing a n d S a l e s at A d v a n c e d Sterilization P r o d u c t s o n S e p t e m b e r 17, 2 0 0 2 to request the toxicology information from the 510(k) s u b m i s s i o n a n d DIN application (Appendix XI). I w a s informed that all toxicology test laboratory reports could be r e l e a s e d if a confidentiality a g r e e m e n t w e r e s i g n e d . T h e confidentiality a g r e e m e n t would be required b e c a u s e the test details contain "a lot of proprietary information." S u c h an agreement could require that a n y scientific p a p e r s planned w o u l d have to be reviewed by J o h n s o n & J o h n s o n before publication. T h i s type of restriction is against U B C policy for r e s e a r c h carried out by graduate students a n d no a g r e e m e n t w a s signed; thus, the detailed information w a s not provided. T h e toxicity s u m m a r i e s already provided for the O c t o b e r 2001 teleconference w e r e sent a g a i n . I w a s also informed that only t h e toxicity s u m m a r i e s w e r e provided to Health C a n a d a a s part of the DIN application. T h e DIN application f o c u s s e d more o n efficacy than o n toxicity; the test details w o u l d have had to be m a d e available only if requested by Health C a n a d a . Health C a n a d a , however, c h a l l e n g e d the product primarily o n equipment compatibility (personal c o m m u n i c a t i o n , D. Fraser, Director of Marketing a n d S a l e s , A S P , O c t o b e r 24, 2002). 2.1.3.3.2 Metrex Data Contact with Metrex, the manufacturer of C o m p l i a n c e ™ , b e g a n with a meeting with the W e s t e r n C a n a d a S a l e s Representative on J u n e 18, 2 0 0 1 . I w a s provided with a brief s u m m a r y of toxicity studies that consisted of the n a m e of the study a n d the stated c o n c l u s i o n (Appendix XII). I w a s unable to obtain additional information from Metrex T e c h n i c a l S e r v i c e s (personal communication, E. T s e u , Metrex T e c h n i c a l Services, July 3, 2001).  21  No further contact w a s m a d e with Metrex until the Freedom of Information Act a n d Access to Information Act requests failed to provide a n y useful toxicological data. A letter w a s mailed to the Director of C o r p o r a t e C o m p l i a n c e of S y b r o n Dental Specialties (the parent c o m p a n y of Metrex) on S e p t e m b e r 18, 2 0 0 2 , a n d to the V i c e President of M e t r e x o n O c t o b e r 22, 2 0 0 2 (Appendix XIII). A r e s p o n s e from S y b r o n Dental S p e c i a l t i e s w a s sent o n N o v e m b e r 14, 2002, w h i c h included the brief toxicity s u m m a r i e s obtained the previous y e a r (Appendix XIII). T h e c o m p a n y later a g r e e d to provide more detailed toxicology s u m m a r i e s , w h i c h w e r e mailed o n D e c e m b e r 13, 2 0 0 2 (personal c o m m u n i c a t i o n , C . B o s w e l l , Director of C o r p o r a t e C o m p l i a n c e , Metrex R e s e a r c h Inc., N o v e m b e r 26, 2002). T h e d o c u m e n t s provided w e r e labelled a s A t t a c h m e n t s 24 through 2 9 , a s referenced in the 510(k) s u b m i s s i o n .  2.1.4 Results: Regulatory Toxicology Data Obtained 2.1.4.1 C i d e x OPA® Data 2.1.4.1.1 Data from Regulatory A g e n c i e s No toxicological information about C i d e x OPA® w a s obtained from Access to Information requests to Health C a n a d a . Only the brief toxicity c o m p a r i s o n tables included in A p p e n d i x IV w e r e received from Freedom of Information Act requests to the United S t a t e s F o o d a n d Drug Administration. N o information h a s yet b e e n received from E n v i r o n m e n t a l Protection A g e n c y . Both Health C a n a d a a n d F o o d a n d Drug Administration r e l e a s e d s o m e information about the identity of the non-active ingredients in t h e product. Health C a n a d a released the n a m e s of the ingredients, while the F o o d a n d Drug Administration r e l e a s e d the function of the ingredients. T h e ingredients, m a t c h e d to their functions, are listed in T a b l e 2.1. T A B L E 2.1. N o n - a c t i v e i n g r e d i e n t s in C i d e x O P A  Ingredient  Function  potassium phosphate salts benzotriazole D & C G r e e n #5 citric a c i d V e r s e n a l *120  p h o s p h a t e buffer c o r r o s i o n inhibitor green dye  ?  1  chelating agent  2  T h e function of citric a c i d is not k n o w n . V e r s e n a l *120 is a s s u m e d to b e a trade n a m e for the c h e l a t i n g a g e n t H E D T A ( N - ( 2 - H y d r o x y e t h y l ) e t h y l e n e d i a m i n e - N , N ' , N'-triacetic a c i d ) T r i s o d i u m salt, a l s o k n o w n a s Versen-01® 1  2  A c c o r d i n g to the Drug Notification F o r m , C i d e x O P A w a s given regulatory approval in C a n a d a in J u n e 1999. T h e market launch w a s in July of the s a m e y e a r (personal c o m m u n i c a t i o n , H. P a c e , Director of Marketing a n d S a l e s , A S P , M a r c h 10, 2003). C i d e x OPA® w a s c o n c l u d e d to be substantially equivalent to C i d e x Activated D i a l d e h y d e Solution® by the United States F o o d a n d Drug Administration in O c t o b e r  22  1999 and marketed shortly thereafter (personal c o m m u n i c a t i o n , H. P a c e , M a r c h 10, 2003). 2.1.4.1.2 Data from Manufacturer Toxicity test s u m m a r i e s provided by A d v a n c e d Sterilization Products, the manufacturer of C i d e x OPA®, included tests for skin irritation, skin sensitization, cytotoxicity, acute d e r m a l toxicity, haemocompatibility/haemolysis, s y s t e m i c toxicity, subchronic oral toxicity, acute oral toxicity, acute single d o s e toxicity, primary ocular irritation, and acute irritation tests. T h e available details of t h e s e tests are d e s c r i b e d below. T h e results of several of the tests place the product into o n e of E P A Pesticide Toxicity C a t e g o r i e s I to IV, with C a t e g o r y I being the most toxic ( E P A 2003b). T h e primary d e r m a l irritation study in rabbits w a s c o n d u c t e d to test skin irritation. Six rabbits were e x p o s e d to 0.5 ml of 0.56% C i d e x OPA® solution on s h a v e d skin for 4 hours. T h e reported results stated that no dermal irritation, no d e c r e a s e in body weight, and no clinical signs of toxicity were o b s e r v e d . T h e solution w a s given the Primary Dermal Irritation Index 0 (no irritation) and Toxicity C a t e g o r y IV (mild or slight irritation at 72 hours). Individual animal results w e r e not provided. Skin sensitization w a s m e a s u r e d using the e p i c u t a n e o u s skin sensitization test in guinea pigs, using full strength C i d e x OPA® (0.56%) to test skin sensitization. T h e test involved an induction p h a s e and challenge using ten test a n i m a l s . A positive control group w a s administered dinitrochlorobenzene ( D N C B ) instead of C i d e x OPA® solution during induction and challenge. N o irritation, toxicity, or body weight c h a n g e s w e r e o b s e r v e d during screening. N o dermal reactions w e r e reported with C i d e x OPA® challenge, but positive reactions w e r e reported in the positive control group. Individual animal results w e r e not provided. B a s e d on the results of this test, the product w a s classified as a non-sensitizer. Cytotoxicity of 0.613, 0.3, 0.15, and 0.08% C i d e x OPA® solutions w e r e tested using the U S P ( U S P h a r m a c o p e i a ) A g a r Diffusion M e t h o d (Liquid). Positive, negative, and filter disc controls w e r e also c o n d u c t e d . M o u s e fibroblast cells w e r e incubated with the solutions for 2 4 to 26 hours at 37 °C and e x a m i n e d at 100-fold magnification for decolourized z o n e s and cell morphology. C i d e x OPA® solutions at 0.08 to 0.3% resulted in cell lysis or toxicity of mild reactivity, which met the requirements of the U S P . T h e 0.613% solution resulted in cell lysis or toxicity of m o d e r a t e reactivity, which did not meet the U S P standard for safety. A c u t e dermal toxicity w a s evaluated by an acute d e r m a l toxicity study in N e w Z e a l a n d white rabbits using O P A powder and an acute single d o s e dermal toxicity study in rabbits using 0.56% C i d e x OPA® solution. T h e acute d e r m a l toxicity test involved a single application of 2 0 0 0 mg O P A per kilogram body weight to 10 animals. A n i m a l s w e r e o b s e r v e d for 15 d a y s and then sacrificed. N o mortality occurred. O b s e r v e d s y m p t o m s included soft stool or diarrhea in three animals, severe d e r m a l irritation at the test site, and 1 to 2% d e c r e a s e in body weight on  23  day 4, followed by s t e a d y weight gain by d a y 8. White a r e a s w e r e found o n the postmortem kidney of o n e test animal. T h e median lethal d o s e ( L D ) w a s set a s greater than 2000 mg/kg for rabbits. T h e c o m p o u n d w a s a s s i g n e d Toxicity C a t e g o r y III (systemic d e r m a l toxicity). B e c a u s e of the severe dermal irritation, the c o m p o u n d w a s c o n s i d e r e d corrosive and a s s i g n e d Toxicity C a t e g o r y I for primary d e r m a l effects. T h e acute single d o s e toxicity test involved a single 24-hour d e r m a l application of 2g/kg to 10% of the body surface o f t e n animals. N o deaths, d e c r e a s e s in body weight, or other clinical signs of toxicity w e r e o b s e r v e d after 14 d a y s . N o irritation w a s o b s e r v e d at the end of 24 hours. T h e L D w a s set at greater than 2 g/kg a n d the product w a s a s s i g n e d to Toxicity C a t e g o r y III. 5 0  5 0  H e m o l y s i s w a s studied using the In Vitro P r o c e d u r e (Extraction Method). C i d e x OPA® solutions at 0.613, 0.04, and 0.02% concentration, a positive control, and a negative control w e r e tested for red blood cell h e m o l y s i s using pooled blood from three rabbits. T h e 0.02% solution w a s not hemolytic (hemolytic index 1%), the 0.04% solution w a s moderately hemolytic (16%), and the 0 . 6 1 3 % C i d e x OPA® solution w a s s e v e r e l y hemolytic (93%). T h e s y s t e m i c toxicity study in mice involved a single injection of 50 ml 0.005% C i d e x OPA® solution (the highest concentration that did not product immediate toxic effects) to five mice, with five control animals. N o a n i m a l s s h o w e d reactions that differed from the control mice, and the 0.005% dilution of C i d e x OPA® w a s c o n c l u d e d to be non-toxic. T h e subchronic oral toxicity study in rats involved administration of C i d e x OPA® Solution (no concentration stated, a s s u m e d to be 0.56%) by oral g a v a g e for 90 days. Twenty a n i m a l s w e r e given 0.5 mg/kg/day, twenty w e r e given 5.0 mg/kg/day, a n d thirty w e r e given 50.0 mg/kg/day ( d e c r e a s e d to 25.0 mg/kg/day on day 11 d u e to high n u m b e r of deaths) in a d o s e of 10 ml/kg. A control group of thirty rats w e r e given distilled water. Eighteen high d o s e a n i m a l s died before study completion for a variety of r e a s o n s , numerous clinical s y m p t o m s w e r e o b s e r v e d , and d e c r e a s e d t h y m u s weights a s well as histological a n d other findings were reported after sacrifice. Middle d o s e animals s h o w e d d e p r e s s e d body weights and other a s s o c i a t e d s y m p t o m s . Interstitial inflammation of the lungs w a s o b s e r v e d in all test animals, but w a s attributed to the dosing technique. T h e lowest o b s e r v e d effect level ( L O E L ) w a s set at 25.0 mg/kg/day; the no o b s e r v e d effect level ( N O E L ) w a s set at 5.0 mg/kg/day. A c u t e oral toxicity w a s evaluated using acute oral toxicity in rat and 28-day acute oral L D study in Mallard d u c k s . Rat acute oral toxicity w a s studied using a 5% w/v a q u e o u s solution of pure O P A . Five groups o f t e n rats e a c h w e r e given a single oral d o s e of 25, 50, 100, 250, or 500 mg/kg, o b s e r v e d for 15 d a y s , and sacrificed. All animals in the 2 5 0 and 500 mg/kg groups died before d a y 4. It w a s not reported whether a n y a n i m a l s from the other d o s e groups died before completion of the study. N u m e r o u s clinical s y m p t o m s were o b s e r v e d during the study, a s w e r e findings upon n e c r o p s y . T h e oral rat L D w a s set a s 121 mg/kg. T h e 28-day study 5 0  5 0  24  involved six d o s e levels of pure O P A given by gelatine c a p s u l e ranging from 0 to1470 mg active ingredient/kg body weight to groups of eighteen Mallard d u c k s . T e n to 7 0 % of the test birds died in e a c h d o s e group. T h e 2 8 - d a y acute oral L D w a s set at 870 mg/kg body weight, with 9 5 % c o n f i d e n c e limits of 3 2 5 - 2 3 3 0 mg/kg. T h e N O E L w a s less than 316 mg/kg body weight. 5 0  A n acute single d o s e oral toxicity in rats study using 0.56% C i d e x OPA® Solution w a s c o n d u c t e d to determine whether the solution could p r o d u c e death within 14 days following a single d o s e . Five rats were given a single d o s e of 5g/kg. N o rats died and no clinical signs of toxicity or body weight c h a n g e s w e r e reported. T h e L D for acute oral toxicity w a s c o n s i d e r e d to be greater than 5g/kg body weight for rats (Toxicity C a t e g o r y IV) and the study author c o n c l u d e d that the formulated 0.56% solution w a s non-toxic to rats.  5 0  T h e primary e y e irritation study in rabbits u s e d 0.56% C i d e x OPA® Solution. T h r e e rabbits were administered 0.1 ml solution to o n e e y e only and o b s e r v e d for 4 d a y s . E y e irritation, including conjuctival r e d n e s s and discharge, w a s o b s e r v e d for up to 3 days, and all test e y e s returned to normal after 4 d a y s . T h e r e w e r e no reports of corneal opacity, clinical toxicity, or body weight c h a n g e s ; the study author considered the solution to be a mild eye irritant. T h e solution w a s given a Primary E y e Irritation Rating of "moderate" and placed into Toxicity C a t e g o r y III (no corneal opacity, and irritation reversible within 7 days). It w a s reported that the acute inhalation test could not be c o n d u c t e d b e c a u s e the vapour p r e s s u r e of C i d e x OPA® Solution is too low to p r o d u c e v a p o u r at room temperature. T h e v a p o u r p r e s s u r e of O P A at 21 °C w a s reported a s 0.0052 m m Hg (0.69 P a ) . It is not stated in the study s u m m a r y h o w this v a p o u r p r e s s u r e w a s determined. It is a l s o not reported whether an attempt w a s m a d e to conduct an inhalation study under different temperature conditions, nor is the detection limit or the method u s e d to test for O P A v a p o u r reported. Additional information provided by A d v a n c e d Sterilization P r o d u c t s in M a y 2 0 0 2 included a report on the v a p o u r pressure of C i d e x OPA®. T h e previously reported vapour p r e s s u r e v a l u e of 0.0052 m m H g w a s for crystalline O P A , w h i c h has a melting point of approximately 55 °C, and may not reflect the v a p o u r p r e s s u r e O P A in solution. A g a s chromatography/ m a s s spectrometry ( G C / M S ) h e a d s p a c e analysis of O P A w a s c o n d u c t e d by D o w C h e m i c a l , the producer of raw O P A . A s y s t e m with 20 ml v a p o u r over 3 ml of solution w a s allowed to equilibrate at 2 5 and 60 °C (Feldman 2001). Fifteen-minute s a m p l e s were taken with a flow rate of 1 l/min using a 2,4-dinitrophenylhydrazine ( D N P H ) treated filter. N o O P A w a s detected in the vapour at 2 5 °C, and traces w e r e detected at 60 °C. T h e detection limit of this method is 0.5 p p m for glutaraldehyde, but has not b e e n quantified for O P A . T h e r e w a s "no w a y of knowing" the quantity of O P A v a p o u r detected at 60 °C. Attempts were also m a d e by D o w C h e m i c a l to m e a s u r e O P A at 2 5 °C using the solid p h a s e microextraction ( S P M E ) method. A n O P A peak w a s detected by g a s  25  chromatography after 72 hours of equilibration ( A S P , u n p u b l i s h e d report, M a y 9, 2002). A n unpublished study of O P A v a p o u r referenced by F e l d m a n (2001) m e a s u r e d O P A and glutaraldehyde in a c l o s e d room. 1000 ml O P A (0.62% solution) w a s left in a shallow pan in a 1000 c u b i c foot room at 25 °C for 1 hour. During 8 hours of sampling at 60 l/hour, 0.00095 ppm O P A v a p o u r w a s detected using g l a s s scrubbers treated with D N P H . Glutaraldehyde results w e r e reported a s 0.0194 ppm (not stated w h e t h e r test conditions for glutaraldehyde w e r e the s a m e a s for O P A ; details about glutaraldehyde concentration are unclear but reference w a s m a d e to Cidex® Activated D i a l d e h y d e Solution, which contains 2.4% glutaraldehyde). T h e method of a n a l y s i s w a s not reported. V a l u e s of 0.21 and 0.71 p p m for O P A and 0.9 and 1.98 ppm for glutaraldehyde w h e n m e a s u r e d in s e a l e d containers at 2 5 and 38.5 °C, respectively, w e r e also reported, but no details about v o l u m e s of solution or size of the containers w e r e provided. D o c u m e n t s provided by A d v a n c e d Sterilization P r o d u c t s a l s o included a report of a study c o n d u c t e d in a hospital that w a s using C i d e x OPA® for e n d o s c o p e disinfection. S a m p l e s w e r e taken during a 4.5-hour period o n a single day, 1.5 m from the floor, during operation of e n d o s c o p e r e p r o c e s s i n g units. A n infrared spectrometer w a s u s e d to m e a s u r e a l d e h y d e activity a n d c o m p a r e it to glutaraldehyde. T h e detection of limit of this method w a s reported a s being greater than [emphasis added] 0.01 p p m for glutaraldehyde; no a l d e h y d e w a s detected "at virtually all times" (Croll 2001). S o m e additional information w a s provided by A d v a n c e d Sterilization P r o d u c t s in r e s p o n s e to q u e s t i o n s regarding sensitization potential a s k e d at the O c t o b e r 2001 teleconference. A d v a n c e d Sterilization Products stated that the O P A raw material can c a u s e d e r m a l sensitization, as it w a s positive in the g u i n e a pig maximization test and the m o u s e local lymph n o d e test, both c o n d u c t e d by U n i o n C a r b i d e Corporation, now D o w C h e m i c a l . T h e Material Safety Data S h e e t ( M S D S ) for O P A d o e s include a statement that it may c a u s e allergic skin reactions (J.T. B a k e r 1999; A p p e n d i x XIV). N o respiratory sensitization studies had b e e n c o n d u c t e d on crystalline O P A or O P A in solution b e c a u s e there w a s no method to monitor the v a p o u r ( A S P , u n p u b l i s h e d report, M a y 9, 2002). However, a laboratory report of ocular and respiratory irritation that w a s d o n e for J o h n s o n & J o h n s o n M e d i c a l Inc. w a s included in the d o c u m e n t s supplied by A d v a n c e d Sterilization P r o d u c t s in M a y 2002. T h e d o c u m e n t includes reports of six studies, e a c h using the A d v a n c e d Sterilization P r o d u c t s methodology. In e a c h , a 300-ml b e a k e r of the solution ( a s s u m e d to be C i d e x OPA®, but reported as "Cold Sterilant" with a n identification number) w a s allowed to equilibrate in a 23 * 24 * 6 1 - c m c l o s e d container for at least 1 hour at a m i n i m u m temperature of 70 °C with constant agitation. Five rats were then placed inside the container for at least 4 hours and o b s e r v e d every 30 minutes. In the first report, o n e animal had laboured breathing at 30 minutes and no animals s h o w e d signs of o c u l a r or respiratory irritation after 24 hours. T h e five other reports found no clinical signs ( N A m S A 1990).  26  At the O c t o b e r 2001 teleconference, a representative from the W o r k e r s ' C o m p e n s a t i o n B o a r d a s k e d A d v a n c e d Sterilization P r o d u c t s to d i s c u s s the possibility of c o m p a r i n g O P A with other c h e m i c a l s of similar m o l e c u l a r weight a n d structure a n d known to c a u s e occupational asthma, s u c h a s phthalic anhydride or glutaraldehyde, to predict possible toxic effects. (Phthalic anhydride, C H 0 3 , molecular weight 148.12, contains the O P A structure with the two aldehydic carbon atoms attached to a single o x y g e n atom with single b o n d s to form an anhydride group; it is well d o c u m e n t e d a s a c a u s e of occupational a s t h m a [ N e w m a n Taylor et al. 1987; V e n a b l e s 1989]). A d v a n c e d Sterilization P r o d u c t s provided the following quote from a n u n n a m e d industrial toxicologist in r e s p o n s e to this question ( A S P , unpublished report, M a y 9, 2002): 8  4  "While the constrained anhydride structure is certainly not the 1,2aldehyde structure of OPA it has reactive chemical features in common with OPA. For example, the anhydride carbonyl groups are susceptible to nucleophilic attack by tissue macromolecules just like OPA's aldehyde groups are. Phthalic anhydride has a lot of baggage in terms of sensitization and mucous membrane irritation effects. So a good question is whether or not we would like to default to the phthalic anhydride data as surrogate information for predicting "hazard" for OPA. At the same time, there may be useful data on phthalic anhydride that could be adopted for OPA and used to avoid expensive toxicity testing. My advice right now would be to proceed with caution until we understand both OPA's toxicity profile and phthalic anhydride. Eventually, we should probably complete a review of both OPA and phthalic anhydride's toxicity profile to see how they compare." 2.1.4.2 C o m p l i a n c e ™ Data 2.1.4.2.1 Data from Regulatory A g e n c i e s A series of six c o m p l e t e laboratory toxicity studies w a s obtained with the DIN application for the original s u b m i s s i o n of E n d o S p o r ™ Plus. T e s t reports w e r e for ocular irritation, g u i n e a pig skin sensitization, A m e s S p o t Test, acute dermal toxicity, acute oral toxicity, a n d primary dermal irritation. T h e test for o c u l a r irritation w a s c o n d u c t e d on six N e w Z e a l a n d white rabbits. A d o s e of 0.1 ml solution w a s administered to o n e e y e of e a c h animal, a n d the animals were o b s e r v e d for 21 days. C o r n e a l opacity w a s o b s e r v e d in three of the animals on day 1 a n d still r e m a i n e d at the e n d of the study period in two of the animals. Iritis w a s o b s e r v e d in all a n i m a l s by 1 hour after administration a n d resolved in all animals by d a y 14. Conjunctivitis w a s o b s e r v e d in all a n i m a l s by d a y 1, with no  27  positive s c o r e s remaining by d a y 14. N o animals s h o w e d a c c e s s o r y orbital growth or abnormal eyelids. T h e solution resulted in e y e irritation in all a n i m a l s a n d irreversible irritation in two of the six animals. T h e split adjuvant g u i n e a pig sensitization test w a s c o n d u c t e d o n ten albino guinea pigs. Induction w a s d o n e with a 0.5 ml d o s e of undiluted solution o n s h a v e d skin o n d a y s 0, 2, 4, a n d 7, a n d stimulated with the adjuvant o n d a y 4. T w o w e e k s later, a 50% concentration c h a l l e n g e d o s e w a s applied to the skin. N o a n i m a l s exhibited positive reactions to the challenge within 72 hours. T h e s a m e d a y a s the challenge d o s e , a n adjuvant c h a l l e n g e w a s applied to a different a r e a of skin o n the test animals a n d on non-adjuvant sensitized animals. All test a n i m a l s h a d positive reactions to the adjuvant a n d were thus s h o w n to be i m m u n o c o m p e t e n t . N o n e of the non-adjuvant sensitized (control) animals reacted to the adjuvant. T h e study concluded that the solution did not c a u s e allergic contact dermatitis. T h e A m e s S p o t T e s t using Salmonella typhimurium w a s c o n d u c t e d to determine mutagenicity. N o mutagenic r e s p o n s e s were o b s e r v e d , e x c e p t in positive control samples. A n acute d e r m a l toxicity test w a s performed o n ten rabbits using 2 g (1.94 ml) /kg body weight. T h e d o s e period w a s 24 hours, followed by 14 d a y s of observation, at which point the a n i m a l s w e r e sacrificed. All animals survived the test period with no behavioural c h a n g e s a n d no g r o s s abnormalities o b s e r v e d during necropsy. T h e dermal L D w a s determined to be greater than 2 g/kg for rabbits. 5 0  A n acute oral toxicity test w a s performed on ten rats using a single oral d o s e of 5 g/kg (0.97 ml solution per 2 0 0 g body weight) followed by 14 d a y s of observation. O n e rat died after d a y 1 a n d 5 rats lost weight. U p o n necropsy, g r o s s abnormalities were o b s e r v e d in eight o f t e n animals. T h e s e were primarily related to distension or discolouration of the gastro-intestinal tract, but also included atrophy of the s p l e e n and thymus. T h e animal that died o n d a y 2 w a s autolyzed a n d c a n n i b a l i z e d a n d had more s e v e r e lung a n d thymus abnormalities. T h e oral L D w a s determined to be greater than 5 g/kg for rats. 5 0  A primary d e r m a l irritation study w a s c o n d u c t e d using a single application of 0.5 ml on six rabbits for 4 hours. A n i m a l s were o b s e r v e d for 3 d a y s . V e r y slight to welldefined e r y t h e m a a n d e d e m a w e r e o b s e r v e d in four of the six animals. B y d a y 2, no e d e m a remained a n d very slight erythema w a s o b s e r v e d in two animals. T h e product w a s not c o n s i d e r e d to be a primary dermal irritant. A c c o r d i n g to the Health C a n a d a Drug Notification F o r m , C o m p l i a n c e ™ w a s first sold in C a n a d a in D e c e m b e r 2 0 0 0 . T h e 510(k) documentation obtained from the F o o d a n d Drug Administration contained brief (less than half-page) s u m m a r i e s of the six tests d e s c r i b e d a b o v e . T h e d o c u m e n t s a l s o included a s u m m a r y of literature related to peracetic acid, but  28  no further information o n C o m p l i a n c e ™ . T h e n a m e of the product at the time of the 510(k) s u b m i s s i o n w a s E n d o S p o r ™ Plus. E n d o S p o r ™ P l u s w a s a w a r d e d substantial e q u i v a l e n c e to the glutaraldehyde products O m n i c i d e , P r o c i d e 14, Cidex, and the peracetic acid sterilizing solution Steris 20 on O c t o b e r 8, 1999. 2.1.4.2.2 Data from Manufacturer T h e toxicity s u m m a r y data obtained from S y b r o n Dental S p e c i a l t i e s in D e c e m b e r 2 0 0 2 w a s labelled a s A t t a c h m e n t s 24 through 29, which w e r e referenced in the 510(k) s u b m i s s i o n for C o m p l i a n c e ™ . T h e s e d o c u m e n t s w e r e received prior to those obtained from the Health C a n a d a DIN s u b m i s s i o n . Both sets of laboratory reports were identical. It s h o u l d also be noted that the brief (one-sentence) s u m m a r i e s of toxicity studies previously provided by Metrex (Appendix XII) w e r e for t h e s e s a m e studies.  29  2.2 Comprehensive Literature Review 2.2.7 Literature Review  Objectives  A c o m p r e h e n s i v e review of the published epidemiological a n d toxicological literature related to currently marketed high-level disinfection products a n d their active ingredients w a s undertaken. T h i s information, c o m b i n e d with d a t a obtained from regulatory a g e n c i e s a n d manufacturers, w a s then u s e d to a s s e s s the relative occupational health impacts of e a c h type of high-level disinfectant.  2.2.2 Literature Review  Methods  T h e e p i d e m i o l o g y literature w a s s e a r c h e d for information related to currently available high-level disinfection products a n d their active ingredients: glutaraldehyde, O P A , hydrogen peroxide, a n d peracetic acid. T h e s e a r c h w a s conducted using the M E D L I N E a n d N I O S H T I C d a t a b a s e s with the following keywords: • glutaraldehyde, glutaral • ortho-phthalaldehyde, o-phthalaldehyde, O P A , 1,2-benzendicarboxaldehyde • peracetic acid • hydrogen peroxide • Cidex O P A • Compliance • high-level disinfection • disinfectants • sterilants • health effects • occupational exposure • occupational asthma • respiratory sensitization • sensitization A s e a r c h of the toxicology literature for information related to high-level disinfection products a n d ingredients w a s conducted using the M E D L I N E , T O X N E T , E M B A S E , and Registry of T o x i c Effects of C h e m i c a l S u b s t a n c e s (RTECS®). T h e following keywords w e r e s e a r c h e d : • glutaraldehyde, glutaral • ortho-phthalaldehyde, o-phthalaldehyde, O P A , 1,2-benzendicarboxaldehyde • peracetic acid • hydrogen peroxide • Cidex O P A • •  Compliance toxicity  30  2.2.3 Results of Literature Review 2.2.3.1 G l u t a r a l d e h y d e Glutaraldehyde is the most c o m m o n l y u s e d c h e m i c a l for high-level disinfection of reusable medical d e v i c e s (Russell 1994). It is listed as a sensitizer in the O c c u p a t i o n a l Health and Safety Regulation of the W o r k e r s ' C o m p e n s a t i o n B o a r d ( W C B ) of British C o l u m b i a ; the regulations state that e x p o s u r e to glutaraldehyde must be kept a s low a s r e a s o n a b l y a c h i e v a b l e ( A L A R A ) . T h e current British C o l u m b i a o c c u p a t i o n a l e x p o s u r e limit for glutaraldehyde is a ceiling limit of 0.25 m g / m (approximately 0.06 ppm) ( W C B 1999). T h e T h r e s h o l d Limit V a l u e (TLV®) r e c o m m e n d e d by the A m e r i c a n C o n f e r e n c e of G o v e r n m e n t a l Industrial Hygienists (ACGIH®) for occupational e x p o s u r e to glutaraldehyde is a ceiling of 0.05 ppm (approximately 0.2 mg/m ). Glutaraldehyde is currently undergoing further study by the T L V C o m m i t t e e ( A C G I H 2000). 3  3  2.2.3.1.1 D e r m a l Effects of Glutaraldehyde E x p o s u r e Glutaraldehyde h a s been a s s o c i a t e d with allergic dermatitis following occupational exposure to disinfecting solutions, with the first published report occurring in 1968 ( S a n d e r s o n & C r o n i n 1968). T h e r e are n u m e r o u s c a s e reports of workers w h o have d e v e l o p e d persistent, chronic dermatitis, usually on the h a n d s a n d forearms and occasionally o n the face, neck, and feet, after working with glutaraldehyde solutions ( S a n d e r s o n & C r o n i n 1968; J o r d a n et al. 1972; G o n c a l o et al. 1984; B a r d a z z i et al. 1986; Fowler 1989). S y m p t o m s include dryness, redness, hardening, cracking, itching, and p a p u l e s on the skin, often in people with no history of atopy or e c z e m a . In patch tests on symptomatic health care workers with o c c u p a t i o n a l e x p o s u r e to glutaraldehyde solutions, 100% had positive reactions to 1 to 2% glutaraldehyde (Bardazzi et al. 1986; Nethercott et al. 1988; Tarn & F r e e m a n 1989). There are relatively few published epidemiological studies of glutaraldehyde e x p o s u r e and health. O n e s u c h study (Norback 1988) found an i n c r e a s e d prevalence of s y m p t o m s s u c h a s hand rash and e c z e m a a m o n g e x p o s e d healthcare workers (n=39) w h e n c o m p a r e d to a control group (n=68). N o c a s e s of allergic contact dermatitis w e r e identified a m o n g the s e v e n individuals w h o underwent patch testing. A d o s e - r e s p o n s e relationship w a s o b s e r v e d b e t w e e n the frequency of e x p o s u r e to glutaraldehyde, e x p r e s s e d as the n u m b e r of d a y s e x p o s e d in 6 months, and the n u m b e r of skin s y m p t o m s . T h e geometric m e a n airborne e x p o s u r e level a m o n g t h e s e w o r k e r s w a s 0.05 m g / m , the geometric standard deviation w a s 3.4, and the m a x i m u m m e a s u r e d e x p o s u r e w a s 0.57 m g / m . All m e a s u r e m e n t s but o n e w e r e well below the current W C B e x p o s u r e limit of 0.5 m g / m . Dermal e x p o s u r e w a s not m e a s u r e d in this study. 3  3  3  31  A study of e n d o s c o p y n u r s e s (Pisaniello et al. 1997) reported a n i n c r e a s e in dermal s y m p t o m s including d r y n e s s and cracking, rash, discolouration, a n d hardening of the skin, a m o n g 135 nurses e x p o s e d to glutaraldehyde. T h e y did not find a d o s e r e s p o n s e relationship b e t w e e n m e a s u r e d airborne glutaraldehyde e x p o s u r e and skin s y m p t o m s ; however, they did find a positive relationship b e t w e e n s y m p t o m prevalence and the n u m b e r s of hours the subjects w e r e e x p o s e d to glutaraldehyde per week. T h e airborne e x p o s u r e levels m e a s u r e d in e n d o s c o p y units in this study were c l o s e to the current British C o l u m b i a e x p o s u r e limit; the geometric m e a n for personal e x p o s u r e m e a s u r e m e n t s w a s 0.045 p p m . L e v e l s w e r e lower in a r e a s with local e x h a u s t ventilation (geometric m e a n = 0.022 ppm) but w e r e a b o v e the British C o l u m b i a e x p o s u r e limit w h e n appropriate ventilation w a s not in place (geometric m e a n = 0.093 ppm). M e d i a n forearm dermal e x p o s u r e ranged from 0.3 ug to 2.0 ug on a 1 0 - c m pad, d e p e n d i n g on whether wrist-length latex or forearm-length nitrile gloves were worn. 2  V y a s and c o l l e a g u e s (2000) s u r v e y e d e n d o s c o p y nurses w h o w e r e e x p o s e d to glutaraldehyde. T h e y found that 4 4 % of currently e x p o s e d w o r k e r s (n=348) suffered from contact dermatitis. E x - e m p l o y e e s w h o had left their j o b s d u e to health r e a s o n s (n=18) w e r e a l s o included in this study; 44.4% of t h e s e r e s p o n d e n t s reported contact dermatitis w h e n they w o r k e d with glutaraldehyde. Of the eight nurses w h o m o v e d a w a y from the e n d o s c o p y unit, 7 5 % had persistent contact dermatitis e v e n without continued e x p o s u r e to glutaraldehyde. In a recent study c o m p a r i n g skin sensitization between healthcare w o r k e r s and nonhealthcare workers, Shaffer and Belsito (2000) found that 17.6% of healthcare workers had positive skin reactions to glutaraldehyde patch tests. A t o p i c dermatitis w a s less c o m m o n a m o n g healthcare workers allergic to glutaraldehyde than a m o n g the full healthcare worker group, suggesting that glutaraldehyde might be a sufficiently potent sensitizer that it frequently c a u s e s allergy in people w h o m are not p r e d i s p o s e d . Of the full study population of 4 6 8 healthcare workers, 3.6% w e r e allergic to glutaraldehyde. In a similar study, K i e c - S w i e r c z y n s k a and c o l l e a g u e s (1998) found positive reactions to glutaraldehyde patch tests in 12.4% of a group of 280 healthcare workers. 2.2.3.1.2 Respiratory Effects of Glutaraldehyde E x p o s u r e Glutaraldehyde e x p o s u r e h a s b e e n linked with a wide range of respiratory symptoms, including rhinitis and a s t h m a . T h e first reference to p o s s i b l e a s t h m a and other respiratory effects of glutaraldehyde w a s m a d e by A l e x a n d e r F i s h e r in 1981 (Fisher 1981), referring to the s u s p i c i o n s of a Dr. Robert Z a c h that glutaraldehyde in x-ray film e m u l s i o n s w a s responsible for several c a s e s of a s t h m a in radiologists and x-ray technicians. Glutaraldehyde has b e e n s h o w n to affect peak expiratory flow rates and produce early, late, and dual reactions following specific bronchial provocation tests ( G a n n o n et al. 1995; Di S t e f a n o et al. 1999; Quirce et al. 1999), thus indicating its ability to  32  c a u s e occupational a s t h m a . It h a s also been s h o w n to e x a c e r b a t e existing a s t h m a and rhinitis ( C o r r a d o et al. 1986; C h a n - Y e u n g et al. 1993). In addition to a s t h m a , other respiratory s y m p t o m s have b e e n reported in epidemiological studies of glutaraldehyde-exposed workers. In o n e of the studies described a b o v e , N o r b a c k (1988) found a positive relationship between s y m p t o m s s u c h a s nasal obstruction, n a s a l inflammation, throat irritation, and c o u g h and the number of d a y s e x p o s e d to glutaraldehyde. In a recent survey by V y a s and c o l l e a g u e s (2000), the respiratory effects of glutaraldehyde e x p o s u r e w e r e s h o w n to persist long after e x p o s u r e c e a s e d . In a survey of current a n d e x - e n d o s c o p y nurses, most of those w h o had left their jobs b e c a u s e of lower respiratory tract s y m p t o m s reported persistent s y m p t o m s e v e n w h e n no longer e x p o s e d to glutaraldehyde. N u r s e s currently e x p o s e d to glutaraldehyde also s h o w e d a n i n c r e a s e d risk of chronic bronchitis and n a s a l irritation. G l u t a r a l d e h y d e - i n d u c e d a s t h m a , like all forms of a s t h m a , is characterized by persistent airway h y p e r r e s p o n s i v e n e s s . S e n s i t i z e d individuals e x p e r i e n c e airway narrowing more readily and more severely in r e s p o n s e to inhaled bronchoconstrictors than do individuals with normal airways ( M a p p et al. 1999). T h e precise m e c h a n i s m of glutaraldehyde-induced occupational a s t h m a and m a n y other low molecular weight allergens is poorly understood. L o w m o l e c u l a r weight allergens often act a s h a p t e n s by forming covalent bonds with proteins in the body. T h e resulting m o l e c u l e s are large e n o u g h to be recognized a s foreign by the h u m a n immune s y s t e m and c a n therefore induce an i m m u n e r e s p o n s e (Sarlo & Clark 1992; A g i u s 2000). There is no identified specific IgE or non-lgE mediated m e c h a n i s m for glutaraldehyde induced a s t h m a . Specific IgE antibodies to glutaraldehyde have not been identified in m a n y patients, suggesting an IgE-independent m e c h a n i s m (Vyas et al. 2000). B e c a u s e of the lack of specific IgE antibodies, it h a s b e e n theorized that a s t h m a from low m o l e c u l a r weight agents may be regulated by T-lymphocytes, which release cytokines that c a n c a u s e an inflammatory r e s p o n s e in the airways. T h e progression of the d i s e a s e d o e s follow a predictable pattern, however. At s o m e point after initial e x p o s u r e , sensitization to the agent o c c u r s followed by a latency period and finally the onset of a s t h m a s y m p t o m s . T h e s y m p t o m s often persist after e x p o s u r e c e a s e s (Malo & C h a n - Y e u n g 1997). C h a n g e s in n a s a l lavage fluid following specific inhalation c h a l l e n g e have been noted a m o n g patients with glutaraldehyde-induced a s t h m a . Both the n u m b e r and percentage of eosinophils w e r e significantly i n c r e a s e d at 4 and 24 hours after inhalation c h a l l e n g e with glutaraldehyde w h e n c o m p a r e d with controls in a singleblind, p l a c e b o controlled c r o s s o v e r study. P r o l o n g e d i n c r e a s e s in eosinophil cationic protein and mast cell tryptase w e r e also o b s e r v e d in the post-challenge n a s a l lavage fluid of glutaraldehyde-sensitized a s t h m a patients ( P a l c z y n s k i et al. 2001).  33  2.2.3.1.3 G l u t a r a l d e h y d e T o x i c o l o g y Studies A n i m a l studies e x a m i n i n g the reproductive effects of glutaraldehyde consistently s h o w that it d o e s not c a u s e teratogenic or other toxic reproductive effects (Marks et al. 1980; E m a et al. 1992; N e e p e r - B r a d l e y & Ballantyne 2000). A n in vitro study that m e a s u r e d inhibition of mitochondrial d e h y d r o g e n a s e activity in h u m a n embryonic lung fibroblast cells w a s c o n d u c t e d to determine the cytotoxic potential of 2.5% glutaraldehyde a s c o m p a r e d with 19% formaldehyde ( W e n S u n et al. 1990). T h e m a x i m u m nontoxic concentration of glutaraldehyde ranged from 3.40 to 3.91 uJ7ml water ( 0 . 8 5 - 1 . 0 3 m M ) , d e p e n d i n g on the duration of e x p o s u r e ( 4 - 2 4 hours). T h e 5 0 % toxic c o n c e n t r a t i o n — t h e concentration that resulted in a 5 0 % reduction of e n z y m e activity—ranged from 8.35 to 19.31 uJ/ml water (2.09^4.83 m M ) . T h e cytoxicity of f o r m a l d e h y d e w a s similar w h e n e x p r e s s e d a s molar concentrations (mM), but m u c h greater w h e n e x p r e s s e d a s dilutions of the original solution (uJ/ml). T h e dermal irritant potential of glutaraldehyde on rabbit skin has b e e n a s s e s s e d for a variety of glutaraldehyde concentrations (Ballantyne & M y e r s 2001). Glutaraldehyde solutions w e r e applied to the skin of g r o u p s of six rabbits e a c h and o c c l u d e d for 4 hours. Solutions of 1 to 2% glutaraldehyde resulted in irritation in the form of mild e r y t h e m a a n d e d e m a . Glutaraldehyde h a s b e e n well d o c u m e n t e d a s a dermal sensitizing agent. Stern and c o l l e a g u e s (1989) e x a m i n e d the potential for glutaraldehyde to c a u s e contact hypersensitivity in m i c e and rats. A n i m a l s were e x p o s e d dermally during 5- or 14day induction periods, followed by a 4 t o l 4-day rest (latency) period, after which a challenge d o s e w a s applied. Dermal hypersensitivity w a s a s s e s s e d visually and using radioisotopic a s s a y . Both s p e c i e s exhibited d o s e - d e p e n d e n t hypersensitivity reactions to 1 and 3% glutaraldehyde. This finding w a s confirmed by Hilton and c o l l e a g u e s (1998) using the m o u s e local lymph node a s s a y . G l u t a r a l d e h y d e , at concentrations ranging from 0.25 to 5%, consistently resulted in strong r e s p o n s e s w h e n administered using two different vehicles of administration and consistently s h o w e d greater skin sensitization potential w h e n c o m p a r e d with formaldehyde. D e a r m a n and c o l l e a g u e s (1999) also s h o w e d e v i d e n c e of skin sensitization c a u s e d by 1 to 15% solutions of glutaraldehyde. T h e g u i n e a pig maximization test w a s u s e d by K i e c - S w i e r c z y n s k a and c o l l e a g u e s (1998) to a s s e s s the skin sensitization potential of glutaraldehyde. Fifty to 7 1 % of animals s h o w e d m o d e r a t e to strong allergic reactions to c h a l l e n g e skin tests with 0.4 to 0.5% glutaraldehyde. Both a thirteen-week and a 2-year study on the effects of glutaraldehyde inhalation in rats and mice h a v e b e e n d o n e with c o m p a r a b l e findings ( G r o s s et al. 1994; v a n Birgelen et al. 2000). E x p o s u r e to glutaraldehyde w a s a s s o c i a t e d with n o n neoplastic lesions, primarily in the anterior region of the n o s e . Inflammatory, degenerative, a n d proliferative lesions were o b s e r v e d in the respiratory a n d s q u a m o u s epithelium in the nasal cavity.  34  S e v e r a l animal studies h a v e b e e n conducted to a s s e s s the potential for glutaraldehyde to induce respiratory sensitization and irritation. W e r l e y a n d colleagues (1995) m e a s u r e d respiratory rate in mice and rats e x p o s e d to v a p o u r from a solution of 51.4% glutaraldehyde. T h e mice s h o w e d a d o s e - d e p e n d e n t d e c r e a s e in respiratory rate that w a s attributed to a peripheral s e n s o r y irritation reaction. T h e e x p o s u r e concentration that c a u s e d a 5 0 % i n c r e a s e in the respiratory rate ( R D ) of mice (14 ppm) w a s u s e d a s an induction d o s e to e x a m i n e respiratory hypersensitivity in rats. Respiratory hypersensitivity w a s m e a s u r e d by an increase in respiratory rate during e x p o s u r e to a challenge d o s e . T h e c h a l l e n g e d o s e of 4.4 ppm (generated from a 50.8% solution) did not result in i n c r e a s e d respiratory rate, leading the authors to c o n c l u d e that respiratory hypersensitivity did not o c c u r in the rats. 5 0  D e a r m a n and c o l l e a g u e s (1999) u s e d the m o u s e local lymph n o d e a s s a y and cytokine profiles to distinguish between contact sensitivity and respiratory sensitivity c a u s e d by glutaraldehyde and formaldehyde w h e n administered via dermal application. C y t o k i n e profiles were determined by secretion of interleukin 4, interleukin 10, and interferon-y. F o r m a l d e h y d e w a s positive in the lymph node a s s a y and resulted in cytokine secretion c o m p a r a b l e to 2,4-dinitrochlorobenzene, a known dermal sensitizer. G l u t a r a l d e h y d e w a s also positive in the lymph node a s s a y , but 5 to 15% a q u e o u s glutaraldehyde solutions resulted in a T helper 2 (TH2)-type cytokine secretion profile high in interleukin 10 and interleukin 4. T h i s cytokine profile is similar to that of trimellitic anhydride, which is known to act a s a respiratory sensitizer, and s u g g e s t s that glutaraldehyde would be c a p a b l e of producing an IgEmediated i m m u n e reaction and respiratory sensitization. In the a b s e n c e of IgE antibody formation, T H 2 cells and related cytokine secretions c a n still c a u s e airway inflammation a n d a s t h m a through direct action on eosinophils. 2.2.3.2 Ortho-phthalaldehyde ( O P A ) There are no published studies examining the health effects a s s o c i a t e d with the u s e of O P A solutions. T h e r e are also no occupational e x p o s u r e limits for O P A in C a n a d a or the United States. T h e most recent material safety data sheet ( M S D S ) for C i d e x OPA®, dated D e c e m b e r 1, 2 0 0 2 , states that "breathing vapors m a y be irritating to the nose, throat, or respiratory s y s t e m , " and that "pre-existing bronchitis or a s t h m a c a n be aggravated." C o n t a c t with the product c a n c a u s e e y e and skin irritation and c a n stain the skin; it c a n c a u s e dermatitis with repeated contact and m a y d a m a g e intestinal m u c o s a if ingested. T h e M S D S also reports that C i d e x OPA® is not known to be a sensitizer "based on current data" [emphasis added], and that it should be used in a well ventilated location according to "building c o d e s or worker e x p o s u r e legislation" ( A S P 2 0 0 2 ; A p p e n d i x X V ) . A n M S D S for crystalline O P A , the raw material u s e d to p r o d u c e C i d e x OPA®, states that the c h e m i c a l c a n irritate the skin and may c a u s e allergic skin reactions. It is a  35  m u c o u s m e m b r a n e , gastrointestinal, eye, and respiratory irritant. T h e M S D S s u g g e s t s that local e x h a u s t ventilation be u s e d w h e n handling the s u b s t a n c e (J.T. B a k e r 1999; A p p e n d i x XIV). A single reference to O P A w a s found in the Registry of T o x i c Effects of C h e m i c a l S u b s t a n c e s ( R T E C S ® ) d a t a b a s e (http://ccinfoweb.ccohs.ca/rtecs/search.html). T h e only information available w a s a lowest published lethal d o s e (reference in French) of 7 mg/kg in the m o u s e , with an unreported route of e x p o s u r e . 2.2.3.3 H y d r o g e n P e r o x i d e T h e current British C o l u m b i a W o r k e r s ' C o m p e n s a t i o n B o a r d Regulation includes a n 8-hour e x p o s u r e limit of 1 ppm and a 15-minute e x p o s u r e limit 2 p p m for occupational e x p o s u r e to hydrogen peroxide vapour. It has no d e s i g n a t i o n s for skin absorption or sensitization ( W C B 1999a). T h e ACGIH® T W A - T L V ® is also 1 ppm ( A C G I H 2000). A n in vitro study w a s c o n d u c t e d by Sagripanti and Bonifacino (2000) to c o m p a r e the relative cytotoxic potentials of s e v e n c h e m i c a l disinfectants a n d sterilants, including 3 0 % w/v h y d r o g e n peroxide, 3 2 % w/v peracetic acid, and 5 0 % w/v glutaraldehyde. T h e concentration toxic to 5 0 % of cells ( T C ) w a s determined for e a c h c h e m i c a l on a variety of h u m a n , monkey, and m o u s e cell lines. G l u t a r a l d e h y d e and peracetic acid were a m o n g the most severely cytotoxic ( T C < 0.1 mmol/l), while hydrogen peroxide w a s o n e of the most mildly cytotoxic (TC50 > 1 mmol/l). 5 0  5 0  2.2.3.3.1 Effects of H y d r o g e n Peroxide Ingestion Most of the published literature on hydrogen peroxide toxicity is related to skin reactions and poisonings through accidental ingestion. Ingestion of small quantities of household (3%) h y d r o g e n peroxide is generally relatively benign, with s y m p t o m s normally non-existent or limited to vomiting or n a u s e a . C a s e reports of reversible gastrointestinal bleeding have occurred (Henry et al. 1996), a n d s e v e r a l deaths have been reported following ingestion of 3 5 % hydrogen peroxide ( D i c k s o n & Caravati 1994). 2.2.3.3.2 Dermal Effects of H y d r o g e n Peroxide E x p o s u r e P o i s o n control calls for d e r m a l e x p o s u r e to household hydrogen peroxide (3%) normally report s y m p t o m s s u c h a s burning or tingling s e n s a t i o n s and whitening of the skin; burning, r e d n e s s , and blurred vision have b e e n reported following eye e x p o s u r e (Dickson & C a r a v a t i 1994). O c c u p a t i o n a l skin e x p o s u r e to 3 5 % hydrogen peroxide w a s reported w h e n a man working in a dry c l e a n i n g s h o p accidentally s p l a s h e d the solution over his s h o u l d e r and back (Izu et al. 2000). E r y t h e m a and reversible v a c u o l a r eruptions resulted, as well a s reversible s u b c u t a n e o u s emphysema.  36  O n e c a s e report of positive patch tests to hydrogen peroxide c o n c l u d e d that allergic contact dermatitis had occurred in two patients (one of w h o m w a s e x p o s e d to hydrogen peroxide solutions of 2 0 - 4 0 % ) ; however, details provided w e r e insufficient to determine w h e t h e r the patch test results were c a u s e d by irritant or sensitization reactions (Aguirre et al. 1994). In a review of patch test results from 189 patients, mostly hairdressers, with s u s p e c t e d occupational skin d i s e a s e s , no allergic reactions and o n e irritant reaction w e r e reported from patch tests with 3% hydrogen peroxide ( K a n e r v a et al. 1998). It is not known to what extent, if any, t h e s e patients were e x p o s e d to h y d r o g e n peroxide. A review by the s a m e authors ( K a n e r v a et al. 1998) of 10,806 c a s e s of allergic d e r m a t o s e s in a Finnish registry revealed no reports of allergic reactions c a u s e d by hydrogen peroxide. 2.2.3.3.3 Respiratory Effects of Hydrogen Peroxide E x p o s u r e Reports to poison control centres for inhalation e x p o s u r e to h y d r o g e n peroxide have been infrequent, but have resulted in respiratory s y m p t o m s s u c h a s s h o r t n e s s of breath and c o u g h i n g (Dickson & Caravati 1994). Unfortunately, e x p o s u r e levels or concentrations w e r e not reported, although t h e s e incidents w e r e related to industrial strength hydrogen peroxide (> 10%) in combination with other noxious c h e m i c a l s . T h e effect of h y d r o g e n peroxide on airways inflammation w a s a s s e s s e d by topical application of hydrogen peroxide (0.1 and 0.5 M) to the tracheobronchial m u c o s a of anaesthetized g u i n e a pigs (Greiff et al. 1999). H y d r o g e n peroxide (0.5 M) c a u s e d severe inflammatory epithelial d a m a g e that w a s e x p r e s s e d through m u c o s a l exudation of p l a s m a and i n c r e a s e d m u c o s a l absorption permeability. Only o n e published p a p e r w a s found that e x a m i n e d the effect of inhaled hydrogen peroxide v a p o u r g e n e r a t e d from a 3 0 % solution ( G a g n a i r e et al. 2002). T o a s s e s s s e n s o r y irritation potential, mice w e r e e x p o s e d to v a p o u r of acetic acid, hydrogen peroxide, peracetic acid, and a mixture of the three for 1 hour. Respiratory irritation w a s a s s e s s e d by determining the R D for e a c h type of vapour. M i c e exhibited a d o s e - d e p e n d e n t d e c r e a s e in respiratory rate w h e n e x p o s e d to hydrogen peroxide at airborne concentrations ranging from 25 to 212 ppm. Respiratory rate rapidly returned to normal upon c e s s a t i o n of e x p o s u r e . T h e R D w a s 113 p p m (157 mg/m ), s u g g e s t i n g that hydrogen peroxide is a relatively strong respiratory irritant. T h e authors u s e d the R D value to estimate a m a x i m u m e x p o s u r e limits. Short-term e x p o s u r e limit ( S T E L ) and time-weighted a v e r a g e ( T W A ) v a l u e s of 0.1 R D and 0.03 R D , respectively, were calculated. T h e authors calculated that a short-term e x p o s u r e limit for hydrogen peroxide should not e x c e e d 10 p p m and a time-weighted a v e r a g e should not e x c e e d 3 ppm. B a s e d on this, the existing ACGIH® T W A - T L V ® v a l u e of 1 ppm w a s c o n s i d e r e d appropriate. 5 0  5 0  3  5 u  5 0  5 0  2.2.3.4 P e r a c e t i c A c i d A s with O P A , the health effects a s s o c i a t e d with the u s e of peracetic acid for highlevel disinfection are largely u n k n o w n . No occupational e x p o s u r e limits are currently  37  in place, although a n internal 8-hour time weighted a v e r a g e of 0.15 p p m is being used at a p h a r m a c e u t i c a l and c h e m i c a l c o m p a n y in B e l g i u m ( E C E T O C 2001). F e w English l a n g u a g e publications regarding potential health effects of peracetic acid were found. B a s e d on a calculated T C value, 3 2 % peracetic acid w a s determined to be s e v e r e l y cytotoxic a s d e s c r i b e d a b o v e (Sagripanti & Bonifacino 2000). 5 0  2.2.3.4.1 D e r m a l Effects of P e r a c e t i c A c i d E x p o s u r e In a 12-month d e r m a l e x p o s u r e study, 0.2% peracetic acid w a s not found to d a m a g e the oral m u c o s a of rabbits w h e n applied at a rate of 1 ml three times per week, but did result in atrophy of the hair follicles of minute a c c e s s o r y hairs (Muller et al. 1988). T h e H a z a r d o u s S u b s t a n c e s Data B a n k ( H S D B ) within T O X N E T (http://toxnet.nlm.nih.gov/cgi-bin/sis/htmlgen7HSDB) reports excerpts of peerreviewed toxicity studies, translated into English w h e r e n e c e s s a r y . T h e peracetic acid entry states that the s u b s t a n c e is a strong skin and e y e irritant. It is corrosive to m u c o u s m e m b r a n e s of the mouth, throat, and o e s o p h a g u s a n d will c a u s e necrosis. Contact with peracetic acid c a n c a u s e ulceration of any t i s s u e or m e m b r a n e and permanent scarring of the c o r n e a . In a guinea pig study, 3% peracetic acid c a u s e d dermatitis after 2 hours of exposure; no dermatitis w a s o b s e r v e d from 5 hours of contact with a 1% solution. Dermatosis and irritation h a s been reported in h u m a n s from e x p o s u r e to mixtures of peracetic acid, acetic acid, and hydrogen peroxide with a peracetic acid content of 0.35 to 0.5%. In different studies on rabbits, peracetic acid h a s b e e n reported a s corrosive at concentrations ranging from 3.4 to 40%, slightly irritating at concentrations of 0.17 and 0.34% and moderately to s e v e r e l y irritating at a concentration of 5%. C o n c e n t r a t i o n s of 0.22 to 17% peracetic acid c a u s e d s e v e r e irritation or corrosion in rabbit e y e s ( E C E T O C 2001). In four g u i n e a pig d e r m a l sensitization studies using concentrations of 0.15 to 14% peracetic acid, no e v i d e n c e of sensitization w a s found ( E C E T O C 2001). 2.2.3.4.2 Respiratory Effects of Peracetic A c i d E x p o s u r e T h e H a z a r d o u s S u b s t a n c e s Data B a n k entry for peracetic acid states that the v a p o u r is irritating to the e y e s , nose, and throat in h u m a n s . A g u i n e a pig inhalation study found a d o s e - d e p e n d e n t relationship between peracetic acid inhalation and eye irritation and c o u g h w h e n animals were e x p o s e d to the v a p o u r of 1 or 3% solutions. P e r a c e t i c acid v a p o u r h a s b e e n reported to be tolerable to h u m a n s for several hours at airborne concentrations of 0.13 to 0.17 p p m . C o n c e n t r a t i o n s of 0.3 to 0.4 ppm  38  would have b e e n "unpleasant" for a n extended time but did not p r o d u c e an immediate irritant effect ( E C E T O C 2001). In the m o u s e s e n s o r y irritation study by G a g n a i r e and c o l l e a g u e s (2002) d e s c r i b e d above, 3 9 % peracetic acid w a s found to have a m u c h stronger irritation capacity than 3 0 % hydrogen peroxide. T h e R D of peracetic acid w a s 5.4 ppm (17 mg/m ) c o m p a r e d with 113 ppm for hydrogen peroxide and 2 2 7 p p m for acetic acid. This level of irritancy is c o m p a r a b l e to that of formaldehyde or chlorine. D e c r e a s e s in respiratory rate o c c u r r e d in a d o s e - d e p e n d e n t m a n n e r at concentrations ranging from 1.8 to 24 p p m peracetic acid vapour. T h e r e s p o n s e o c c u r r e d rapidly upon induction of e x p o s u r e a n d recovery w a s likewise rapid upon c e s s a t i o n of e x p o s u r e . C o m p a r a b l e R D v a l u e s w e r e also determined in rats e x p o s e d to peracetic acid aerosol ( E C E T O C 2001). 3  5 0  5 U  G a g n a i r e and c o l l e a g u e s (2002) also a s s e s s e d , the irritant potential of a mixture of 5 3 % acetic acid, 1 1 % hydrogen peroxide, and 3 6 % peracetic acid. T h e r e s p o n s e to the vapour of the mixture at concentrations ranging from 1.6 to 11.6 p p m w a s essentially the s a m e a s the r e s p o n s e to pure peracetic acid. T h e R D was calculated a s 3.8 p p m (12 mg/m ). B e c a u s e no occupational e x p o s u r e standards currently exist for peracetic acid vapour, the authors u s e d the R D v a l u e s to estimate m a x i m u m appropriate e x p o s u r e limits. Short-term e x p o s u r e limit ( S T E L ) and time-weighted a v e r a g e ( T W A ) values of 0.1 R D and 0.03 R D , respectively, were calculated. T h e y s u g g e s t e d that a short-term e x p o s u r e limit should not e x c e e d 0.5 ppm and a time-weighted a v e r a g e should not e x c e e d 0.2 p p m . 5 0  3  5 0  5 0  5 0  39  2.3 Structure-Activity Relationship Analysis (SAR) Structure-activity relationship ( S A R ) analysis is a m e a n s of predicting a n d characterizing toxicological properties of c h e m i c a l s . It is often u s e d a s a s c r e e n i n g tool to highlight c h e m i c a l s o n which to conduct further time c o n s u m i n g a n d e x p e n s i v e animal or in vitro studies. S A R a s s u m e s that c h e m i c a l structure is related to specific toxicological properties or activities. Basically, c h e m i c a l structure determines the physical c h e m i c a l properties a n d reactive capabilities of a substance; t h e s e properties, w h e n introduced into a biological s y s t e m s u c h a s h u m a n s , c a n result in specific biological or toxicological o u t c o m e s ( M c K i n n e y et al. 2000; S c h u l t z & S e w a r d 2000). S A R involves both qualitative a n d quantitative elements. T h e r e a r e two b a s i c methods of conducting quantitative S A R ( Q S A R ) . Correlative m e t h o d s u s e statistical procedures to ascertain a s s o c i a t i o n s between properties a n d o u t c o m e s . R u l e - b a s e d or expert s y s t e m Q S A R looks for a s s o c i a t i o n s between g r o u p s of c h e m i c a l s , a n d puts c h e m i c a l s with similar activities into c l a s s e s ( M c K i n n e y et al. 2000). A qualitative S A R c a n be d o n e by simply examining the structure a n d reactive capabilities of a given c h e m i c a l , a n d comparing it with known structural predictors of a specific toxicological o u t c o m e .  2.3.1 Use of SAR to Predict Respiratory  Sensitization  S A R h a s b e e n u s e d in a variety of settings including e c o t o x i c o l o g y a n d c a n c e r risk a s s e s s m e n t , but its u s e in predicting respiratory sensitization h a s b e e n fairly limited to date. O n l y five p a p e r s — f o u r studies a n d o n e r e v i e w — w e r e found o n the subject (Agius et al. 1991; A g i u s et al. 1994; Karol e t a l . 1996; G r a h a m et al. 1997; A g i u s 2000). M u c h of this work involved qualitative a s s e s s m e n t s of known a s t h m a g e n s to identify structural c o m p o n e n t s related to respiratory sensitization potential (Agius et al. 1991; A g i u s e t a l . 1994). S a r l o a n d Clark (1992) d e v e l o p e d a "tier a p p r o a c h " to predicting respiratory sensitization that incorporated S A R a s the first tier. T h e y proposed four tiers for a s s e s s i n g respiratory sensitization potential. T h e first tier is to use S A R to determine w h e t h e r the c h e m i c a l contains a reactive group that could form covalent b o n d s with h u m a n proteins, whether the c h e m i c a l h a s b e e n a s s o c i a t e d with a n y i m m u n e r e s p o n s e , or whether it b e l o n g s to a c h e m i c a l c l a s s known to c a u s e i m m u n e r e s p o n s e s ; the s e c o n d tier is in vitro a s s e s s m e n t of protein conjugation; the third is a n in vivo (guinea pig) injection m o d e l for immunogenicity; and the fourth tier is the g u i n e a pig inhalation m o d e l . Others (Karol et al. 1996; G r a h a m et al. 1997) have u s e d c o m p u t e r - b a s e d expert s y s t e m s to d e v e l o p correlative Q S A R s for respiratory sensitization. A g i u s a n d c o l l e a g u e s (1991) published a qualitative hypothesis of structure-activity relationships for respiratory sensitization. T h e y reviewed the published literature and identified 60 low m o l e c u l a r weight ( M W < 1000) c h e m i c a l s known to c a u s e occupational a s t h m a . T h e s e s u b s t a n c e s were then a s s e s s e d to identify c h e m i c a l  40  properties s u c h a s structural c o m p o n e n t s and reactivity that tend to be a s s o c i a t e d with a s t h m a g e n i c capability. In a follow-up to this work (Agius et al. 1994), a subset of a s t h m a - c a u s i n g c h e m i c a l s with molecular weights l e s s than 250, containing carbon and hydrogen, a n d with or without nitrogen or o x y g e n , w a s identified. T h e s e were c o m p a r e d with a list of h a z a r d o u s s u b s t a n c e s that met the s a m e criteria but were not known to c a u s e a s t h m a . All c o m p o u n d s w e r e a s s e s s e d for atomic composition, unsaturation, and reactive groups. M u l t i C A S E (Multiple C o m p u t e r A u t o m a t e d Structure Evaluation) is a computerb a s e d Q S A R m o d e l that fragments c h e m i c a l s into substructures consisting of two or more non-hydrogen a t o m s and identifies substructures, orH'biophores," that are statistically a s s o c i a t e d with biological activity. T h e m e c h a n i s m of toxicity d o e s not need to be known. Karol and c o l l e a g u e s (1996) u s e d M u l t i C A S E to d e v e l o p a d a t a b a s e of 39 known respiratory sensitizers with low m o l e c u l a r weight. A similar group of c h e m i c a l s with no reports of respiratory sensitization and that w e r e known not to be d e r m a l sensitizers w e r e u s e d as a "learning set" of inactive c h e m i c a l s . Both h u m a n and animal data w e r e u s e d to classify s u b s t a n c e s a s sensitizers or non-sensitizers. M e a n v a l u e s for physical c h e m i c a l properties w e r e calculated for e a c h set of c h e m i c a l s and c o m p a r e d . T h i s model differed from the qualitative a p p r o a c h taken by A g i u s and c o l l e a g u e s (1991, 1994) in that it did not identify broad categories s u c h a s the p r e s e n c e of specific reactive groups. T h i s model identified physical c h e m i c a l properties s u c h as m e a n molecular weight, electronic energies, and water solubility. This preliminary m o d e l w a s further d e v e l o p e d by G r a h a m and c o l l e a g u e s (1997) using C A S E a n d M u l t i C A S E . C A S E differs slightly from M u l t i C A S E in that it identifies not only b i o p h o r e s a s s o c i a t e d with activity, but also "biophobes," which are substructures a s s o c i a t e d with inactivity. T h e C A S E / M u l t i C A S E m o d e l d e v e l o p e d by G r a h a m and c o l l e a g u e s (1997) identified a series of biophores and b i o p h o b e s for respiratory sensitivity. T h e model w a s also validated by using it to predict the sensitizing activity of s u b s t a n c e s known to be active or inactive; 9 5 % of known c h e m i c a l s w e r e correctly predicted as active or inactive for respiratory sensitization. A n on-line C h e m i c a l A s t h m a H a z a r d A s s e s s m e n t P r o g r a m (Hazassess) is available, which is b a s e d o n structure-activity relationships (http://homepages.ed.ac.uk/jjarvis/research/hazassess/; J a r v i s 1999). T h e program is b a s e d on M D L molfile representations of structure. (Molfiles are text-based molecule files d e v e l o p e d by M D L Information S y s t e m s , Inc.; e a c h molfile d e s c r i b e s a single m o l e c u l a r structure, including atoms, bonds, and properties). With a data set of 76 low m o l e c u l a r weight ( M W < 1000) organic respiratory sensitizers and 303 controls, logistic regression analysis w a s u s e d to calculate the o d d s ratios for the a s t h m a h a z a r d a s s o c i a t e d with individual structural fragments. Structures of new c o m p o u n d s in M D L molfile format c a n be input to the program, w h i c h will calculate a hazard index (odds ratio of hazard) for respiratory sensitization. T h e h a z a r d index ranges from 0.00 to 1.00, with 0 being very low o d d s and 1 being very high o d d s that the c o m p o u n d is a sensitizer.  41  A n i m a l and in vitro m o d e l s have been limited in predicting respiratory sensitization (Agius et al. 1991; Karol et al. 1996). W e l l - d e v e l o p e d S A R m o d e l s could therefore prove invaluable for prediction of respiratory hypersensitivity or a s t h m a . This is particularly the c a s e for low molecular weight c h e m i c a l s that h a v e no specific IgE m e c h a n i s m (Karol 1994; M a l o & C h a n - Y e u n g 1997; V y a s et al. 2000). T h e r e are a n u m b e r of limitations a s s o c i a t e d with the u s e of S A R for predicting respiratory sensitization potential. T h e use of Q S A R for respiratory sensitization is relatively new and h a s not b e e n fully validated (Karol et al. 1996). Qualitative S A R is a less precise method and at best can only determine whether a c h e m i c a l h a s structural c o m p o n e n t s that have b e e n related to respiratory hypersensitivity. Unfortunately, the only completely accurate method to a s s e s s sensitization potential is to d o c u m e n t clinical c a s e s of occupational a s t h m a known to h a v e b e e n c a u s e d by a given s u b s t a n c e . If a s u b s t a n c e has been in u s e for an e x t e n d e d period of time with no identified c a s e s , it is not likely to have sensitization potential; however, there is no guarantee that existing c a s e s will have b e e n identified or d o c u m e n t e d in the published literature.  2.3.2 SAR Objectives A qualitative S A R a n a l y s i s w a s c o n d u c t e d to a s s e s s the respiratory sensitization potential of the active ingredients contained in the two currently available glutaraldehyde alternatives. Marketing claims for both t h e s e products state that they are safer than glutaraldehyde. T h e primary health c o n c e r n a s s o c i a t e d with glutaraldehyde e x p o s u r e is occupational a s t h m a , and the potential for t h e s e alternatives to h a v e the s a m e effect has not b e e n directly a s s e s s e d .  2.3.3 SAR Methods T h e relative respiratory sensitization potential of O P A , peracetic acid, hydrogen peroxide, and glutaraldehyde w e r e a s s e s s e d using a qualitative S A R a p p r o a c h . Using the literature published on structural and reactive a s s o c i a t e d with respiratory sensitizers, a list of predictors w a s a s s e m b l e d . T h i s list w a s c o m p r i s e d of physical, chemical, and reactive properties that indicate that a c h e m i c a l h a s the potential to act a s a respiratory sensitizer. T h e structure and properties of the four c h e m i c a l s of interest w e r e then e x a m i n e d and c o m p a r e d with the list of sensitizing predictors. T h e more predictors a given c h e m i c a l had relative to glutaraldehyde, a known sensitizer, the more likely that c h e m i c a l is to have respiratory sensitization potential. 2.3.3.1 Respiratory Sensitizing Predictors A g i u s and c o l l e a g u e s (1991) d e s c r i b e d several broad c l a s s e s of c o m p o u n d s that have been implicated a s c a u s e s of a s t h m a . T h e s e include m o l e c u l e s that c a n  42  undergo coordination bonding, reactive s u b s t a n c e s that undergo covalent bonding, and certain instances of hydrogen bonding between xenobiotics and h u m a n m a c r o m o l e c u l e s . A plausible m e c h a n i s m by which a low m o l e c u l a r weight s u b s t a n c e c a n bond with h u m a n proteins and act a s a hapten c a n be a g o o d indicator of its sensitizing potential. Transition metals from groups V b , V l b , and VIII of the periodic table, e.g., platinum or nickel, c a n form stable "coordination c o m p o u n d s " with ligands, w h i c h in turn act a s haptens and c a n c a u s e a s t h m a . This p h e n o m e n o n will not be d e s c r i b e d in detail, as none of the s u b s t a n c e s of c o n c e r n here are metals. A c o m m o n feature of m a n y low molecular weight a s t h m a g e n s is that they are strongly basic. T h e s e include certain a z o c o m p o u n d s , d i i s o c y a n a t e s , a m i d e s , and diamines, a s well a s reactive d y e s . T h e s e a s t h m a - c a u s i n g c o m p o u n d s all have two reactive groups, often involving nitrogen atoms. Other agents, s u c h a s f o r m a l d e h y d e and the d i a l d e h y d e glutaraldehyde, have the capacity to undergo nucleophilic addition. T h e resulting Schiff b a s e formation is a possible m e c h a n i s m by w h i c h they could bind with the a m i n e function of proteins to form haptens. T h e Schiff b a s e is an unstable intermediate that forms by the c o n d e n s a t i o n reaction between an amino group (present on proteins) and a carbonyl group (present on a l d e h y d e s ) . T h e nitrogen atom in the Schiff b a s e h a s a positive charge, making it highly reactive and thus able to form covalent b o n d s with other c o m p l e x organic m o l e c u l e s in the body (Mathews & v a n H o l d e 1996). B e c a u s e Schiff b a s e s are unstable, their formation allows a l d e h y d e s to act a s haptens by combining with e n z y m e s or other proteins normally found in the h u m a n body to form "abnormal" proteins, which the immune s y s t e m might attack, c a u s i n g a sensitization reaction. S o m e unsaturated h y d r o c a r b o n s s u c h as styrenes and i s o p r e n e s c a n c a u s e a s t h m a . T h e y are highly b a s i c b e c a u s e of the high d e g r e e of unsaturation, and m a y bind with proteins through the formation of unstable e p o x i d e intermediates. Other unsaturated h y d r o c a r b o n s s u c h as certain reactive d y e s c o m b i n e with proteins by nucleophilic substitution, while others s u c h as the resin acid abietic acid undergo reactions at the site of their carboxyl groups. Sensitizers s u c h a s phthalic anhydride and other acid a n h y d r i d e s of carboxylic acids have two acyl g r o u p s that c a n undergo nucleophilic substitution and react with amino groups o n protein molecules. S o m e respiratory sensitizers do not undergo covalent bonding, but likely form threedimensional h y d r o g e n b o n d s at the cell surface. T h i s group includes s u c h s u b s t a n c e s a s propanolol (Agius et al. 1991). In a more quantitative work, A g i u s and c o l l e a g u e s (1994) identified structural c o m p o n e n t s that w e r e present significantly (p < 0.05) more often in a s t h m a g e n s  43  than in s u b s t a n c e s not known to c a u s e a s t h m a . T h e structural properties identified as being a s s o c i a t e d with a s t h m a - c a u s i n g s u b s t a n c e s included the p r e s e n c e of o x y g e n a n d nitrogen a t o m s in a single molecule, at least two reactive groups, c a r b o n - n i t r o g e n d o u b l e bonds, a n d o x y g e n - n i t r o g e n d o u b l e bonds! C a r b o n - c a r b o n , c a r b o n - o x y g e n , a n d nitrogen-nitrogen double bonds, a s well a s aromatics, were also more prevalent in the a s t h m a g e n i c agents, but the trend w a s not statistically significant. A review by A g i u s (2000) further stressed the importance of a n u m b e r of c h e m i c a l c l a s s e s a s having the potential to c a u s e a s t h m a . T h e s e included acid anhydrides, a l d e h y d e s (particularly dialdehydes), resin acids with a carboxylic group, epoxides, and c o m p o u n d s with nucleophilic nitrogen atoms s u c h a s d i i s o c y a n a t e s . Unsaturated m o l e c u l e s , particularly those with carboxylic acid groups, a n d those with polyfunctionality w e r e also identified a s possible a s t h m a a g e n t s . Increasing molecular weight, e v e n a m o n g low molecular weight s u b s t a n c e s , w a s also identified as a factor. Aliphatic, unsaturated m o l e c u l e s with a single reactive group w e r e identified a s low h a z a r d m o l e c u l e s . In a preliminary Q S A R , Karol et al. (1996) identified m e a n v a l u e s for s o m e physical chemical properties of respiratory sensitizers. T h e molecular weight of sensitizers w a s found to be 3 1 9 ± 241 versus 191 ± 5 0 for non-sensitizers. S e n s i t i z e r s were more soluble in water, with m e a n water solubility (log S, S = g/100 g water) of 1.12 ± 2.8 versus - 0 . 6 6 8 ± 1.45, a n d they had lower octanol/water partition coefficients (log P) (2.22 ± 2.7 vs. 3.44 ± 1.0). Differences w e r e also noted in electron energies. W a t e r solubility, log P, a n d electron energy w e r e not u s e d for this qualitative S A R , a s no information about these properties w a s available for the c h e m i c a l s being e v a l u a t e d . In a more c o m p l e t e Q S A R model, ( G r a h a m et al. 1997) identified structural biophores with a statistically significant (p < 0.07) relationship to active respiratory sensitizers. T h e s e biophores included the following substructures: N—CH— = N—CH= NH—C= NH—CH2— NH2—CH— OH—C= CO—NH— CO—OH  0= C= N— Cl—C= S02—OH CO—O—CO— C H = C — C H = C H (attached to 2 NH—C= CH—CH= C= CH—CH= C— CH= CH—C= C H —  n d  C of fragment)  With the exception of C = C H — C H = C — a n d C H = C H — C = C H — , n o n e of the a b o v e substructures w e r e contained in the /nactive (non-respiratory sensitizing) compounds.  44  T h e Hazassess P r o g r a m similarly identified isocyanates, acid anhydrides, carboxylic acid groups ( C O O H ) , d o u b l e bonds, carbonyl ( C = 0 ) , and e t h a n o l a m i n e ( N — C — C — O ) fragments a s being significantly a s s o c i a t e d with respiratory sensitizers (Jarvis 1999). A complete list of identified predictors of respiratory sensitization w a s created (Table 2.2) b a s e d o n the results of published S A R a n a l y s e s for respiratory sensitization d e s c r i b e d below. W h i l e the p r e s e n c e of a n y n u m b e r of t h e s e predictors d o e s not g u a r a n t e e that a given s u b s t a n c e will act a s a sensitizer, they are c o m m o n l y found in known sensitizers, and thus indicate the possibility that the s u b s t a n c e could c a u s e a s t h m a . T A B L E 2.2. S t r u c t u r a l a n d c h e m i c a l predictors of respiratory s e n s i t i z a t i o n potential identified from published S A R reports. Predictor Transition m e t a l Higher molecular weight S u s c e p t i b l e to n u c l e o p h i l i c a d d i t i o n / S c h i f f b a s e formation 3D h y d r o g e n b o n d i n g 0 + N >2 reactive g r o u p s S02—OH Cl—C= C H = C — C H = C H — 2 C of f r a g m e n t C= CH—CH= C — CH= CH—C= C H — Unsaturation C=N N=N C=0 n a  aromatic C=C C=CO—OH 0=N  Oxygen-containing molecules dialdehyde resin a c i d epoxide acid anhydride ( — C O — O — C O — ) carboxyl groups ( C O — O H ) OH—C= Nitrogen-containing molecules diisocyanates (—N=C=0) reactive d y e s nucleophilic N a t o m s diamines azo compounds (—N=N—) n u c l e o p h i l i c substitution c a p a b i l i t y ethanolamine ( N — C — C — 0 ) N—CH— =N—CH= NH—C= NH—CH2— NH2—CHCO—NH— = C=N— NH—C=CH—CH=  2.3.3.2 C h e m i c a l A s t h m a H a z a r d A s s e s s m e n t P r o g r a m :  Hazassess  E a c h of the four active ingredients u s e d in high-level disinfectants—glutaraldehyde, O P A , hydrogen peroxide, a n d peracetic a c i d — w e r e a s s e s s e d using the on-line S A R program for respiratory sensitization potential (Jarvis 1999). M D L molfiles w e r e generated for e a c h of the c o m p o u n d s using the M D L ISIS/Draw 2.4 drawing package, which is available for free d o w n l o a d on the Internet (http://www.mdli.com/chime/). O n c e the molfiles w e r e g e n e r a t e d , they w e r e o p e n e d as text files, c o p i e d , and pasted directly into the Hazassess p r o g r a m . T h e program  45  then calculated a h a z a r d index between 0.00 a n d 1.00. T h e author cautions that the h a z a r d index is only a n estimate a n d cannot g u a r a n t e e that a n y given s u b s t a n c e is or is not a respiratory sensitizer; thus, the program includes a d i s c l a i m e r stating that all c h e m i c a l s s h o u l d be treated a s potentially h a z a r d o u s a n d multiple data s o u r c e s s h o u l d be c o n s u l t e d . However, the author s u g g e s t e d that any c h e m i c a l with a h a z a r d index greater than 0.7 is definite c a u s e for c o n c e r n a n d s h o u l d be further investigated (personal c o m m u n i c a t i o n , J . Jarvis, University of E d i n b u r g h , N o v e m b e r 27, 2 0 0 2 ) .  2.3.4 Results of SAR Analysis 2.3.4.1 G l u t a r a l d e h y d e A s d e s c r i b e d in s e c t i o n 2.2.3.1.2 a b o v e , glutaraldehyde is k n o w n to be a respiratory sensitizer; it c a u s e s o c c u p a t i o n a l a s t h m a without a n identified specific IgE m e c h a n i s m . B e c a u s e it is a low molecular weight agent, it most likely forms h a p t e n s with proteins in the body, which then elicit an i m m u n e r e s p o n s e . Figure 2.1 illustrates the structure of glutaraldehyde. In the t h r e e - d i m e n s i o n a l ("ball and stick") models, c a r b o n a t o m s are pictured in grey and o x y g e n a t o m s are pictured in red.  F I G U R E 2.1. Glutaraldehyde.  G l u t a r a l d e h y d e ( C H 0 ) is a linear dialdehyde; thus it h a s bifunctional reactivity a n d unsaturated c a r b o n - o x y g e n b o n d s . W i t h a molecular weight of 100.11, it is just within the lower e n d of the range of molecular weights reported by K a r o l and c o l l e a g u e s (1996) for respiratory sensitizers. 5  8  2  A s a n a l d e h y d e , glutaraldehyde is susceptible to nucleophilic addition and c a n form Schiff b a s e s by the following reaction (Patlewicz et al. 2001):  Schiff b a s e s f o r m e d from aliphatic a l d e h y d e s s u c h a s glutaraldehyde are very unstable a n d h a v e a t e n d e n c y to polymerize or react with additional a m i n o g r o u p s to form c o m p l e x products ( G e i s s m a n 1968). G l u t a r a l d e h y d e c a n thus form a variety of  46  haptens that could result in an i m m u n e r e s p o n s e . B e c a u s e it h a s two a l d e h y d e functional groups, this reaction c a n o c c u r at both sites. W h e n a molfile of glutaraldehyde w a s entered into the Hazassess program, it g e n e r a t e d a h a z a r d index of 0.8242 and the c o m m e n t "This m o l e c u l e is undoubtedly h a z a r d o u s . " T h i s a g r e e s with the known respiratory sensitization potential of glutaraldehyde, w h i c h w a s d e s c r i b e d a b o v e . 2.3.4.2 Ortho-phthalaldehyde ( O P A ) T h e structure of O P A ( C H 0 2 ) is illustrated in Figure 2.2. It h a s a m o l e c u l a r weight of 134.13, the highest of all four c h e m i c a l s being a s s e s s e d . 8  6  F I G U R E 2.2. Ortho-phthalaldehyde (OPA).  O P A , like glutaraldehyde, is a dialdehyde. It h a s c a r b o n - o x y g e n d o u b l e b o n d s a n d bifunctional reactivity. It is also s u s c e p t i b l e to nucleophilic addition to form Schiff b a s e s . Unlike the linear structure of glutaraldehyde, however, O P A h a s a b e n z e n e ring (aromatic) structure. T h e Schiff b a s e s that are f o r m e d from a r o m a t i c a l d e h y d e s tend to be more stable than those f o r m e d from aliphatic a l d e h y d e s s u c h a s glutaraldehyde. B e n z a l d e h y d e , for e x a m p l e , forms Schiff b a s e s that are stable e n o u g h to be isolated ( G e i s s m a n 1968). T h e following reaction s h o w s the Schiff b a s e formation from O P A ; note that both a l d e h y d e g r o u p s h a v e the potential to undergo this type of reaction.  T h e structure of O P A w a s entered into the Hazassess program, w h i c h g e n e r a t e d a h a z a r d index of 0.7251; "This m o l e c u l e is undoubtedly h a z a r d o u s . " T h i s lower  47  h a z a r d index than glutaraldehyde m a y be related to the i n c r e a s e d stability of the Schiff b a s e s that are f o r m e d from aromatic structures. T h e British C o l u m b i a W o r k e r s ' C o m p e n s a t i o n B o a r d a n d the industrial toxicologist quoted by the manufacturer of C i d e x OPA® raised the i s s u e of similarities in structure, a n d possibly reactivity, between O P A a n d phthalic anhydride. A l t h o u g h a n in-depth review of the reactive properties and health effects of phthalic anhydride are b e y o n d the s c o p e of this study, the structure of phthalic a n h y d r i d e w a s entered into the Hazassess program. T h e program g e n e r a t e d a h a z a r d index of 0.9984 (note that the m a x i m u m p o s s i b l e hazard index is 1.0) a n d the statement, "This m o l e c u l e is undoubtedly h a z a r d o u s , " which is consistent with the known ability of phthalic anhydride to c a u s e o c c u p a t i o n a l a s t h m a ( N e w m a n T a y l o r et al. 1987; V e n a b l e s 1989). T h e structural similarities b e t w e e n O P A a n d phthalic anhydride c a n be s e e n by c o m p a r i n g Figures 2.2 and 2.3.  FIGURE 2.3. Phthalic anhydride.  2.3.4.3 H y d r o g e n P e r o x i d e H y d r o g e n peroxide ( H 0 ) has a very simple m o l e c u l a r structure, a s c a n be s e e n from Figure 2.4. 2  2  FIGURE 2.4. Hydrogen peroxide.  T h e m o l e c u l a r weight of hydrogen peroxide, 34.02, is the lowest of the m o l e c u l e s being a s s e s s e d here. T h e only property a s s o c i a t e d with respiratory sensitization is the p r e s e n c e of two functional groups; hydrogen peroxide simply c o n s i s t s of two hydroxyl ( — O H ) g r o u p s bound together by a single o x y g e n - o x y g e n b o n d .  48  A molfile of h y d r o g e n peroxide w a s c r e a t e d a n d entered into the Hazassess program. A low h a z a r d ratio of 0.0081 w a s generated; "This is a low h a z a r d index, but it is p o s s i b l e that it m a y still b e hazardous." 2.3.4.4 P e r a c e t i c A c i d P e r a c e t i c acid ( C 2 H 4 O 3 ) , pictured in Figure 2.5, is a very small m o l e c u l e ( M W = 76.05). It is a highly unstable m o l e c u l e with two reactive sites; however, it contains only o n e of the reactive substructures identified from the literature. It contains o n e c a r b o n - o x y g e n d o u b l e bond.  FIGURE 2.5. Peracetic acid.  P e r a c e t i c acid w a s a s s e s s e d using the Hazassess program. Its h a z a r d ratio w a s c a l c u l a t e d a s 0.0261; "This is a low h a z a r d index, but it is p o s s i b l e that it m a y still be hazardous." 2.3.4.5 S A R A n a l y s i s S u m m a r y T a b l e 2.3 s u m m a r i z e s the qualitative S A R analysis. E a c h of the four s u b s t a n c e s are c o m p a r e d for their relative n u m b e r s of respiratory sensitization predictors. T h e m o r e predictors present in a molecule, the more likely it is to have sensitization potential. Glutaraldehyde, the known respiratory sensitizer, contains five of the predictors. O P A contains six p r e d i c t o r s — t h e five found in glutaraldehyde a n d the additional factor of having a n aromatic structure—indicating that it might h a v e the capacity to induce sensitization reactions. H y d r o g e n peroxide a n d peracetic a c i d e a c h h a v e o n e or two sensitization predictors, respectively.  49  T A B L E 2.3. Results of qualitative S A R . Predictor Transition metal Higher M W Susceptible to nucleophilic addition / Schiff base formation 3D hydrogen bonding 0 + N ^2 reactive groups S0 -OH Cl-C= C H = C - C H = C H — 2 C of fragment C=CH-CH=CCH=CH-C=CHUnsaturation C=N N=N C=0 C=C C=CO—OH 0=N aromatic Oxygen-containing molecules dialdehyde resin acid epoxide acid anhydride (-CO-O-CO-) carboxyl groups ( C O — O H ) OH-C= Nitrogen-containing molecules diisocyanates ( - N = C = 0 ) reactive dyes nucleophilic N atoms diamines azo compounds ( - N = N - ) nucleophilic substitution capability ethanolamine ( N - C - C - O ) N—CH— =N—CH= NH—C= NH-CH2NH2-CHCO-NH= C=NNH-C=CH-CH= 2  n a  Glutaraldehyde no 100.11 (yes) yes  OPA no 134.13 (yes) yes  Hydrogen Peroxide no 34.02 (no) no  Peracetic Acid no 76.05 (no) no  no no yes no no no  no no yes no no no  no no yes no no no  no no yes no no no  no no  no no  no no  no no  no no yes(*2) no no no no  no no yes (*2) no no no yes  no no no no no no no  no no yes no no no no  yes no no no  yes no no no  no no no no  no no no no  no no  no no  no no  no no  no no no no no no  no no no no no no  no no no no no no  no no no no no no  no no no no no no no no no  no no no no no no no no no  no no no no no no no no no  no no no no no no no no no  50  2.4 D i s c u s s i o n o f P r e d i c t e d T o x i c  2.4.1 Glutaraldehyde  Effects  Toxicity and Prediction of Respiratory  Sensitization  2.4A A G l u t a r a l d e h y d e Toxicity T h e published literature related to glutaraldehyde e x p o s u r e and its a s s o c i a t e d health effects c o n s i s t s of in vitro studies, animal toxicology, h u m a n c a s e reports, and epidemiologic studies. T h e general c o n s e n s u s of this body of work is that glutaraldehyde v a p o u r is irritating to the eyes, m u c o u s m e m b r a n e s , a n d respiratory tract and the a q u e o u s solution c a u s e s skin and eye irritation upon contact. Glutaraldehyde h a s also b e e n s h o w n to c a u s e respiratory sensitization and a s t h m a and allergic contact dermatitis in e x p o s e d persons. B e c a u s e of its sensitizing potential, local British C o l u m b i a regulations require that glutaraldehyde v a p o u r s in the w o r k p l a c e must be kept a s low as reasonably a c h i e v a b l e ( A L A R A ) ( W C B 1999a). In addition to h u m a n studies and c a s e reports, animal toxicology tests for respiratory and dermal sensitization h a v e b e e n carried out for glutaraldehyde o v e r a range of concentrations. S k i n sensitization tests have consistently b e e n positive for glutaraldehyde: the e p i c u t a n e o u s skin sensitization test in g u i n e a pigs using 2.4% glutaraldehyde ( A d v a n c e d Sterilization Products data; A p p e n d i x IV), the radioisotope a s s a y in m i c e a n d rats using 1 a n d 3% glutaraldehyde (Stern et al. 1989), the m o u s e local lymph node a s s a y using 0.25 to 5% (Hilton et al.1998) and 1 to 15% ( D e a r m a n et al. 1999) glutaraldehyde, and the g u i n e a pig maximization test using 0.4 to 0.5% glutaraldehyde ( K i e c - S w i e r c z y n s k a et al. 1998). Respiratory sensitization tests for glutaraldehyde h a v e b e e n positive for mice but not rats. G l u t a r a l d e h y d e w a s not s h o w n to act as a respiratory sensitizer in rats at a concentration of 4.4 p p m , using increased respiratory rate a s a n indicator of airways •hypersensitivity (Werley et al. 1995). Using m o u s e lymph n o d e cells, 5 to 15% glutaraldehyde stimulated T helper 2 type cytokine secretion profiles indicative of IgE antibody production and respiratory sensitization ( D e a r m a n et al. 1999). A s u m m a r y of the most relevant health and toxicology literature for glutaraldehyde, O P A , hydrogen peroxide, and peracetic acid is included in T a b l e 2.4. T a b l e 2.5 s h o w s the reported o u t c o m e s a s s o c i a t e d with concentrations of t h e s e c h e m i c a l s u s e d for high-level disinfection.  51  T A B L E 2.4. Toxicity and health effects comparison of chemicals used for high-level disinfection (superscripts refer to type or source of data). Glutaraldehyde  Hydrogen P e r o x i d e  OPA  Peracetic Acid  Occupational exposure limits: BC W C B ceiling limit = 0.25 mg/m (0.06 ppm), A L A R A A C G I H T L V ceiling limit = 0.05 ppm  No occupational exposure limits  Occupational exposure limits: BC W C B 8-h EL = 1 ppm; 15-min S T E L = 2 ppm A C G I H T L V = 1 ppm  No occupational exposure limits; internal corporate 8-h limit = 0.15 ppm  Published epidemiology, human and animal toxicology, and in vitro studies  No published human or animal epidemiology, case reports, or toxicology studies; unpublished animal and in vitro studies  Published human case reports, animal toxicology and in vitro studies  No human toxicology published in English; published animal toxicology and in vitro studies  Cytotoxic  Cytotoxic  Cytotoxic  Cytotoxic  3  1  Allergic contact dermatitis/skin sensitization  2  Allergic contact dermatitis (crystalline form)  3,4  Non-sensitizing  1  Non-sensitizing  3  6  5  Non-sensitizing Skin irritation  1  6  Skin, eye & mucous membrane irritation; non-allergic dermatitis  3,4,6  Irreversible eye irritation 6  Skin & eye irritation  Skin & eye irritation; corrosive  3  7  5  Non-irritating to skin  Non-irritating to skin; moderate eye irritant; corrosive  Dermatitis  4  4  6  Respiratory sensitization/ Occupational asthma  No known studies of respiratory sensitization  No known studies of respiratory sensitization  Respiratory irritation & aggravation of existing respiratory conditions  Respiratory irritation  No known studies of respiratory sensitization  3,4  Respiratory irritation  3,4  3,4  Respiratory irritation  4  5  Published in vitro d a t a ; Unpublished in vitro data; Published human s t u d i e s ; Published animal d a t a ; M S D S c l a i m ; Unpublished animal d a t a ; Unpublished human reports. 1  2  5  6  3  4  7  52  2 X o  o  0  Cm" N G  ro "2 P CM o  a.  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CO  Z  L  to c:  TO  c E go co E  I  o o  I  •D  £S O  T CN  C  re >_  0 CO 3  C —  CD  £  CD  c  ro — .y  u  u C U°  o re >. o QEai <>/§ -55  0)  i  C  >. o a; •-re ^ . _  c  35 .-2  CO  c  0)  to - - '  c o  o +->  5 c\i  CO o~~ N LO  X  o o % O  0 > ^ 0  I  iS 5  4_i  CO .!=  a:  A,  ^  .i= O  >..2  ° 3  o  o 5  ro E  c o  "to  D. in Brto  r:  .!=  o ro to N 0 o  *!  4-i  re  re  N  •- '-5 to c  O  « - i  CHCD ro  co ^ c ro L^.9 S ro N co  LO LO  to '—' 0 to  ro CD i CL CO 0 O l "  S  to  xz  CM  Q-O to T -  o co  to 0 TD  T3  LO  to  E>8 g o ro >> CO _Q) o 2:! v h C LO LO X. Q . tO a> £  <= "2l_  ^  . - CO c E CD co  §1  CD  'N  o o o •5. O  co 3 °  LU  CO — O •!= * * CD  CD  CD O  g o co o ro £  CD  CU to  tO  a:  4-t  X  0  C O  o  2.4.1.2 Limitations of A n i m a l M o d e l s for Predicting Respiratory Sensitization Although animal m o d e l s have been well validated for d e r m a l sensitization, they are still limited for predicting respiratory sensitization potential. G u i n e a pig m o d e l s have been most c o m m o n l y u s e d . T h e s e m o d e l s generally i n d u c e sensitization using s u b c u t a n e o u s or intradermal injection or inhalation e x p o s u r e s , followed by inhalation challenge and evaluation of antibody production or induced pulmonary reaction (Kimber, Bernstein et al. 1996). G u i n e a pig models h a v e b e e n validated for s o m e low molecular weight c h e m i c a l s , s u c h a s anhydrides a n d i s o c y a n a t e s (Kimber, Bernstein et al. 1996; P a u l u h n 1996), but not for glutaraldehyde. A rat model h a s been p r o p o s e d by P a u l u h n (1996), which u s e s inhalation induction and a s s e s s m e n t of airway inflammation, but this model has only b e e n u s e d for phenyl m o n o i s o c y a n a t e . T h e s e m o d e l s are limited in their ability to distinguish between allergic asthmatic reactions and reactive airways dysfunction s y n d r o m e ( R A D S ) , which has no immunologic aetiology. T h i s is at least in part d u e to difficulties in determining the best c h a l l e n g e d o s e , i.e., that which will induce a sensitization reaction but no irritant reaction (Pauluhn 1996). T w o murine m o d e l s for predicting respiratory sensitization h a v e also been d e v e l o p e d . T h e m o u s e IgE test m e a s u r e s the ability of respiratory allergens to stimulate total s e r u m IgE production following topical application of the allergen. T h i s test has not b e e n validated for m a n y c h e m i c a l s . Furthermore, it c a n only identify those c h e m i c a l s that induce a detectable IgE response; m a n y low molecular weight c h e m i c a l s including glutaraldehyde do not exhibit s u c h an effect. C y t o k i n e fingerprinting is a newer method that h a s also been u s e d to detect respiratory sensitization in mice. T h i s test is b a s e d on the preferential secretions of T y p e 2 cytokines s u c h as interleukins and 10 a s s o c i a t e d with IgE antibody production (Kimber, Bernstein et al. 1996; Kimber, Hilton et al. 1996; P a u l u h n 1996). G i v e n the uncertainties surrounding the immunological m e c h a n i s m s of a s t h m a c a u s e d by sensitization to m a n y low m o l e c u l a r weight c h e m i c a l s , particularly the role of IgE antibodies, all of these animal m o d e l s are a s yet limited in their ability to predict respiratory sensitization potential. Still, they c a n prove useful by identifying detectable immunological r e s p o n s e s until more a c c u r a t e endpoints or detection m e t h o d s c a n be determined (Kimber et al. 1998).  2.4.2 OPA Toxicity 2.4.2.1 P r o d u c t i o n of O P A V a p o u r T h e manufacturer claims that b e c a u s e the concentration of C i d e x OPA® solution (0.55%) and the v a p o u r p r e s s u r e of the active ingredient are very low, e x p o s u r e to the product v a p o u r will be minimal or nonexistent. T h e v a p o u r p r e s s u r e reported for solid O P A (0.0052 m m H g @ 21 °C; F e l d m a n 2001) is m u c h lower than the reported vapour p r e s s u r e of a stock (70%) solution of glutaraldehyde (17 m m H g @ 20 °C; L a d d R e s e a r c h Industries 2002), but the relationship b e t w e e n the v a p o u r p r e s s u r e of C i d e x OPA® and glutaraldehyde-based high-level disinfectants is not known. T h e difference in v a p o u r p r e s s u r e of the raw materials and the low concentration of  54  C i d e x O P A c o m p a r e d with glutaraldehyde disinfectants (0.55% vs. 2.4%) s u g g e s t s that e x p o s u r e to O P A v a p o u r will be lower than e x p o s u r e to glutaraldehyde v a p o u r under normal u s e conditions. Still, there is a significant d e g r e e of uncertainty in this conclusion. B e c a u s e airborne e x p o s u r e levels to O P A v a p o u r are e x p e c t e d to be low, the manufacturers a p p e a r to believe that the inhalation route will not present a significant health h a z a r d ( F e l d m a n 2001). T h e s e factors m a y indicate that the risk of e x p o s u r e is low, but they d o not indicate that the product is not h a z a r d o u s , particularly if it is found to act a s a sensitizer. Although there d o e s tend to be a d o s e - r e s p o n s e relationship for sensitization (Hollander et al. 1997; H e e d e r i k et al. 1999), e x p o s u r e to high levels of v a p o u r m a y not be required for sensitization a n d its a s s o c i a t e d health effects to occur. T i m e e x p o s e d to a n allergen m a y be more important than the intensity of e x p o s u r e (Gautrin et al. 2000). Furthermore, animal studies have s h o w n that dermal e x p o s u r e is c a p a b l e of inducing respiratory sensitization, a n d m a y e v e n be a more effective route of sensitization for s o m e low molecular weight c h e m i c a l s (Erjefalt & P e r s s o n 1992; Rattray et al. 1994; K i m b e r 1996). O n c e people h a v e b e e n sensitized, high e x p o s u r e intensities a r e not n e c e s s a r y to induce reactions. Glutaraldehyde, for e x a m p l e , often p r o d u c e s asthmatic reactions in sensitized people w h e n airborne e x p o s u r e s a r e below or near the limit of detection of the test method or below the o c c u p a t i o n a l e x p o s u r e limit of 0.05 p p m (Norback 1988; J a c h u c k & B o u n d 1989; G a n n o n et al. 1995; Pisaniello et al. 1997; Di S t e f a n o et al. 1998, 1999; Quirce et al. 1999). T h e possibility of e x p o s u r e to the a e r o s o l i z e d product, particularly in the event of spills, must also be c o n s i d e r e d . T h u s , if O P A is a sensitizer, low v a p o u r p r e s s u r e and/or low inhalation e x p o s u r e s will not n e c e s s a r i l y protect against sensitization. T h e unpublished in-use study of C i d e x OPA® in a hospital setting (Croll 2 0 0 1 ) c o n c l u d e d that e x p o s u r e s to O P A vapour w e r e negligible, in the range of 0.01 p p m . T h e infrared detection method u s e d in this study, however, is not the usual m e a n s of measuring a l d e h y d e vapour, a n d is less sensitive than other readily available test methods. T h e British C o l u m b i a W o r k e r s ' C o m p e n s a t i o n B o a r d ( W C B 2000), the O c c u p a t i o n a l Safety a n d Health Administration ( O S H A ) ( O S H A 1998), a n d the National Institute for O c c u p a t i o n a l Safety a n d Health ( N I O S H ) ( N I O S H 1994a) in the United States all r e c o m m e n d the u s e of high performance liquid c h r o m a t o g r a p h y ( H P L C ) with ultraviolet ( U V ) detection for quantification of glutaraldehyde. T h e limit of detection using this method is in the range of 0.004 to 0.12 p p m ( W C B 2000), m u c h lower than the detection limit for the infrared detection u s e d in the Croll study. Alternate m e t h o d s for a l d e h y d e screening, which test for the p r e s e n c e of a variety of different a l d e h y d e s in air, u s e either H P L C ( W C B 1999b) or g a s c h r o m a t o g r a p h y with a flame ionization detector, or g a s c h r o m a t o g r a p h y / m a s s spectrometry ( N I O S H 1994b) to identify the p r e s e n c e of a l d e h y d e vapour. T h e H P L C or g a s chromatography m e t h o d s would have been a m u c h more sensitive method to detect a s u b s t a n c e that is believed to be present only in low concentrations.  55  2.4.2.2 O P A Toxicity D a t a T h e toxicological data obtained for O P A w a s minimal. A l t h o u g h b a s i c oral and dermal toxicity information is useful, it is not sufficient to a s s e s s the safety of a new chemical to be introduced into the workplace. B e c a u s e of its c l o s e relationship with glutaraldehyde in structure, size, and c h e m i c a l class, the primary c o n c e r n for O P A is respiratory sensitization and the potential to c a u s e a s t h m a in e m p l o y e e s w h o may be e x p o s e d . T h e u s e solution of O P A (0.56%) w a s tested for d e r m a l irritation a n d skin sensitization and reported to be non-irritating and non-sensitizing. T h e s e s a m e tests were carried out using a solution of 2.4% glutaraldehyde, w h i c h w a s reported to be mildly to moderately irritating and sensitizing (Appendix IV). It is not known whether the manufacturer ever c o n d u c t e d tests for respiratory sensitization potential for glutaraldehyde. It w a s reported that s u c h tests w e r e not d o n e for O P A b e c a u s e sufficient v a p o u r could not be generated for any inhalation studies. At the O c t o b e r 2001 t e l e c o n f e r e n c e d i s c u s s e d previously, a representative of A d v a n c e d Sterilization P r o d u c t s mentioned a e r o s o l c h a l l e n g e s using C i d e x OPA® solution, but no details w e r e available about what w a s done. T h u s , the results of predictive tests for the respiratory sensitization potential of O P A and glutaraldehyde cannot be compared. T h e O P A raw material c a n act as a potential dermal sensitizer (J.T. B a k e r 1999; A S P , unpublished report, M a y 9, 2002). T h e crystalline form of O P A h a s not been tested for respiratory sensitization potential as no method h a s b e e n identified by the manufacturer to m e a s u r e the v a p o u r ( A S P , unpublished report, M a y 9, 2002). A c c o r d i n g to a n o c c u p a t i o n a l physician at the British C o l u m b i a W o r k e r s ' C o m p e n s a t i o n B o a r d , toxicology a s s e s s m e n t s are generally performed using parent c o m p o u n d s rather than dilute solutions (personal c o m m u n i c a t i o n , S. M a h , occupational physician, W C B , O c t o b e r 2 1 , 2001). T h i s implies that if the O P A raw material c a n induce dermal sensitization, O P A in solution probably h a s the potential to be a dermal sensitizer and possibly a respiratory sensitizer. B e c a u s e there h a v e b e e n no studies published about potential health impacts of O P A e x p o s u r e in crystalline or a q u e o u s form, it is difficult to evaluate its toxicity relative to glutaraldehyde. G i v e n that crystalline O P A h a s the potential to c a u s e dermal sensitization reactions, it is essential that studies be c o n d u c t e d to evaluate any potential sensitization h a z a r d s from e x p o s u r e to O P A in solution. A n y c h e m i c a l introduced into a n o c c u p a t i o n a l setting without existing e x p o s u r e - r e s p o n s e data n e e d s to be a s s e s s e d , a n d this is particularly true w h e n there is a possibility that the s u b s t a n c e could be a sensitizer and thus an A L A R A s u b s t a n c e . 2.4.2.3 Structure-Activity Relationships for O P A T a b l e 2.6 s u m m a r i z e s the structure-activity relationship ( S A R ) results presented earlier in T a b l e 2.3, p a g e 4 9 . T o facilitate c o m p a r i s o n of the c h e m i c a l s , only those  56  predictors present in at least o n e of the c h e m i c a l s of interest are s h o w n here. T h e qualitative S A R a n a l y s i s allowed a c o m p a r i s o n of the structural c o m p o n e n t s of highlevel disinfectant active ingredients, with particular attention to t h o s e c o m p o n e n t s that are c o m m o n l y a s s o c i a t e d with respiratory sensitizers or a s t h m a - c a u s i n g agents. T A B L E 2.6. Summary of qualitative S A R results. Predictor Higher MW Susceptible to nucleophilic addition / Schiff base formation >2 reactive groups C=0 aromatic dialdehyde TOTAL  Glutaraldehyde 100.11 (yes)  OPA 134.13 (yes)  Hydrogen Peroxide 34.02 (no)  Peracetic 76.05 (no)  yes  yes  no  no  yes y e s (*2) no yes 5  yes yes(*2) yes yes 6  yes no no no 1  yes yes no no 2  Acid-V ,  O P A contains e v e r y predictor found in glutaraldehyde, a c h e m i c a l known to c a u s e asthma, a s well a s o n e additional predictor. W h i l e it c a n n o t be c o n c l u d e d from this that e x p o s u r e to O P A will result in respiratory sensitization, it d o e s indicate that O P A m a y have the potential to act in this manner. Further study into the sensitization potential of O P A from both dermal and inhalation e x p o s u r e is definitely warranted. If O P A is found to act a s a sensitizer, respiratory sensitization might still be induced by dermal e x p o s u r e or by e x p o s u r e to the aerosol during spills, e v e n if O P A v a p o u r is not detected in m e a s u r a b l e quantities during use of the C i d e x OPA® product. C o m p a r i s o n s b e t w e e n O P A a n d glutaraldehyde d i s c u s s e d thus far indicate that O P A could act a s a respiratory sensitizer. T h e similarities b e t w e e n O P A a n d phthalic anhydride e x p r e s s e d by the industrial toxicologist from A d v a n c e d Sterilization P r o d u c t s a d d s a n interesting element to the S A R analysis. O P A s h a r e s s e v e r a l structural a n d reactive c o m p o n e n t s with phthalic anhydride, a k n o w n respiratory sensitizer ( N e w m a n T a y l o r et al. 1987; V e n a b l e s 1989), thus giving additional weight to the possibility that O P A could also act a s a sensitizer. O n e important factor that S A R d o e s not take into a c c o u n t is the potential effect of c o m b i n e d e x p o s u r e s . It m a y be possible for a c o m p o u n d s u c h a s O P A to react synergistically with other allergens, resulting in a stronger effect or o n e that would not otherwise be present. Furthermore, S A R d o e s not take into a c c o u n t the impact that previous sensitization to other a l d e h y d e s might h a v e on the ability of O P A to induce sensitization reactions. T h e results of this S A R a n a l y s i s s u g g e s t that O P A , a n d therefore the high-level disinfection product C i d e x OPA®, could potentially c a u s e a s t h m a . A l t h o u g h no reports have b e e n published a s of this time, there have b e e n reports of occupational a s t h m a linked to O P A . T h r e e c a s e s of a s t h m a c a u s e d by C i d e x OPA® h a v e b e e n reported to the United S t a t e s National Institute of O c c u p a t i o n a l Health and Safety  57  ( N I O S H ) through the Sentinel Event Notification S y s t e m for O c c u p a t i o n a l R i s k s ( S E N S O R ) (personal c o m m u n i c a t i o n , M. Filios, S E N S O R T e c h n i c a l Advisor, A s t h m a and Silicosis, N I O S H , February 6, 2003). T h e S E N S O R program collects occupational a s t h m a data from four A m e r i c a n states (Michigan, M a s s a c h u s e t t s , California, and N e w J e r s e y ) . B e t w e e n 1999 w h e n the product first b e c a m e available and N o v e m b e r 2 0 0 1 , no reports of a s t h m a attributed to O P A w e r e reported (personal c o m m u n i c a t i o n , M. Filios, N o v e m b e r 8, 2002). B e t w e e n N o v e m b e r 2001 and February 2 0 0 3 , o n e definite c a s e and two probable c a s e s h a v e b e e n identified. T h e probable c a s e s are c o n s i d e r e d a s s u c h b e c a u s e there is a s yet no specific e x p o s u r e c o d e for O P A or C i d e x OPA® in the A s s o c i a t i o n of O c c u p a t i o n a l and Environmental C l i n i c s e x p o s u r e c o d e s y s t e m u s e d by S E N S O R . T h e two probable c a s e s were believed to be a s s o c i a t e d with O P A by the reporting states; the definite c a s e included specific references to the product in the S E N S O R report. In British C o l u m b i a , no c a s e s of a s t h m a or other health problems c a u s e d by O P A have been identified. O u t s i d e of British C o l u m b i a , there have b e e n isolated reports of respiratory irritation in hospitals w h e r e C i d e x OPA® w a s being u s e d in poorly ventilated a r e a s (personal communication, L. D e G u s s e m e , B C W C B , M a r c h 10, 2003). 2.4.2.4 Tier A p p r o a c h to Predicting Respiratory Sensitization Potential of O P A Sarlo and Clark (1992) outlined a four-tiered a p p r o a c h to evaluating low molecular weight c h e m i c a l s with u n k n o w n respiratory sensitization potential. T h e first tier is evaluation of structure-activity relationships, the s e c o n d is a n in vitro test to determine w h e t h e r the c h e m i c a l c a n conjugate with protein (guinea pig s e r u m albumin), the third is a n evaluation of dermal and respiratory sensitization by the guinea pig injection m o d e l , and finally a g u i n e a pig inhalation test for respiratory sensitization. B a s e d on the results of the qualitative S A R and the Hazassess hazard index, which is b a s e d on a c o m p l e x quantitative structure-activity m o d e l , O P A would be positive in the first level a s s e s s m e n t . It would thus be useful to evaluate the r e s p o n s e of O P A in the next level and use this tier a p p r o a c h to guide further predictive testing for respiratory sensitization.  2.4.3 Peracetic Acid and Hydrogen  Peroxide  T h e toxicity data available for C o m p l i a n c e ™ indicates that the product is highly corrosive and irritating to the e y e s . T h e M S D S (Appendix X V I ) states that the product is a mild inhalation irritant, a serious eye irritant, a n d a mild to moderate skin irritant. B a s e d on the test reports provided, it d o e s not a p p e a r to be a dermal sensitizer. Although the only studies related to hydrogen peroxide e x p o s u r e in h u m a n s are retrospective reviews of skin test results and c a s e reports of poisonings and other accidental e x p o s u r e s , the potential health effects of using a hydrogen peroxideb a s e d disinfectant are r e a s o n a b l y well understood. H y d r o g e n peroxide solutions  58  have b e e n widely u s e d for a variety of functions in the h o m e a n d in industry for over 100 years (Hugo 1991). T h e health effects a p p e a r to be limited to its irritancy potential or to direct toxicity a s s o c i a t e d with ingestion (the latter is not a likely route of e x p o s u r e to high-level disinfectants in an occupational setting). N o e v i d e n c e of sensitization or other s e v e r e or life threatening effects h a s b e e n reported from w i d e s p r e a d historical u s e of hydrogen peroxide solutions. B e c a u s e of its highly irritating nature, however, it is essential to prevent skin contact with disinfectants containing relatively high concentrations of hydrogen peroxide. T h e potential health impacts of e x p o s u r e to peracetic acid, w h i c h is found in solution with hydrogen peroxide, are less well understood. P e r a c e t i c acid d o e s h a v e a corrosive, irritating effect o n skin, m u c o u s m e m b r a n e s , a n d the respiratory tract. T h e r e are no published studies examining the effect of peracetic acid and its v a p o u r on people, although the few unpublished reports available s u g g e s t that it c a u s e s slight skin, e y e irritation, respiratory irritation. Peracetic acid h a s b e e n u s e d for disinfection prior to the introduction of C o m p l i a n c e ™ . T h e peracetic acid product Renalin® (Minntech Corp., Minneapolis, M N ) h a s b e e n u s e d since 1983 for the disinfection of renal dialysis equipment, and there h a v e b e e n no published reports of a d v e r s e effects a s s o c i a t e d with its u s e . T h e S t e r i s ™ S y s t e m is a sterile p r o c e s s i n g s y s t e m that u s e s single-use cartridges containing 3 5 % peroxyacetic acid, which is diluted during the cycle to 0.2% peracetic acid, for sterilization of medical instruments. S t e r i s ™ h a s b e e n used since 1990 ( S G N A 2000), again with no published reports of a d v e r s e health o u t c o m e s . A l t h o u g h the lack of reports s u g g e s t s that peracetic acid disinfectants may not be a s s o c i a t e d with occupational health problems, a study to e x a m i n e any e x p o s u r e - r e s p o n s e relationships a s s o c i a t e d with this c h e m i c a l , particularly dermal or respiratory irritation, w o u l d be useful. T h e active ingredients u s e d in C o m p l i a n c e ™ have b e e n u s e d in solution for m a n y years without reports of d e r m a l or respiratory sensitization. In addition, the results of the S A R a n a l y s i s reported a b o v e do not indicate that the active ingredients hydrogen peroxide and peracetic acid are likely to act a s sensitizers. T h i s a d d s weight to the c o n c l u s i o n s in the toxicity test reports that C o m p l i a n c e ™ is n o n sensitizing. Unlike C i d e x OPA®, there is no e v i d e n c e available at this time to suggest that sensitization might be a c o n c e r n for C o m p l i a n c e ™ . It is essential, however, to prevent skin and eye contact with this product.  59  CHAPTER 3. Assessing High-Level Disinfection Practices in the Healthcare Industry 3.1 Current Practices Survey Objectives T h e overall goal of this survey w a s to e x a m i n e practices related to high-level disinfection in acute c a r e hospitals. T h e survey w a s not d e s i g n e d to test any preformed h y p o t h e s e s ; rather, it w a s an exploratory s u r v e y intended to gather descriptive information about the u s e of high-level disinfectants in British C o l u m b i a hospitals. It w a s d e s i g n e d to a n s w e r the following questions: (1) W h a t products are currently u s e d for high-level disinfection? (2) W h e r e in the hospital is high-level disinfection d o n e ? (3) W h a t quantities of high-level disinfection products are u s e d ? (4) H o w m a n y e m p l o y e e s are potentially e x p o s e d to high-level disinfection products? (5) W h a t plans are currently in place to substitute other high-level disinfectants for glutaraldehyde? (6) W h y d o hospitals introduce glutaraldehyde alternatives? (7) W h i c h glutaraldehyde alternatives are currently in u s e ? (8) W h o m a k e s d e c i s i o n s regarding high-level disinfection u s e ? (9) H o w are d e c i s i o n s m a d e regarding which high-level disinfection product to c h o o s e ? T h e current practices survey w a s initially planned to provide preliminary descriptive information about current practices related to high-level disinfection in hospitals as part of the planning s t a g e s for a s u b s e q u e n t epidemiologic study of the potential health effects of O P A a m o n g hospital workers. This study w a s o n e of a group of projects related to e m p l o y e e health in the healthcare industry being m a n a g e d under the umbrella of the O c c u p a t i o n a l Health and Safety A g e n c y for Healthcare in British C o l u m b i a ( O H S A H ) . A n advisory committee consisting of U B C researchers, representatives from O H S A H and the W o r k e r s ' C o m p e n s a t i o n B o a r d , as well as union and industry s t a k e h o l d e r s w a s involved in the d e v e l o p m e n t of the project. W h e n it b e c a m e apparent to the committee that descriptive information about highlevel disinfectant u s e w a s difficult to obtain, the survey grew into a more c o m p r e h e n s i v e a n d t i m e - c o n s u m i n g task.  60  3.2 Current P r a c t i c e s Survey Methods 3.2.1 Preliminary  Notices  Prior to c o m m e n c i n g the survey, a n information letter (Appendix XVII) w a s sent to the Chief E x e c u t i v e Officer of all R e g i o n a l Health B o a r d s , C o m m u n i t y Health Councils, C o m m u n i t y Health S e r v i c e Societies, and applicable healthcare unions in British C o l u m b i a . C o n t a c t information for the recipients of this letter w a s obtained from the British C o l u m b i a Ministry of Health S e r v i c e s a n d from union websites. T h e letter included information about w h o w a s funding and c o n d u c t i n g the project and about the c o m m u n i t y s t a k e h o l d e r s involved. A brief overview of the p r o p o s e d project w a s provided, a s well a s the purpose, the a p p r o a c h the e p i d e m i o l o g i c study would take, and the potential benefits of the project. T h e letter also included contact information for t h o s e wishing to obtain further details. It w a s printed on O H S A H / U B C letterhead, and w a s mailed July 23, 2 0 0 1 . N o n e of the individuals to w h o m letters were sent objected to the survey being c o n d u c t e d in the hospitals under their jurisdiction.  3.2.2 Database  Development  After c o n v e r s a t i o n s with the project stakeholders, it w a s d e c i d e d that the survey would be directed to the occupational health and safety professional at every acute care hospital a n d healthcare centre in British C o l u m b i a . T h e o c c u p a t i o n a l health and safety professionals w e r e c h o s e n as the recipients of the questionnaire b e c a u s e they w e r e e x p e c t e d to k n o w what c h e m i c a l s are u s e d throughout the hospital; they were also e x p e c t e d to know how to obtain any additional relevant information. T h e r e w a s no existing d a t a b a s e of hospital occupational health and safety professionals available from O H S A H or the British C o l u m b i a Ministry of Health S e r v i c e s . A list with the n a m e s and phone numbers of 121 "acute care" hospitals in British C o l u m b i a w a s obtained from O H S A H and u s e d for original contact information. A c o m p r e h e n s i v e d a t a b a s e of occupational health and safety personnel w a s d e v e l o p e d by telephoning the switchboard at e a c h acute c a r e hospital and requesting the n a m e and title of the person responsible for o c c u p a t i o n a l health and safety in that hospital. W h e r e there w a s no staff person d e d i c a t e d to maintaining e m p l o y e e health and safety, the n a m e and title of the person responsible for highlevel disinfection w a s requested. W h e r e neither w a s available or known, the hospital administrator or C h i e f E x e c u t i v e Officer w a s u s e d as the contact for the survey.  3.2.3 Questionnaire  Development  T h e questionnaire w a s d e v e l o p e d b a s e d on a literature review of high-level disinfection c o n d u c t e d in spring and s u m m e r 2 0 0 1 , d i s c u s s i o n s with project stakeholders in M a y 2 0 0 1 , and key informant interviews with e m p l o y e e s w h o u s e d  61  high-level disinfectants in J u n e 2 0 0 1 . T h e key informant interviews w e r e intended to gather detailed practical information about high-level disinfection u s e to assist in the d e v e l o p m e n t of a useful survey tool. Referrals from O H S A H a n d cold calling of local hospitals w e r e u s e d to contact a c o n v e n i e n c e s a m p l e of o c c u p a t i o n a l health and safety p e r s o n n e l from St. Paul's, R o y a l C o l u m b i a n , Burnaby, a n d E a g l e R i d g e hospitals. T h e s e individuals arranged for site tours in hospital a r e a s that u s e d highlevel disinfection a n d meetings with e m p l o y e e s directly involved with high-level disinfection in the following departments: cardiology (Royal C o l u m b i a n ) , e n d o s c o p y (Royal C o l u m b i a n a n d St. Paul's), ear, n o s e and throat (St. Paul's), sterile processing (Royal C o l u m b i a n ) , and medical imaging (Royal C o l u m b i a n and E a g l e Ridge). Other meetings with personnel from sterile p r o c e s s i n g a n d e n d o s c o p y at University of British C o l u m b i a and V a n c o u v e r G e n e r a l Hospitals w e r e arranged by calling the departments directly. T h e s e visits, which included a variety of different s i z e d hospitals, w e r e u s e d to b e c o m e more familiar with the practices related to high-level disinfection. T h e y helped determine which products and brands are c o m m o n l y u s e d , w h i c h departments are most likely to carry out high-level disinfection procedures, what types of equipment, e.g., s o a k e r boats, automatic w a s h e r s , etc., m a y be u s e d , and how frequently c h e m i c a l solutions m a y be c h a n g e d or refilled. T h i s information w a s then utilized to inform the questionnaire development. T h e questionnaire w a s a c c o m p a n i e d by a cover letter (Appendix XVIII) that provided information about the p u r p o s e of the overall study, information about w h o to contact for further information, and statements ensuring that participation w a s voluntary and all information would be kept confidential. Recipients w e r e informed that they may be contacted again and a s k e d to participate further. T h e 11-page questionnaire (Appendix XIX) w a s d e s i g n e d to be e a s y to read and simple to c o m p l e t e in a short period of time. It w a s h o p e d that by minimizing the requirements of the person completing the questionnaire, the r e s p o n s e rate would be m a x i m i z e d . T h e cover p a g e of the questionnaire included an O H S A H identification number, the n a m e of the hospital, and the n a m e and contact information of the person to w h o m it w a s mailed. T h e r e w a s s p a c e provided for n a m e , job title, and contact information if s o m e o n e other than the person to w h o m it w a s mailed c o m p l e t e d the questionnaire. T h e first section of the questionnaire included a definition of high-level disinfection and questions about high-level disinfection products currently u s e d in the hospital. T h e r e w a s a p a g e for e a c h department likely to u s e high-level disinfection and a page on which r e s p o n d e n t s could add additional d e p a r t m e n t s not included in the original questionnaire that w e r e also using high-level disinfection. W h e n a department included on the questionnaire did not exist within that hospital, the respondent w a s instructed to leave the p a g e blank. T h e q u e s t i o n s included in this section gathered information about (1) whether high-level disinfection w a s u s e d in e a c h department, (2) what high-level disinfection products (main ingredient, brand  62  name, and formulation) w e r e u s e d in e a c h department, (3) h o w m a n y p i e c e s of equipment w e r e c l e a n e d with e a c h product per month, and (4) what v o l u m e of e a c h product w a s u s e d per month. T h e s e c o n d section of the questionnaire applied to hospitals currently using glutaraldehyde for high-level disinfection. It included q u e s t i o n s about whether there were any plans to introduce a different high-level disinfection c h e m i c a l a n y w h e r e in the hospital. If there were plans to introduce a new product, the hospital w a s a s k e d (1) what product, (2) in w h i c h department(s), (3) w h y the c h a n g e w a s being considered, and (4) w h e n the c h a n g e w a s e x p e c t e d to occur. T h i s section also questioned whether a glutaraldehyde alternative had ever b e e n tried or c o n s i d e r e d in the past. If it had, r e s p o n d e n t s were a s k e d (1) which product w a s tried, (2) in which department(s) it w a s tried, and (3) why it w a s not introduced or w h y w a s it discontinued. T h e third section of the questionnaire w a s directed toward hospitals that had already introduced o n e of the new glutaraldehyde alternatives. T h i s section gathered the following information: (1) how long the alternative had b e e n in use, (2) what highlevel disinfection c h e m i c a l s had b e e n u s e d previously, (3) w h y a glutaraldehyde alternative had b e e n introduced, (4) whether the hospital planned to continue using the glutaraldehyde alternative, and (5) r e a s o n s for continuing or discontinuing the alternative product. R e s p o n d e n t s w e r e also given an opportunity to provide any additional information they felt might be relevant to the i s s u e of high-level disinfection and glutaraldehyde alternatives.  3.2.4 Survey Implementation and Follow-up T h e original set of 121 questionnaires w a s mailed on S e p t e m b e r 5, 2 0 0 1 . T e l e p h o n e follow-up c o m m e n c e d S e p t e m b e r 19, two w e e k s after the initial mail out. T h e s e calls were u s e d to remind people to complete and return the questionnaire and to a n s w e r any questions people m a y h a v e h a d . All hospitals w e r e contacted by telephone, even if the s u r v e y s w e r e returned without telephone prompting, b e c a u s e additional information not included in the original survey w a s gathered by t e l e p h o n e query (Appendix X X ) . T h e s e additional questions were d e s i g n e d to minimize s o m e of the limitations identified in the original questionnaire. B e c a u s e of difficulties identifying knowledgeable p e r s o n n e l within the hospitals and with obtaining the descriptive information included in the mailed survey, it b e c a m e apparent that the survey n e e d e d to be more in-depth than initially planned. T h e advisory committee a g r e e d that all hospitals s h o u l d be contacted to a n s w e r t h e s e additional questions. Hospital personnel w e r e a s k e d to clarify w h y p a g e s may have b e e n left blank in the first section, i.e., w a s the information not known or w a s a given department not present in the hospital? T h e y w e r e also a s k e d about the n u m b e r of e m p l o y e e s working in departments using high-level disinfection. W h e r e glutaraldehyde alternatives had been introduced, hospitals w e r e a s k e d how that specific alternative had b e e n c h o s e n and w h o w a s involved in the decision to introduce the new product. T h e  63  telephone follow-up w a s a l s o u s e d to clarify ambiguities in c o m p l e t e d questionnaires and to fill in the blanks w h e n questionnaires w e r e not fully c o m p l e t e d . In s o m e c a s e s , the entire questionnaire w a s completed o v e r the t e l e p h o n e . A survey r e s p o n s e goal w a s set at 60%. It w a s d e c i d e d that the s u r v e y a n d telephone follow-up w o u l d continue until a minimum overall r e s p o n s e rate of 6 0 % and a m i n i m u m r e s p o n s e of 6 0 % from e a c h health authority a n d hospital size category (described below) h a d been a c h i e v e d . B e c a u s e of difficulties finding people with sufficient k n o w l e d g e about high-level disinfectant u s e to fill out the questionnaire, this goal w a s not met until April 5, 2002, at w h i c h point the telephone follow-up c e a s e d .  3.2.5 Data Management and Analysis T h e initial d a t a b a s e s a n d additional site information obtained from t e l e p h o n e conversations w e r e created using the Microsoft E x c e l version W i n d o w s 9 8 . S u b s e q u e n t data m a n a g e m e n t a n d a n a l y s e s were c o n d u c t e d using the S A S S y s t e m for W i n d o w s , version 8.01 ( S A S Institute, Cary, N C ) . S u r v e y s w e r e c o d e d a n d e a c h variable w a s a s s i g n e d a unique n a m e consisting of eight o r fewer characters a s required by the S A S program. 3.2.5.1 Hospital Characteristics B e c a u s e O H S A H identification n u m b e r s were only available for s o m e hospitals, e a c h site w a s chronologically a s s i g n e d a unique 3-digit 'hospital ID' c o d e . E a c h hospital in the data set w a s a s s i g n e d to o n e of the six provincial health authorities: Northern, Interior, V a n c o u v e r Island, V a n c o u v e r C o a s t a l , Fraser, or Provincial Health S e r v i c e s . Hospitals run by the P r o v i d e n c e Health C a r e S o c i e t y are not included in a n y of the provincial health authorities, s o P r o v i d e n c e Health C a r e Society w a s a d d e d a s a s e v e n t h category. Information about the n u m b e r of acute care patients ( c a s e s ) for the fiscal year 2000/2001 w a s obtained from the British C o l u m b i a Ministry of Health S e r v i c e s . This w a s u s e d a s a n indicator of 'hospital size.' A c a s e w a s defined a s "one a d m i s s i o n for a given diagnosis/procedure/hospitalization at a given point in time for a given individual" (personal communication, D. Brar, B C Ministry of Health S e r v i c e s , April 30, 2002). B a s e d o n the n u m b e r of acute care c a s e s per year, the hospitals were divided into three broad size categories (Table 3.1). T A B L E 3.1. Hospital size categories. Cases per Year < 1000 1000-4999 > 5000  Hospital Size Category small medium large  64  T h e v a l u e s for determining size category w e r e d e s i g n e d to give a relatively equal distribution of hospitals b e t w e e n the categories. Different cut-off points w e r e tried, e.g., 10,000 or more c a s e s for large size hospitals, but there w o u l d h a v e b e e n very few hospitals in s o m e categories. Hospital municipalities w e r e m a t c h e d with 1 9 9 6 - 2 0 0 0 population data from the Population S e c t i o n of the BC Stats w e b site (http://www.bcstats.gov.bc.ca/data/pop/popstart.htm) and with the Statistics C a n a d a 2001 c e n s u s (Statistics C a n a d a 2001). 'Municipality s i z e ' w a s divided into three categories b a s e d o n population (Table 3.2). T A B L E 3.2. Municipality size categories. Population <2500 2500-19,999 > 20,000  Municipality Size Category. ; rural town urban  T h e size c a t e g o r i e s u s e d here w e r e b a s e d on the B e a l e c o d e s u s e d by Statistics C a n a d a (Statistics C a n a d a 2002). Statistics C a n a d a defines rural a r e a s a s having a population of less than 2 5 0 0 . A r e a s with a population of 2 5 0 0 to 19,999 are considered less u r b a n i z e d small towns. A r e a s with a population of 20,000 or greater are c o n s i d e r e d cities. Three municipalities w e r e placed into the urban category despite having a population of l e s s than 20,000. T h e s e suburban towns, A b b o t s f o r d (population 6825), W h i t e R o c k (population 17,371), and S a a n i c h t o n (population 15,348), are in c l o s e proximity to major urban a r e a s , and thus w e r e expected to h a v e characteristics similar to urban centres. Data from the H e a l t h c a r e Benefit Trust (October 15, 1999 data) w e r e u s e d to estimate the n u m b e r of ' e m p l o y e e s ' working in e a c h of the s u r v e y hospitals. T h i s d a t a b a s e includes only those e m p l o y e e s w h o receive benefits through the Trust, i.e., full time e m p l o y e e s and those working more than 2 5 hours per w e e k . Part time or contract e m p l o y e e s are not represented in t h e s e n u m b e r s . Total e m p l o y e e numbers m a y be therefore underestimated, but the data are sufficient to c o m p a r e hospitals and obtain a general idea of the n u m b e r of people e m p l o y e d in e a c h hospital. A variable w a s a l s o created for 'occupational health staff ( O H S ) availability.' T h e p r e s e n c e of o c c u p a t i o n a l health and safety staff in the survey hospitals w a s determined from the initial telephone conversations u s e d to d e v e l o p the d a t a b a s e of survey contacts. During t h e s e calls, e a c h hospital w a s a s k e d for the person responsible for o c c u p a t i o n a l health and safety. It w a s noted at that time whether there w a s s o m e o n e working within the hospital, whether a regional staff m e m b e r or  65  personnel from another hospital w a s responsible, or w h e t h e r the hospital did not have a c c e s s to a d e d i c a t e d occupational health and safety e m p l o y e e . Descriptive information w a s c o m p i l e d using the P R O C M E A N S , P R O C M E A N S M E D I A N , P R O C F R E Q , and P R O C P R I N T functions in S A S . 3.2.5.2 Exploratory Statistical A n a l y s i s A s d i s c u s s e d a b o v e , this questionnaire w a s intended to be u s e d to gather basic descriptive information about high-level disinfectant u s e in the province s o that sites could be c h o s e n for a n in-depth epidemiologic e x p o s u r e - r e s p o n s e study; there were no plans to conduct statistical a n a l y s e s of the results and no specific h y p o t h e s e s were identified in a d v a n c e . W h e n it b e c a m e apparent, however, that the survey w a s more c o m p r e h e n s i v e and the information being collected w a s more valuable, i.e., as an end rather than just a s a m e a n s to an end, than initially p l a n n e d , the study t e a m d e c i d e d to a d d another objective to this part of the project. T h e post hoc hypothesis w a s that there might be differences a m o n g British C o l u m b i a hospitals with respect to the decision to u s e alternatives. It w a s therefore decided to explore what factors might have contributed to t h e s e differences, if any. T o this e n d , statistical a n a l y s e s w e r e carried out to e x a m i n e t h e s e differences and to explore any relationships that might exist between the u s e of alternatives and potential explanatory factors. T h e reader should be a w a r e that t h e s e a n a l y s e s were exploratory in nature and not hypothesis-testing. C o m p a r i s o n s of proportions a c r o s s categories were carried out using chi-square tests ( P R O C F R E Q / C H I S Q ) . Univariate and multivariable logistic regression modelling w a s c o n d u c t e d to explore what factors might be a s s o c i a t e d with the u s e of glutaraldehyde alternatives. F o r these models, the u s e of s u c h alternatives w a s defined a s any u s e of O P A - or hydrogen peroxide/peracetic a c i d - b a s e d products for high-level disinfection in the hospital, whether or not glutaraldehyde w a s still in use as well. All logistic r e g r e s s i o n a n a l y s e s were performed using the P R O C L O G I S T I C D E S C E N D I N G function in S A S . Logistic regression is u s e d to find relationships between independent variables w h e r e the possible o u t c o m e s for the d e p e n d e n t variable (y) are y e s (1) or no (0); the independent variables (x) c a n be continuous or dichotomous. Logistic regression analysis calculates a n o d d s ratio ( O R ) a s the m e a s u r e of c h a n c e . T h e c o n c e p t of o d d s ratio c a n be defined by the following equations:  66  Odds =  # u s i n g a l t e r n a t i v e s , with factor x  =  rj^  # not u s i n g a l t e r n a t i v e s , with factor x OR =  O d d s of h a v i n g the factor O d d s of not h a v i n g the factor  1 - p  , y  (v=1) (y=0)  = (# u s i n g a l t e r n a t i v e s , with factor Xi) / (# not u s i n g a l t e r n a t i v e s , with factor Xi) (# u s i n g a l t e r n a t i v e s , with factor x ) / (# not u s i n g a l t e r n a t i v e s , with f a c t o r x ) 2  2  T h e logistic m o d e l follows the form:  CU (Py/1 - P y ) = (30 + (PlXO + (P X ) + 2  + (P iXi),  2  or [In (p(y)/1 - p(y))] _  e  g  a  +  e  (b)1(x)1  +  e  (b)2(x)2  +  +  e  (b)i(x)i  where p or a is the intercept; Pi or b is the slope. 0  Solving this equation, it c a n be s h o w n that, for e a c h independent variable in the model, ' e is e q u a l to the o d d s ratio for the c o m p a r i s o n of the effect of a one unit increase of Xi on the d e p e n d e n t variable, given that all other variables remain constant, i.e., the effect of Xi adjusted for the effects of the other variables. In the c a s e of a d i c h o t o m o u s independent variable, c o d e d '0/1,' this o n e unit increase reflects the o d d s ratio for the "effect" of the factor on the o u t c o m e . (b>1,  A list of candidate variables, or possible factors that could be a s s o c i a t e d with the use of alternatives, w a s c o m p i l e d (Table 3.3). T A B L E 3.3. C a n d i d a t e v a r i a b l e s for logistic r e g r e s s i o n . Variable • Hospital s i z e (3 c a t e g o r i e s ) Municipality s i z e (3 c a t e g o r i e s ) H e a l t h authority (7 c a t e g o r i e s ) O H S availability (3 c a t e g o r i e s ) E x i s t e n c e of c o m m o n H L D d e p a r t m e n t s : o p e r a t i n g r o o m , sterile p r o c e s s i n g , g a s t r o e n t e r o l o g y , u l t r a s o u n d D e p a r t m e n t i n v o l v e d in H L D d e c i s i o n s (7 c a t e g o r i e s ) ;  ;  C h i - s q u a r e and correlation a n a l y s e s were u s e d to find any a s s o c i a t i o n s a m o n g the candidate variables. W h e n two variables were found to be highly a s s o c i a t e d (p < 0.01), only o n e of the pair w a s included in the multivariable regression models. T h e d e c i s i o n about w h i c h variable to include w a s b a s e d o n the r e l e v a n c e of that variable to the issue. C h i - s q u a r e analysis w a s u s e d for variable selection rather than P e a r s o n correlations in most c a s e s b e c a u s e of the categorical nature of the independent variables.  67  " D u m m y variables" w e r e created for e a c h of the candidate v a r i a b l e s s o that univariate logistic m o d e l s could be calculated for e a c h p o s s i b l e category within a given variable. F o r e x a m p l e , categories for hospital s i z e could be 'small,' 'medium,' or 'large.' T h e effect of being a 'small hospital' w a s c o m p a r e d to the effect of not being a 'small hospital,' i.e., being a 'medium hospital' or 'large hospital.' V a r i a b l e categories w e r e then g r o u p e d s o that the effect a s s o c i a t e d with a given category could be estimated, a s s u m i n g the effect a s s o c i a t e d with all other p o s s i b l e categories w a s equal. F o r e x a m p l e , the effect of being a 'small hospital' w a s c o m p a r e d with the effect of being a ' m e d i u m hospital,' taking the effect of being a 'large hospital' into account. W h e n s e v e r a l categories for a given variable w e r e put into a m o d e l , the "default" category that w a s left out of the model for c o m p a r i s o n w a s the category with the largest n u m b e r of r e s p o n s e s . Univariate logistic r e g r e s s i o n m o d e l s w e r e a n a l y z e d for the relationship between the o u t c o m e and e a c h of the independent variables. F o r multivariable a n a l y s e s , any variable that w a s a s s o c i a t e d with the o u t c o m e at the level of p < 0.10 or with an o d d s ratio greater than 2.0 or less than 0.5 w a s retained for testing in the multivariable m o d e l . F o r the final multivariable regression m o d e l , variables were retained if they met t h e s e s a m e criteria for o d d s ratio and/or p-value.  68  3.3 Current Practices Survey Results From the original list of 121 "acute care" hospitals, 26 w e r e later found not to be acute c a r e hospitals and w e r e r e m o v e d from the data set. T h i s information w a s gathered from questionnaires returned with the c o m m e n t that the site w a s not acute care and from t e l e p h o n e conversations with contacts at the hospitals, w h o informed us that the centre w a s not an acute care site. T h e s e sites w e r e determined to be long-term c a r e centres, diagnostic and treatment centres, clinics, rehabilitation centres, or c o m m u n i t y health centres. T h e remaining eligible data set w a s c o m p r i s e d of 9 5 acute c a r e centres to which questionnaires w e r e mailed.  3.3.1 Survey Response and Hospital  Characteristics  Of the 95 acute c a r e centres that received surveys, a total of 64 r e s p o n s e s (67%) were received by April 2 0 0 2 . R e s p o n s e rates by hospital size, municipality size, health authority, and occupational health staff availability c a t e g o r i e s are s h o w n in T a b l e 3.4. T h e r e w e r e no important differences in the participation rates for hospital size, municipality size, or occupational health staff availability. All three hospitals in the Provincial Health S e r v i c e s Authority r e s p o n d e d , and n o n e of the three hospitals within the P r o v i d e n c e Health C a r e Society r e s p o n d e d . R e s p o n s e from the V a n c o u v e r Island Health Authority w a s slightly lower, but this difference w a s not statistically significant. T A B L E 3.4. Survey response rates. Hospital S i z e Small Medium Large Municipality S i z e Rural Town Urban Health Authority (Region) Interior Northern Vancouver Island Fraser Vancouver Coastal Providence Health Care Society Provincial Health Services O c c u p a t i o n a l Health Staff Availability On-site Off-site None  Sent  Received  R e s p o n s e Rate  36 34 25  21 24 19  58% 71% 76%  18 42 35  11 26 27  61% 62% 77%  32 19 18 13  22 12 10 11  7 3 3  6 0 3  69% 63% 56% 85% 86% 0% 100%  36 14 45  26 11 27  72% 79% 60%  69  T h e survey included questions about use of sterilizer products that c a n be u s e d to clean s o m e of the instruments normally c l e a n e d using high-level disinfection; however, t h e s e r e s p o n s e s w e r e not included in a n y of the a n a l y s e s . T h e definition of high-level disinfection included in section 1.1.3 (page 2), w h i c h e x c l u d e d t h e s e products, w a s u s e d for the survey. Products included on the questionnaire but not included in the data analysis b e c a u s e they w e r e not c o n s i d e r e d to be high-level disinfectants w e r e Sterrad® (vapourized water and o x y g e n sterilizer), Steris® (peracetic acid sterilizer), Pasteurmatic® (hot water pasteurizer), and ethylene oxide (sterilizing gas). Of the 64 respondent hospitals, 51 (80%) reported that they w e r e using c h e m i c a l high-level disinfection (HLD). T a b l e 3.5 s h o w s the descriptive characteristics of all respondent hospitals and hospitals using high-level disinfection. Overall r e s p o n s e w a s fairly evenly distributed a m o n g hospital size categories, although fewer small hospitals u s e d high-level disinfection. This is most likely d u e to the d e c r e a s e d likelihood that small hospitals conduct procedures that require high-level disinfection. Similarly, rural municipalities were under-represented in overall r e s p o n s e and hospitals using high-level disinfection. T h e u n e v e n distribution of respondents a m o n g health authorities w a s at least partially d u e to the u n e v e n distribution of hospitals a m o n g the health authorities. N o s u r v e y s w e r e received from P r o v i d e n c e Health C a r e S o c i e t y hospitals, but there w e r e only three sites under this authority. T a b l e 3.6 s h o w s the characteristics related to high-level disinfectant u s a g e of respondent hospitals. TABLE 3.5. Descriptive characteristics of respondent hospitals. All Hospitals  Hospitals Using HLD  64  51 (80%)  21 (33%) 24 (37%) 19 (30%)  11 (22%) 21 (41%) 19 (37%)  11 (17%) 26 (41%) 27 (42%)  5 (10%) 21 (41%) 25 (49%)  22 12 10 11 6 0 3  18 8 6 10 6 0 3  n Hospital Size  Small Medium Large Municipality Size  Rural Town Urban Health Authority  Interior Northern Vancouver Island Fraser Vancouver Coastal Providence Health Care Society Provincial Health Services  (34%) (19%) (15%) (17%) (10%) (0%) (5%)  (35%) (16%) (12%) (19%) (12%) (0%) (6%)  Occupational Health Staff Availability  On-site Off-site None  26 (41%) 11 (17%) 27 (42%)  26 (51%) 8 (16%) 17 (33%)  70  in  0) o j in W c e LO re CM < I s-  CM  S °p  00  4-  CN  i  LO  crel  S  § ci | CN  LSI  o  CN  cn I  oo I  ool  o  o  o d  LO  LO  CN  w w T—  re +•»  a. ST  v.  CO 00 CD  O IX  ~  CD  d '  CN  CN  co CN  CN CN  LO  CD  ai  CJ>  LO  CD  T—  T—  LO  LO  LO  1 0  CO  "  CM LO  CO CN  O CN  co-  co  LO  a> cn c re  00  LO  LO O  Oi w  1  LO 1  C D LO  00 0 5  w  00  I  oo  o  CNI  J-  ^  LO  £ rS  CM ^ CN T  re>  Tf  " s  CD CN  00 00  LO CO  ™ -  a  (fl  fC  I*  ^ LO  c ra 0)  CT>  LO O  -  ~ -  T -  LO CN_  LO CN  2 2  cr>  o  oi d oo •st"  CO  CD  ^  CD"  CD  CD  CD  CD  -o 0  CD Q.  !s ° CD  •=  to  t  I  CL  CO O  c ~ CO  C  tz o E "O  0  CO ZJ  tz co 0  o c 0  0  Q.  a  0 >> 0 >  i col c 'co  -o  _i  o Z! 3 ^ O" E 2 _C0 CO CO W 0 CD CD cz «- Q 0 CD ° O 0 0 <o o o a. E l ^ >^ co 0 CO t t , o o £ E ca CO 0 O CD C L Z> co o >^ CD JZ C L CO C L C L C L co =2 0 JZ) CL 0 O E E o 0 0. > Q 1 a. LU UJ Q CD CO CD  O r-  CD CL  g  5  X  OT  *1  High-level disinfection is d o n e in variety of different hospital departments, a s c a n be s e e n from T a b l e 3.7. T h e category 'other diagnostic units' includes reproductive health, urology, a n d pulmonary diagnostics. T h e c o m m o n a r e a s using high-level disinfection are ultrasound/medical imaging, operating room, gastroenterology, and sterile p r o c e s s i n g . Gastroenterology departments a c c o u n t e d for only 15% of the total n u m b e r of d e p a r t m e n t s using high-level disinfection. T A B L E 3.7. Departments using chemicals for high-level disinfection. All Hospitals Department Operating Room  n Surveyed 40  Ultrasound/Medical Imaging Gastroenterology Sterile Processing Ear, Nose & Throat Respiratory/Bronchoscopy Cardiology Outpatients/Ambulatory Care Emergency Room/Ward Other Diagnostic Units Total  39 30 48 21 30 24 7 7 3 249  1  Hospitals Using HLD % of Departments n ("u of Depts U s i n g H L D (n=118) surveyed) 23% 27 (68%) 23% 27 (69%) 18 (60%) 15% 15% 17 (35%) 5% 6 (29%) 4% 5 (17%) 4% 5 (21%) 4% 5 (71%) 4% 5 (71%) 3% 3 (100%) 118  100%  Some hospitals (n=21) did not return surveys for those departments not using chemical high-level disinfection. Therefore, these values will under-report the total number of each department and thus over-report the proportion of departments in which HLD is used. 1  3.3.2 Chemicals Used for High-Level  Disinfection  U n l e s s otherwise stated, the data reported from this point relate to only t h o s e hospitals using high-level disinfection. O n e of the primary objectives of this survey w a s to determine w h i c h c h e m i c a l s w e r e being u s e d for high-level disinfection in British C o l u m b i a hospitals. A s s h o w n in T a b l e 3.8, approximately half of the hospitals using high-level disinfectants are currently using only glutaraldehyde, while half have introduced alternative products into the hospital environment, either exclusively or in addition to glutaraldehyde. T a b l e 3.9 s h o w s the u s e of different high-level disinfection c h e m i c a l s a m o n g different departments.  72  T A B L E 3.8. Chemicals used for high-level disinfection. r HLD Chemical Total Hospitals Using HLD Glutaraldehyde only Glutaraldehyde + Alternatives Alternatives only (n=18) O P A only P A A / H P only  nj%) 51 25 (49%) 8 (16%) 15(29%) 3 (6%)  1  1  P A A = peracetic acid; HP = hydrogen peroxide  T A B L E 3.9. Types of chemicals used for high-level disinfection according to department. Department Gastroenterology Ultrasound/Medical Imaging Ear, Nose & Throat Cardiology Respiratory/Bronchoscopy Operating Room Sterile Processing Outpatients/Ambulatory Care Emergency Room/Ward Other Diagnostic Units  Using HLD 18 27 6 5 5 27 17 5  Glutaraldehyde G l u t a r a l d e h y d e Only + Alternatives 13 (72%) 0 17 (63%) 0 5 (83%) 0 4 (80%) 0 4 (80%) 0 1 (4%) 13 (48%) 0 10 (59%) 2 (40%) 0  5  2 (40%)  3  1 (33%)  0 0  OPA Only 1 (6%) 10 (37%) 1 (17%) 1 (20%) 1 (20%) 12 (44%) 6 (35%) 2 (40%) 3 (60%) 1 (33%)  PAA/HP Only 4 (22%) 0 0 0 0 1 (4%) 1 (6%) 1 (20%) 0 1 (33%)  3.3.3 Relationships Between Hospital Characteristics and Choice of High-Level Disinfection Chemicals Figures 3.1 through 3.3 and T a b l e s 3.10 through 3.12 d e s c r i b e the relationship between hospital characteristics and high-level disinfection c h e m i c a l s u s e d . T h e s e a n a l y s e s included all hospitals in the data set, including t h o s e that did not u s e any high-level disinfectants. T h e type of high-level disinfection c h e m i c a l s u s e d w a s not evenly distributed a m o n g hospitals of differing s i z e (p < 0.01), in different municipality types (p < 0.05), or with different a c c e s s to o c c u p a t i o n a l health staff (p < 0.05). S m a l l hospitals u s e d high-level disinfection less frequently than did m e d i u m or large s i z e d hospitals. M e d i u m s i z e d hospitals u s e d alternatives more frequently; in fact, more m e d i u m hospitals were using alternatives than glutaraldehyde. Similarly, hospitals in rural a r e a s u s e d high-level disinfectants less frequently; hospitals in towns and urban a r e a s u s e d more of all products than those in rural a r e a s . Hospitals without an occupational health staff p e r s o n on-site u s e d less high-level disinfection. A m o n g hospitals using high-level disinfectants, the availability of o c c u p a t i o n a l health staff did not a p p e a r to be related to the type of high-level disinfection c h e m i c a l u s e d , although hospitals with on-site occupational health staff u s e d alternatives more frequently than glutaraldehyde.  73  • No HLD d Glutaraldehyde only B Any alternatives  r~  =  60  Small  Medium  Large  Hospital S i z e F I G U R E 3.1. Use of high-level disinfection chemicals according to hospital size. T A B L E 3.10. Use of high-level disinfection chemicals according to hospital size*. Small 10 (48%) 6 (28%) 5 (24%)  HLD Product None G l u t a r a l d e h y d e only A n y alternatives  Hospital S i z e Medium 3 (12%) 9 (38%) 12 (50%)  Large 0 (0%) 10 (53%) 9 (47%)  *p = 0.003, chi-square analysis  • No HLD M Glutaraldehyde only 13 Any alternatives 60  Rural  Town  Urban  Municipality S i z e F I G U R E 3.2. Use of high-level disinfection chemicals according to municipality size. T A B L E 3.11. Use of high-level disinfection chemicals according to municipality size*. HLD Product None G l u t a r a l d e h y d e only A n y alternatives  Rural 6 (55%) 2 (18%) 3 (27%)  *p = 0.027, chi-square analysis  Municipality S i z e Town 5 (19%) 11 (42%) 10 (39%)  Urban 2 (7%) 12 (45%) 13 (48%)  • No HLD El Glutaraldehyde only • Any alternatives 60  None  Off-site  On-site  O H S Staff Availability F I G U R E 3.3. Use of high-level disinfection chemicals according to occupational health staff availability. T A B L E 3.12. Use of high-level disinfection chemicals according to occupational health staff availability*. HLD P r o d u c t None G l u t a r a l d e h y d e only A n y alternatives  None 10 (37%) 9 (33%) 8 (30%)  OHS Availability Off-site 3 (28%) 4 (36%) 4 (36%)  On-site 0 (0%) 12 (46%) 14 (54%)  *p = 0.019, chi-square analysis  W h e n only t h o s e hospitals using any high-level disinfection w e r e e x a m i n e d , the differences w e r e not a s dramatic. (No statistical testing w a s carried out here, a s the s a m p l e s s i z e s are small). C h o i c e of high-level disinfection c h e m i c a l differed only slightly a m o n g hospitals of varying size, municipality type, a n d with variations in availability of o c c u p a t i o n a l health staff ( O H S ) . T h e differences in c h o i c e of high-level disinfectant c h e m i c a l w e r e s o m e w h a t more p r o n o u n c e d a c r o s s different health authorities. T h e s e results are s h o w n in T a b l e s 3.13 through 3.16. T A B L E 3.13. Types of chemicals used for high-level disinfection according to hospital size.  49% 16%  Small 11 6 (55%) 0 (0%)  Hospital Size Medium 21 9 (43%) 4 (19%)  Large 19 10 (53%) 4 (21%)  29% 6%  3 (27%) 2 (18%)  8 (38%) 0 (0%)  4 (21%) 1 (5%)  % of Hospitals Using HLD Hospitals Using H L D (n=51) Glutaraldehyde only Glutaraldehyde + Alternatives Alternatives only O P A only P A A / H P only  75  T A B L E 3.14. Types of chemicals used for high-level disinfection according to municipality size. % of H o s p i t a l s Using HLD Hospitals Using HLD (n=51) Glutaraldehyde only Glutaraldehyde + Alternatives Alternatives only O P A only P A A / H P only  49% 16%  Rural 5 2 (40%) 0 (0%)  29% 6%  3 (60%) 0 (0%)  Municipality Size Town Urban 21 25 11 (52%) 12 (48%) 6 (24%) 2 (10%) 6 (24%) 1 (4%)  6 (28%) 2 (10%)  T A B L E 3.15. Types of chemicals used for high-level disinfection according to health authority. %of Hospitals Using HLD Hospitals Using HLD (n=51) Glutaraldehyde only Glutaraldehyde + Alternatives Alternatives only O P A only P A A / H P only  Health Authority Interior  Northern  Vancouver Island  Fraser  Vancouver Coastal  Provincial Health Services  18  8  6  10  6  3  49%  10 (55%)  3 (38%)  1 (17%)  6 (60%)  3 (50%)  2 (67%)  16%  2 (11%)  1 (12%)  2 (33%)  0 (0%)  2 (33%)  1 (33%)  29% 6%  3 (17%) 3 (17%)  4 (50%) 0 (0%)  3 (50%) 0 (0%)  4 (40%) 0 (0%)  1 (17%) 0 (0%)  0 (0%) 0 (0%)  T A B L E 3.16. Types of chemicals used for high-level disinfection according to occupational health staff availability. °» of Hospitals Using HLD Hospitals Using HLD (n=51) Glutaraldehyde only Glutaraldehyde + Alternatives Alternatives only O P A only P A A / H P only  49% 16%  O H S Availability On-site Off-site 8 26 12 (46%) 4 (50%) 2 (25%) 5 (19%)  29% 6%  8 (31%) 1 (4%)  1 (13%) 1 (13%)  None 17 9 (53%) 1 (6%) 6 (35%) 1 (6%)  T h e a m o u n t of high-level disinfection c h e m i c a l s u s e d by individual hospitals differed a c c o r d i n g to the type of product being u s e d . H o s p i t a l s that w e r e u s i n g both g l u t a r a l d e h y d e a n d alternatives t e n d e d to u s e a greater v o l u m e of product, c l e a n more instruments by high-level disinfection, a n d h a v e m o r e e m p l o y e e s w o r k i n g in high-level disinfection a r e a s (Table 3.17). Hospitals u s i n g only g l u t a r a l d e h y d e alternatives t e n d e d to h a v e m o r e e m p l o y e e s overall u s i n g t h e s e products (Table 3.18).  76  T A B L E 3.17. Amount of chemical high-level disinfectants used in hospitals. n'  M e a n (SD)  Median  Ranged  All Sites U s i n g H L D Volume used/month (gallons) Pieces of equipment cleaned using HLD/month Employees working in departments using HLD Departments using HLD  44 38 51 51  15.5 204.6 19.7 2.3  (23.7) (227.6) (20.9) (1.3)  4.5 117.5 15.0 2.0  0.01-104.5 1-972 1-85 1-8  U s i n g Glutaraldehyde O n l y Volume used/month (gallons) Pieces of equipment cleaned using HLD/month Employees working in departments using HLD Departments using HLD  23 19 25 25  12.0 192.3 13.8 2.3  (20.2) (208.3) (13.8) (1.0)  3.0 80.0 8.0 2.0  0.25-86.1 3-578 1-52 1-5  U s i n g Glutaraldehyde & Alternatives Volume used/month (gallons) Pieces of equipment cleaned using HLD/month Employees working in departments using HLD Departments using HLD  7 6 8 8  28.4 313.7 49.3 3.4  (35.9) (187.4) (25.8) (2.1)  14.0 245.5 45.0 3.0  2-104.5 110-572 20-85 1-8  Using Alternatives Only Using O P A Only Volume used/month (gallons) Pieces of equipment cleaned using HLD/month Employees working in departments using HLD Departments using HLD  12 10 15 15  16.2 190.6 15.6 1.9  (22.9) (303.3) (16.7) (1.2)  6.0 69.5 12.0 2.0  0.01-74 1-972 2-68 1-4  Using P A A / H P Only Volume used/month (gallons) Pieces of equipment cleaned using HLD/month Employees working in departments using HLD Departments using HLD  2 3 3 3  5.4 111.0 11.7 1.7  (4.4) (120.9) (11.5) (0.6)  5.4 53.0 5.0 2.0  2.3-8.5 30-250 5-25 1-2  1  n refers to the number of hospitals supplying data.  T A B L E 3.18. Full-time employees reported to be working in departments that use high-level disinfectants ('exposed' employees). n Glutaraldehyde only Alternatives only Glutaraldehyde & Alternatives 1  1  Hospitals 25 18 8  ' E x p o s e d ' E m p l o y e e s per Hospital M e a n (SD) „ Median .Range 14(13.8) 8.0 1-52 15(15.8) 9.5 2-68 49 (25.8) 45.0 2-85  n refers to the number of hospitals supplying data.  77  3.3.4 Hospitals Using Only Glutaraldehyde for High-Level  Disinfection  Twenty-five hospitals reported that they were using only g l u t a r a l d e h y d e - b a s e d products for high-level disinfection. T a b l e 3.19 s h o w s that at the time of the survey, s o m e of t h e s e hospitals w e r e considering introducing substitutes. Others had previously looked into the possibility of using alternatives but had d e c i d e d against introducing them, while s o m e had introduced them for a trial period but had not continued their u s e . A large proportion of hospitals using only glutaraldehyde had no plans to c h a n g e the c h e m i c a l u s e d for high-level disinfection. T a b l e s 3.20 and 3.21 illustrate this data in terms of hospital characteristics a n d specific departments. T a b l e 3.22 s h o w s the high-level disinfectant u s a g e characteristics a m o n g hospitals using only glutaraldehyde. M o r e m e d i u m s i z e d hospitals w e r e currently considering substitution, while few s m a l l e r hospitals had ever c o n s i d e r e d introducing alternatives and larger hospitals t e n d e d to have c o n s i d e r e d but d e c i d e d against alternatives. Furthermore, all t h o s e hospitals that d e c i d e d against substitution had a c c e s s to occupational health staff. At the department level, substitution of glutaraldehyde occurred m u c h l e s s frequently. Hospitals that w e r e not planning to introduce glutaraldehyde alternatives had fewer e m p l o y e e s overall but more ' e x p o s e d ' e m p l o y e e s , and they a p p e a r e d to u s e more high-level disinfection c h e m i c a l s .  T A B L E 3.19. Hospitals using only glutaraldehyde for chemical high-level disinfection. n (%) 25 7 (28%) 11 (44%) 7 (28%) 3 4  :  Hospitals using glutaraldehyde only Currently considering substitution Continuing glutaraldehyde use (Never considered substitution) Considered substitution but decided against it Tried but didn't switch Considered but didn't switch  T A B L E 3.20. Characteristics of hospitals using only glutaraldehyde.  n Hospital s i z e Small Medium Large Municipality S i z e Rural Town Urban O H S Availability On-site Off-site None  n (%) 25  Currently Considering Substitution 7  Never Considered Substitution 11  Decided Against Substitution 7  6 (24%) 9 (15%) 10 (40%)  1 (14%) 4 (57%) 2 (29%)  5 (45%) 4 (37%) 2 (18%)  0 (0%) 1 (14%) 6 (86%)  2 (8%) 11 (44%) 12 (48%)  1 (14%) 3 (43%) 3 (43%)  1 (9%) 7 (63%) 3 (28%)  0 (0%) 1 (14%) 6 (86%)  12 (48%) 4 (16%) 9 (36%)  4 (57%) 0 (0%) 3 (43%)  2 (18%) 3 (27%) 6 (55%)  6 (86%) 1 (14%) 0 (0%)  78  T A B L E 3.21. Characteristics of departments using only glutaraldehyde.  Department Gastroenterology Ultrasound/Medical Imaging Ear, Nose and Throat Cardiology Respiratory/Bronchoscopy Operating Room Sterile Processing Outpatients/Ambulatory Care Emergency Room/Ward Other Diagnostic Units  n 13 17 5 4 4 13 10 2 2 1  Currently Considering Substitution 5 (38%) 3 (18%) 0 (0%) 0 (0%) 1 (25%) 6 (46%) 3 (30%) 1 (50%) 0 (0%) 0 (0%)  Never Considered Substitution 8 (62%) 12 (70%) 5 (100%) 4 (100%) 3 (75%) 7 (54%) 7 (70%) 1 (50%) 2 (100%) 1 (100%)  Decided Against Substitution 0 (0%) 2 (12%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%) 0 (0%)  79  0)  c ra  o  ^ S col  CM fyl O)  00  in  in I  ce.CN CN  CN  00  in I  00  d  i.oolo oo ai oo  (1.1)  CN  LO  LO  00  LO  00  LO  £1  LO  CD 00 LO LO  c  p csi  (2.0)  w.  o  d oo  (191.2)  (582.4)  (A  o  (22.8)  V *•* 3  (15.6)  c  •c—  csi  C  k*ra  CN  o z  oo  oo  CN CN  oo  0)  ra  00  » CN CN  CN  7  m in I  «  i mi  00  oo  I  CD  CN O  II  •31  o  CO 0 0 OO CN  o  m  CD  3 W XI •,3.  ;(/)  CO  CO CD  o  1^o  c "E c ra Q.  T-  1^ LO  .  CO  00  o  00 CN CN  LO  00 CO  00 0 0 _^  00  ^ CN  ^ in  CO  |^  h - CD  1  LO 00  CD  0  CO CD  C iD "U 0 C  ra Q —' x: X c c o "O  TZ O  (0 3  3  0  E  ci  CL  CO  c E E o LU LLI >  0  0  12 CD  a  a.  0 CJ  CO £ C  0  co  3  J=  0  o  M_  o  lo CD CJ ^cn 0  CO  Ii  E  co £ co Q. O 0  Q  CL 0  Q  80  A m o n g those hospitals planning to introduce substitutes for glutaraldehyde, more were planning to u s e O P A rather than the peracetic acid/hydrogen peroxide formula, although few hospitals not already using alternatives w e r e planning to substitute at the time of the survey (Table 3.23). T A B L E 3.23. Products planned to replace glutaraldehyde in future (n=7 hospitals). Department  OPA  PAA/HP  Gastroenterology Ultrasound/Medical Imaging Ear, Nose and Throat Cardiology Respiratory/Bronchoscopy OR Sterile processing Outpatients/Ambulatory Care Emergency roomA/Vard Other diagnostic units  3 (43%) 1 (14%) 0 0 0 4 (57%) 0 0 0 0  1 (14%) 1 (14%) 0  All Hospitals  5(71%)  2  3.3.5 Hospitals Using Glutaraldehyde  0 0 1 (14%) 1 (14%) 1 (14%) 0 0 (29%)  Alternatives  Twenty-six r e s p o n d i n g hospitals reported using glutaraldehyde alternatives, either exclusively or in combination with glutaraldehyde products. T h e descriptive and u s a g e characteristics of t h e s e hospitals are s h o w n in T a b l e s 3.9 through 3.18. A m o n g t h e s e hospitals, almost all of them were planning to continue using glutaraldehyde alternatives (Table 3.24). T A B L E 3.24. Plans to continue using alternatives for high-level disinfection (n=26). n  (%)  24 (92%)  Y E S : Planning to continue use of alternatives NO: Not planning to continue using alternatives  1 (4%)  No response  1 (4%)  3.3.6 Decision Making for High-Level  Disinfection  O n e of the key i s s u e s dealt with in the questionnaire w a s d e c i s i o n m a k i n g with respect to high-level disinfection. Q u e s t i o n s were included to ascertain why particular c h o i c e s w e r e m a d e , how d e c i s i o n s got m a d e , and who m a d e those decisions. 3.3.6.1 Why: R e a s o n s for C h o o s i n g Disinfectants W h e r e hospitals indicated that a decision had b e e n m a d e relating to using or not using glutaraldehyde alternatives, they were a s k e d what the r e a s o n s w e r e for  81  m a k i n g that d e c i s i o n . A m o n g t h o s e hospitals u s i n g only g l u t a r a l d e h y d e for high-level disinfection, the m o s t c o m m o n r e a s o n s w h y t h e y h a d not i n t r o d u c e d substitutes w e r e related to t e c h n i c a l i s s u e s ; e m p l o y e e health a n d cost w e r e a l s o highly r e p r e s e n t e d (Table 3.25). A m o n g the hospitals u s i n g e x c l u s i v e l y g l u t a r a l d e h y d e a n d planning to introduce substitutes, e m p l o y e e health i s s u e s w e r e the m o s t c o m m o n r e a s o n for c o n s i d e r i n g c h a n g e (Table 3.26). B e c a u s e m a n y slightly different r e a s o n s w e r e given for w h y d e c i s i o n s w e r e m a d e , similar r e a s o n s w e r e g r o u p e d for e a s e of viewing. C o m p l e t e t a b l e s without grouping are included in A p p e n d i x X X I ( T a b l e s A1 and A2). T A B L E 3.25. Reasons for not introducing glutaraldehyde substitutes (n=18). Reason Technical issues Cost  n (%) 9 (50%) 6 (33%) 5 (28%) 1  2  Employee health Administrative issues Patient Safety 3  ,  1 (6%) 1 (6%)  4  5  Percent values may add to more than 100% because some hospitals gave more than one reason for considering substitution. Technical issues includes the following responses: staining, no advantage over glutaraldehyde, new equipment made change unnecessary, damage to equipment. Employee health includes the following responses: health concerns, lack of health information. Administrative issues includes the following responses: hospital policy. Patient safety includes the following responses: efficacy of glutaraldehyde product. 1  2  3  4  5  T A B L E 3.26. Reasons for considering substitution (n=7). Reason Employee health  n (%) 5 (71%) 1  2  Technical issues Administrative issues 3  Odour Cost  5  4  2 (29%) 1 (14%) 1 (14%) 1 (14%)  Percent values may add to more than 100% because some hospitals gave more than one reason for considering substitution. Employee health includes the following responses: health concerns, decrease employee exposure employee health problems. Technical issues includes the following responses: shelf/reuse life, results of product trial. Administrative issues includes the following responses: regional product change, sales representative recommended change, previous product no longer available. Odour includes the following responses: less fumes. 1  2  3  4  5  W h e r e hospitals h a d a l r e a d y introduced g l u t a r a l d e h y d e substitutes, they w e r e a s k e d w h y they h a d d e c i d e d to introduce the alternative products. T h e m o s t frequent r e a s o n given for introducing alternatives w a s the protection of e m p l o y e e health, which w a s reported by 7 3 % of t h o s e hospitals (Table 3.27). T h e s e r e a s o n s h a v e  82  b e e n g r o u p e d for e a s e of c o m p a r i s o n ; c o m p l e t e t a b l e s are i n c l u d e d in A p p e n d i x X X I (Table A 3 ) . T A B L E 3.27. Reasons for introducing glutaraldehyde substitutes (n=26). Reason  n  Employee health Technical issues Administrative issues Odour Patient safety  19 (73%) 10(38%) 7 (27%) 7 (27%) 3 (12%)  2  3  4  5  6  Percent values may add to more than 100% because some hospitals gave more than one reason for introducing glutaraldehyde substitutes for chemical high-level disinfection. Employee health includes the following responses: employee health concerns, employee health problems, decrease employee exposure. Technical issues includes the following responses: processing time, equipment compatibility, preparation time, minimize mixing errors, decrease volume of product used. Administrative issues includes the following responses: product used at another hospital, regional change, sales representative recommended the change, availability. Odour includes the following responses: odour, fumes, vapour concentration. Patient safety includes the following responses: efficacy, patient safety. 1  2  4  5  6  A m o n g the hospitals u s i n g g l u t a r a l d e h y d e substitutes, only o n e w a s not planning to continue u s i n g the alternative. T h e r e a s o n for discontinuing the product w a s the i n c r e a s e d c o s t of the n e w product. T h e r e a s o n s provided by the hospitals that did plan to continue u s i n g the alternatives are s h o w n in T a b l e 3.28. L i k e the r e a s o n s for originally i m p l e m e n t i n g substitutes, e m p l o y e e health w a s the m o s t frequent r e a s o n for continuing their u s e . A c o m p l e t e table of r e s p o n s e s is i n c l u d e d in A p p e n d i x X X I (Table A 4 ) . T A B L E 3.28. Reasons for continuing to use alternatives (n=24). R e a s o n for C o n t i n u i n g Employee health  Administrative issues Technical issues  4  n (%)  1  10(42%)  2  3  7 (29%) 3 (13%)  Odour  1 (4%)  Cost  1 (4%)  Patient safety  5  1 (4%)  Percent values may add to more than 100% because some hospitals chose alternatives based on more than one factor. Employee health includes the following responses: employee health concerns, employee health problems with glutaraldehyde. Administrative issues includes the following responses: only known alternative to glutaraldehyde, regional decision. Technical issues includes the following responses: ease of use, processing time, equipment compatibility. Patient safety includes the following responses: patient safety.  1  2  4  5  83  3.3.6.2 How: Criteria for C h o o s i n g Specific Alternatives Hospitals that h a d introduced glutaraldehyde alternatives w e r e a s k e d about the criteria o n which they h a d b a s e d their decision, i.e., how they c h o s e the specific product that they d e c i d e d to introduce (Table 3.29). T h e s e criteria did not always follow logically from the r e a s o n s given for deciding to substitute. O n c e the d e c i s i o n w a s m a d e to introduce a substitute, different factors g a i n e d importance. S p e c i f i c products w e r e usually c h o s e n b e c a u s e of administrative i s s u e s , with e m p l o y e e health falling to the third most freguent criterion o n which the d e c i s i o n w a s b a s e d . A complete list of r e s p o n s e s is included in A p p e n d i x X X I (Table A 5 ) . T A B L E 3.29. Criteria for choosing specific alternatives (n=26). ;How C h o s e n Administrative issues Technical issues Employee health Odour 3  4  5  Cost Patient safety Don't know  6  2  n 22 (85%) 11 (42%)  ;  6 (23%) 5 (19%) 4 (15%) 3 (12%) 1 (4%)  Percent values may add to more than 100% because some hospitals chose alternatives based on more than one factor. Administrative issues includes the following responses: only known alternative to glutaraldehyde, guess, product used at another hospital, in-service or seminar information, regional decision, sales representative recommendation (10 r e s p o n s e s ) , availability. Technical issues includes the following responses: shelf/reuse life, equipment manufacturer recommendation, processing time, minimization of mixing errors, decrease in volume used, user friendly, results of product trial. Employee health includes the following responses: employee health concerns, decrease employee exposure. Odour includes the following responses: odour, fumes, vapour concentration. Patient safety includes the following responses: efficacy. 1  2  3  4  5 6  Figures 3.4 through 3.6 s h o w a c o m p a r i s o n of the r e a s o n s provided for deciding not to substitute glutaraldehyde, deciding to substitute, a n d for c h o o s i n g which c h e m i c a l s to introduce a s substitutes.  84  CO T—  11  ft <2^ re >> sz  Q. CD in TJ  3?  I Technical issues  e>  Cost  Employee health  1  Admin, issues  1  Patient safety  R e a s o n s for Not S u b s t i t u t i n g F I G U R E 3.4. Reasons for not introducing glutaraldehyde substitutes.  80 70 60 50  a # '5. > +-»  CO  5I tn  +s  o  s  40 30 20 10 0 Employee health  Technical issues  Admin, issues  Odour  Patient safety  R e a s o n s for S u b s t i t u t i n g F I G U R E 3.5. Reasons for introducing glutaraldehyde substitutes.  ro .E  coin CM  D  tn ro +^  a in o X  II c  in o >  ZZ  ro c i_  o cu ~ wwwwwwwwww  <  Admin. issues  Technical issues  Employee health  Odour  Cost  Patient safety  Don't know  Criteria for D e c i s i o n F I G U R E 3.6. Criteria for choosing specific alternatives.  85  3.3.6.3. Who: D e c i s i o n M a k e r s for Hiqh-Level Disinfection T h e relationship b e t w e e n the people involved in m a k i n g high-level disinfection d e c i s i o n s a n d the u s e of glutaraldehyde alternatives for high-level disinfection is shown in Figure 3.7.  Dept. Senior O H S staff/ Dept. not Infection Health Personnel using H L D admin. Safety using HLD control authority outside committee hospital P e r s o n n e l Involved in H L D D e c i s i o n s F I G U R E 3.7. Use of high-level disinfection chemicals according to decision makers.  T a b l e s 3.30 and 3.31 s h o w the hospital departments a n d p e r s o n n e l involved in making d e c i s i o n s regarding what c h e m i c a l s to u s e for high-level disinfection. In e a c h u s a g e group, the d e p a r t m e n t actually doing high-level disinfection w a s most frequently involved in the d e c i s i o n process. O c c u p a t i o n a l health a n d infection control were also highly r e p r e s e n t e d a m o n g decision m a k e r s . A m o n g hospitals using only glutaraldehyde, the health authority w a s involved in the d e c i s i o n s p r o c e s s in almost half. A m o n g hospitals that c o n s i d e r e d but d e c i d e d against substitution, occupational health staff w a s just a s involved in the decisions a s the d e p a r t m e n t s . T A B L E 3.30. Decision makers in hospitals using high-level disinfection. Any HLD (n=51) 37 (73%) 21 (41%)  Giutaral. Only (n=25) 18 (72%) 13 (52%)  Giutaral. + Alternatives (n=8) 7 (88%) 3 (40%)  OPA Only (n=15) 10 (67%) 4 (27%)  PAA/HP Only  17(33%)  12(48%)  4 (50%) 0 (0%)  Department not using H L D  12 (48%) 8 (32%)  1 (7%) 4 (27%)  0 (0%)  16 (31%) 14(27%)  1 (13%)  4 (27%)  1 (33%)  Outside personnel  7 (14%)  4 (16%)  1 (13%)  1 (7%)  1 (33%)  Senior administration/management  5 (10%)  1 (4%)  0 (0%)  3 (20%)  1 (33%)  Job Category Department using HLD O H S staff or safety committee Infection control Health authority  1  (n=3) 2 (67%) 1 (33%) 0 (0%)  Percent values may add to more than 100% because some hospitals have more than one decision maker for chemical high-level disinfection issues. 1  86  T A B L E 3.31. Decision makers in hospitals using only glutaraldehyde. Currently Considering J o b Category Department using H L D O H S staff or safety committee Infection control Health authority Department not using H L D Outside personnel Senior administration/management  Never C o n s i d e r e d D e c i d e d A g a i n s t Substitution Substitution  Substitution (n=7)  (n=11)  (n=7)  6 (86%) 4 (57%) 5 (71%) 3 (43%) 3 (43%) 0 (0%) 0 (0%)  6 (55%) 3 (27%) 3 (27%) 6 (55%) 3 (27%) 1 (9%) 1 (9%)  6 (86%) 6 (86%) 4 (57%) 3 (43%) 2 (29%) 3 (43%) 0 (0%)  Percent values may add to more than 100% because some hospitals have more than one decision maker for chemical high-level disinfection issues.  1  T h e relationships b e t w e e n occupational health staff availability, occupational health staff involvement in d e c i s i o n s , a n d the u s e of a n y glutaraldehyde alternatives were e x a m i n e d for the 51 hospitals using high-level disinfection. T a b l e s 3.32 through 3.34 s h o w the relationships between t h e s e three variables. T h e availability of occupational health staff w a s not a s s o c i a t e d with whether the hospital had introduced glutaraldehyde alternatives (p = 0.908), or with w h e t h e r or not they were actively involved in the high-level disinfection decision p r o c e s s (p = 0.419). T h e active involvement of occupational health staff in the decision p r o c e s s , however, w a s a s s o c i a t e d with w h e t h e r alternatives were u s e d (p = 0.029). W h e r e occupational health staff w e r e involved, hospitals introduced alternatives less frequently. T A B L E 3.32. Relationship between availability of occupational health staff and the use of glutaraldehyde alternatives* (n=51).  Use of Alternatives No Yes  None 9 (53%) 8 (47%)  O H S Availability On-site 12 (46%) 14 (54%)  Off-site 4 (50%) 4 (50%)  *p = 0.908, chi-square analysis  T A B L E 3.33. Relationship between availability of occupational health staff and their involvement in high-level disinfection decisions* (n=34). O H S Availability Involved Not Involved  On-site  Off-site  14 (54%) 12 (46%)  3 (38%) 5 (62%)  *p = 0.419, chi-square analysis  87  T A B L E 3.34. Relationship between involvement of occupational health staff in high-level disinfection decisions and the use of glutaraldehyde alternatives* (n=51). Use of Alternatives No Yes  O H S Involvement Involved Not Involved 12(71%) 13(38%) 5 (29%) 21 (62%)  *p = 0.029, chi-square analysis  T h e relationship b e t w e e n the u s e of s a l e s representatives' r e c o m m e n d a t i o n s for c h o o s i n g high-level disinfection c h e m i c a l s and the type of c h e m i c a l u s e d is s h o w n in T a b l e 3.35. Hospitals that had not substituted b a s e d s u c h d e c i s i o n s on s a l e s representative r e c o m m e n d a t i o n s less frequently. A m o n g hospitals that u s e d information from s a l e s representatives in c h o o s i n g products, more had introduced alternatives than a m o n g hospitals not using s a l e s information (p = 0.072). T A B L E 3.35. Relationship between choice of high-level disinfection chemical and use of sales representative information* (n=51). Sales Representative Information Not U s e d Used  Glutaraldehyde Only 21(84%) 4 (16%)  Any Alternatives 16(62%) 10 (38%)  *p = 0.072, chi-square analysis  T h e relationship b e t w e e n the u s e of s a l e s representatives' r e c o m m e n d a t i o n s and occupational health staff involvement in the decision p r o c e s s w a s also a s s e s s e d (Table 3.36). In hospitals w h e r e occupational health staff w a s involved in d e c i s i o n s about which c h e m i c a l to use, s a l e s representative information w a s u s e d less often, although this relationship w a s not statistically significant (p = 0.267). T A B L E 3.36. Relationship between occupational health involvement in decisions and use of sales representative information* (n=51).  O H S Involvement Involved Not Involved  S a l e s Representative Information Not U s e d Used 14 (38%) 3 (21%) 23 (62%) 11 (79%)  *p = 0.267, chi-square analysis  3.3.7 Factors Associated with the Use of Any  Alternatives  Prior to carrying out multiple regression analysis to evaluate factors a s s o c i a t e d with the use of alternatives, e a c h of the candidate variables w a s c o m p a r e d with all other candidate variables to identify variables that w e r e a s s o c i a t e d with o n e another. A table showing the p-value for e a c h individual analysis is included a s T a b l e A 7 in  88  A p p e n d i x XXII. P e a r s o n correlation coefficients w e r e a l s o c a l c u l a t e d for e a c h pair of candidate variables (Table A 8 , A p p e n d i x XXII). T h e P e a r s o n correlation coefficients a g r e e d with the results of the chi-square a n a l y s e s , with all but o n e of the variable pairs with p < 0.01 having coefficients greater than 0.5. T h e m o s t highly a s s o c i a t e d candidate v a r i a b l e s (p < 0.01, R < - 0 . 5 , or R > 0.5) are s h o w n in T a b l e 3.37. T A B L E 3.37. Highly associated candidate variables (p < 0.01). Variables Municipality size * Hospital size Municipality size * O H S availability Municipality size x Health authority Municipality size * O H S or safety committee involved in decisions Municipality size * Senior administration involved in decisions _ Hospital size x O H S availability Hospital size x Presence of operating room Hospital sizeix O H S or safety committee involved indecisions^ Presence of ultrasound/medical imaging x Presence of operating room Presence of ultrasound/medical imaging x Presence of sterile processing O H S or safety committee involved in decisions x Personnel outside hospital involved in decisions O H S or safety committee involved in decisions x O H S availability Health authority x O H S availability " " " Health authority x Health authority involved in decisions Northern Health Authority x O H S availability Northern Health Authority x Senior administration involved in decisions Fraser Health Authority x Health authority involved in decisions 8  p  <0.0001 <0.0001 0.005 0.003  <0.001 <6.6o01 0.006 0.004 0.004 0.001  <6.001 0.005  0.002 0.004  0.002 0.004 O.001  T h e strong a s s o c i a t i o n b e t w e e n hospital s i z e a n d municipality s i z e w a s e x p e c t e d ; large hospitals a r e generally located in large urban centres while small towns tend to have only small hospitals or community health centres. Likewise, hospital s i z e a n d the availability of o c c u p a t i o n a l health staff w e r e a s s o c i a t e d , a s small rural hospitals would not b e e x p e c t e d to have a specific occupational health a n d safety department. It w a s thus d e c i d e d that municipality s i z e would not be included in the m o d e l . Hospital s i z e w a s c h o s e n over municipality s i z e a s the variable to include b e c a u s e the objective of t h e m o d e l w a s to e x a m i n e hospital d e c i s i o n s . T h e s e v a r i a b l e s w e r e included in the initial s t a g e s of model building, i.e., univariate a n a l y s e s ) despite being a s s o c i a t e d (p < 0.01); however, it w a s r e c o g n i z e d that having a s s o c i a t e d variables in t h e s a m e multivariable m o d e l w o u l d not likely b e p o s s i b l e . T a b l e 3.38 s h o w s the results of the univariate logistic r e g r e s s i o n modeling, highlighting the c a n d i d a t e variables that met the criteria to b e included in the initial step of the multivariable logistic regression m o d e l (p < 0.10, O R < 0.5, or O R > 2.0).  89  Table 3.38. Univariate logistic regression models of the relationship between hospital characteristics and the use of glutaraldehyde alternatives. OR Variable(s) Hospital s i z e * (variables entered as a g r o u p ) 1.00 Large hospital 0.93 Small hospital 0.48 Medium hospital* O H S Availability (variables entered a s a g r o u p ) 1.00 O H S available on-site 0.86 O H S available off-site 0.76 No O H S available Health Authority (variables entered a s a g r o u p ) 1.00 Interior 2.08 Northern* 6.25 Vancouver Island* 0.83 Fraser 1.25 Vancouver Coastal 0.63 Provincial Health Authority (variables entered one at a time) 0.67 Interior 1.75 Northern 5.71 Vancouver Island* 0.58 Fraser 0.96 Vancouver Coastal 0.46 Provincial* D e c i s i o n M a k e r s (variables entered one at a time) 1.06 Department using H L D 4.36 Senior administration* 0.41 O H S or safety committee* 0.64 Department not using H L D 0.69 Outside personnel 0.26 Infection control* 0.20 Health authority* Departments (variables entered one at a time) 1.01 Presence of operating room 0.56 Presence of gastroenterology 0.84 Presence of ultrasound/medical imaging 1.10 Presence of sterile processing  95% C o n f i d e n c e Interval  P  default category 0.21-4.11 0.43-5.16  — 0.9194 0.5371  default category 0.18-4.19 0.22-2.60  — 0.8489 0.6636  default category 0.38-11.48 0.60-64.85 0.17-4.01 0.20-7.96 0.05-8.20  0 3993 0.1248 0.8200 0.8132 0.7205  0.21-2.12 0.37-8.24 0.62-52.89 0.14-2.35 0.17-5.26 0.40-5.42  0.4914 0.4813 0.1248 0.4416 0.9592 0.5372  0.31-3.61 0.45-42.08 0.13-1.29 0.18-2.20 0.14-3.42 0.07-0.90 0.05-0.74  0.9313 0.2026 0.1270 0.4768 0.6447 0.0339 0.0161  0.82-1.24 0.18-1.73 0.45-1.57 0.88-1.37  0.9313 0.3147 0.5889 0.4112  1  1  1  2  2  * Variables indicated by * meet criteria to be included in multivariable regression model. One model comparing all categories for this variable was calculated; the 'default category' was the category with the largest number of responses and was not included in the model, i.e., was used as the comparison. Individual models were created for each category within the variable. This was done for variables with more than one possible response for a given hospital, i.e., 'decision makers' or 'departments,' or for variables with categories that could not be put into a rank order, i.e., 'Health Authority.' 1  2  S t e p w i s e multivariable logistic regression m o d e l s w e r e calculated with all the remaining variables. At e a c h step, any variable with an o d d s ratio that did not meet  90  the criteria of p < 0.05, O R > 2.0, or O R < 0.3 w a s r e m o v e d from the m o d e l . T h e model w a s then recalculated without that variable and the p r o c e s s continued until only t h o s e variables with o d d s ratios meeting the criteria r e m a i n e d . T h e final multivariable logistic regression model included s e v e n variables (Table 3.39). T h e formula for the model w a s : _(//„(py/1 -py))  — c  a  + _(b)(hospital size—small) . _(b)(hospital size—medium)  + «(b)(Vancouver Island Health Authority) ,  (b)(senior administration involved in decisions)  + g(b)(OHS/safety committee involved in decisions) ,  +  ^(bXinfection control involved in decisions)  (b)(health authority involved in decisions)  T A B L E 3.39. Multivariable logistic regression model of the relationship between hospital characteristics and the use of glutaraldehyde alternatives. Variable Hospital S i z e — S m a l l * Hospital Size—Medium Vancouver Island Health Authority Senior Administration Involved in HLD Decisions O H S or Safety Committee Involved in HLD Decisions* Infection Control Involved in HLD Decisions** Health Authority Involved in HLD Decisions**  OR 0.12 0.36 5.48 2.70 0.25 0.13 0.12  95% C o n f i d e n c e Interval 0.10-1.44 0.06-2.20 0.40-75.36 0.14-53.77 0.05-1.28 0.02-0.75 0.02-0.77  P 0.095 0.269 0.203 0.515 0.096 0.022 0.025  * O R significant at p < 0.10; ** O R significant at p < 0.05  A n examination of the variables in the final multivariable logistic regression model revealed that hospital s i z e w a s highly a s s o c i a t e d with o c c u p a t i o n a l health or safety committee involvement in d e c i s i o n s (p = 0.004); in large hospitals, occupational health or safety committee personnel were more frequently involved in high-level disinfection d e c i s i o n s than in m e d i u m hospitals, and in small hospitals, occupational health or safety committee personnel w e r e less frequently involved in high-level disinfection d e c i s i o n s . T h i s is likely d u e to the fact that o c c u p a t i o n a l health staff were less available in small hospitals and more available in large hospitals than in m e d i u m hospitals. In addition, although the association b e t w e e n hospital size and senior administration involvement in high-level disinfection d e c i s i o n s w a s not very strong (i.e., p = 0.05), it w a s noted that in large hospitals, s e n i o r administration w e r e never involved in the d e c i s i o n s , resulting in a zero-cell w h e n t h e s e two variables were in the model together. Therefore, the model w a s rerun, first removing hospital size but leaving in all other variables, and s e c o n d removing o c c u p a t i o n a l health or safety committee a n d senior administration involvement in d e c i s i o n s . W h e n hospital s i z e w a s r e m o v e d from the model, the o d d s ratio estimates c h a n g e d (Table 3.40). T h e a s s o c i a t i o n between being in the V a n c o u v e r Island Health Authority and the u s e of glutaraldehyde alternatives declined slightly. T h e relationship b e t w e e n senior administration involvement in the d e c i s i o n and the use  91  of glutaraldehyde substitutes also declined to an o d d s ratio very c l o s e to one, indicating no a s s o c i a t i o n . Finally, the relationship b e t w e e n o c c u p a t i o n a l health or safety committee involvement in d e c i s i o n s and the use of glutaraldehyde substitutes increased, a l s o indicating a l e s s strong association b e t w e e n t h e s e variables than in the previous m o d e l . W h e n occupational health or safety committee and senior administration involvement in high-level disinfection d e c i s i o n s w e r e r e m o v e d from the model (with hospital size left in), hospital size a p p e a r e d to have a less strong a s s o c i a t i o n with the u s e of glutaraldehyde alternatives (Table 3.40). T A B L E 3.40. Effect of removing associated variables on odds ratio estimates in the multivariable logistic regression model.  Variable Hospital size—Small Hospital size—Medium Vancouver Island Health Authority Senior Administration Involved in Decisions O H S or Safety Committee Involved in Decisions Infection Control Involved in Decisions Health Authority Involved in Decisions  A l l Variables in M o d e l 0 12' 0.36 5.48  Hospital S i z e Removed — — 3.32  O H S or Safety C o m m i t t e e and S e n i o r A d m i n i s t r a t i o n Involvement in D e c i s i o n s Removed 0 38 0.66 5.40  2.70  1.17  —  0.25*  0.46  —  0.13**  0.19**  0.13**  0.12**  0.12**  0.13**  * O R significant at p < 0.10; ** O R significant at p < 0.05.  T h e s e results s u g g e s t that the apparent association b e t w e e n s e n i o r administration involvement in high-level disinfection d e c i s i o n s is in fact a spurious a s s o c i a t i o n . W h e n all variables are included in the model, it a p p e a r s that the involvement of senior administration in the decision p r o c e s s is a s s o c i a t e d with i n c r e a s e d u s e of glutaraldehyde alternatives. S e n i o r administration involvement in d e c i s i o n s is, however, probably a n effect of being a small hospital, a s they w e r e rarely involved in d e c i s i o n s in m e d i u m hospitals and never involved in large hospitals. T h u s , including both hospital s i z e and senior administration involvement in d e c i s i o n s in the logistic regression model e x a g g e r a t e s the association between senior administration decision m a k e r s and the u s e of alternatives ( b e c a u s e of the a s s o c i a t i o n between hospital s i z e and senior administration involvement in d e c i s i o n s ) . By examining the three m o d e l s s h o w n in T a b l e 3.40, the only c h a n g e in the overall interpretation of the logistic regression model for factors a s s o c i a t e d with the u s e of glutaraldehyde alternatives is the effect of senior administration involvement in highlevel disinfection d e c i s i o n s . T h e involvement of senior administration in d e c i s i o n s  92  d o e s not a p p e a r to be a s s o c i a t e d with the u s e of glutaraldehyde alternatives. S m a l l hospitals a p p e a r to u s e alternatives l e s s frequently than large hospitals. Hospitals in the V a n c o u v e r Island Health Authority a p p e a r to u s e alternatives more frequently. W h e n occupational health or safety committee, infection control, or health authority personnel are involved in high-level disinfection d e c i s i o n s , f e w e r hospitals had introduced glutaraldehyde alternatives.  93  3 . 4 Discussion of Current Practices Survey  3.4.1 Discussion of Survey Results A n unexpected finding of this work w a s that it w a s extremely difficult to locate the person responsible for high-level disinfection in most hospitals. W h e n developing the original d a t a b a s e for the questionnaire mailing, hospitals with no o c c u p a t i o n a l health staff or department w e r e a s k e d for the n a m e of the p e r s o n r e s p o n s i b l e for high-level disinfection. T h i s proved to be extremely difficult for the p e r s o n a n s w e r i n g the phone call and n u m e r o u s staff m e m b e r s often had to be contacted before the person responsible (or lack thereof) could be identified. W h e n the survey w a s sent directly to the occupational health department, the staff in the department w a s often unable to fill out the questionnaire. In s o m e c a s e s , they n e e d e d to c h e c k with individual departments to find out details s u c h a s the v o l u m e of a given c h e m i c a l that w a s u s e d ; frequently, however, they did not e v e n know w h i c h d e p a r t m e n t s w e r e doing high-level disinfection or what kind of c h e m i c a l s were being u s e d . M a n y occupational health m a n a g e r s in large hospitals had to s e n d the questionnaire to several different people in order to gather the information. In addition to its importance for patient safety, high-level disinfection is a p r o c e s s that h a s b e e n linked with s o m e very serious occupational health issues, including a s t h m a . Despite this, there s e e m s to be a lack of general knowledge of what is h a p p e n i n g within the hospital, and practices often do not a p p e a r to be o v e r s e e n at the hospital level by people e d u c a t e d about occupational health i s s u e s . In spite of this lack of k n o w l e d g e at the hospital level, there s e e m s to be a high d e g r e e of c o n c e r n about health a m o n g e m p l o y e e s w h o a r e directly involved in highlevel disinfection. T h e desire to eliminate glutaraldehyde b e c a u s e of health i s s u e s w a s often e x p r e s s e d during telephone calls with survey r e s p o n d e n t s . Health w a s the most frequent r e s p o n s e for considering or introducing glutaraldehyde substitutes. Ironically, c o n c e r n for health w a s also a frequent r e a s o n for w h y substitution had not been tried. T h i s points to the uncertainty about the potential health effects of new glutaraldehyde alternatives. T h e fact that this overriding c o n c e r n about e m p l o y e e health w a s not e x p r e s s e d in the criteria u s e d to c h o o s e high-level disinfectants presents an interesting contrast. Factors s u c h as product availability, practices at other hospitals, and r e c o m m e n d a t i o n s from s a l e s representatives a p p e a r e d to override g o o d intentions for protecting e m p l o y e e health. B e c a u s e marketing claims for these alternative products are b a s e d on lower health risks, the impact of s a l e s representatives cannot be underestimated. If they claim to h a v e a safer product, they are likely to influence d e c i s i o n s . R e c o m m e n d a t i o n s from s a l e s representatives w e r e c o m m o n l y u s e d to c h o o s e an alternative product. S a l e s representatives thus a p p e a r to be a trusted s o u r c e for health effects information. Despite the lack of information from a n y s o u r c e other than manufacturers' representatives, glutaraldehyde alternatives are already widely in use in British C o l u m b i a . It would be interesting to study w h e t h e r s a l e s information  94  would be s o widely u s e d if information about the c h e m i c a l s w e r e more readily available. T h e fact that the u s e of these alternatives is most prevalent in m e d i u m a n d large s i z e hospitals brings up the question of w h e t h e r t h e s e larger hospitals are targeted by the s a l e s representatives of these new products. F r o m a s a l e s perspective, this would s e e m obvious, but it m a y not n e c e s s a r i l y be the best situation for the protection of e m p l o y e e health. T h e impact of s a l e s representatives is well illustrated by the relationship between the use of s a l e s information in c h o o s i n g alternatives a n d the involvement of occupational health staff in the d e c i s i o n (Table 3.36). W h e n people k n o w l e d g e a b l e about occupational health i s s u e s were involved in the d e c i s i o n s , they u s e d s a l e s information l e s s frequently, although this relationship w a s not statistically significant. However, they w e r e involved in d e c i s i o n s in less than half of the hospitals. G i v e n the potentially serious negative health impacts of high-level disinfectants a n d the uncertainty about the potential health effects a s s o c i a t e d with currently available products, it would be w i s e for occupational health professionals to b e c o m e more aware of the i s s u e s a n d more involved in d e c i s i o n s related to high-level disinfectants. Participation at the early stage w h e n d e c i s i o n s are being m a d e would help departments and others m a k e the safest possible c h o i c e for high-level disinfection, and might help prevent s e v e r e and irreversible health effects s u c h as asthma. Interestingly, small s i z e hospitals u s e d alternatives l e s s frequently than large hospitals. T h i s w a s the c a s e e v e n w h e n taking into a c c o u n t the modifying role of occupational health or infection control personnel in d e c i s i o n m a k i n g , despite the fact that there w e r e fewer o c c u p a t i o n a l health or infection control staff available to small hospitals. It is possible that this finding is related to i n c r e a s e d health authority involvement in d e c i s i o n s in small hospitals, as health authority involvement w a s a s s o c i a t e d with lower u s e of glutaraldehyde alternatives. T h e use of glutaraldehyde alternatives a p p e a r e d to be a s s o c i a t e d with factors related to health authority. Overall, w h e n health authorities w e r e involved in highlevel disinfection d e c i s i o n s , alternatives were u s e d less frequently. Despite this association, o n e particular health authority ( V a n c o u v e r Island) had the highest u s e of alternatives, w h e n other factors s u c h a s hospital s i z e a n d d e c i s i o n m a k e r s w e r e taken into account. In the V a n c o u v e r Island Health Authority, however, those decision m a k e r s a s s o c i a t e d with d e c r e a s e d u s e of glutaraldehyde alternatives, namely o c c u p a t i o n a l health or safety committee, infection control, and health authority p e r s o n n e l , w e r e rarely involved in the d e c i s i o n p r o c e s s . T h e association b e t w e e n health authority involvement in d e c i s i o n s a n d d e c r e a s e d use of alternatives could possibly be explained by the involvement of occupational health staff or safety committees in high-level disinfection d e c i s i o n s . It would be interesting to k n o w w h i c h health authority p e r s o n n e l w e r e m a k i n g d e c i s i o n s for t h e s e hospitals; if d e c i s i o n m a k e r s at the health authority level w e r e occupational health personnel, this might explain the association between health authority  95  involvement and d e c r e a s e d u s e of glutaraldehyde alternatives. Unfortunately, the s a m p l e size in this study w a s too small to investigate s u c h an hypothesis. N e v e r t h e l e s s , t h e s e results highlight the importance for d e c i s i o n m a k e r s at the health authority level to be k n o w l e d g e a b l e about the health and safety i s s u e s of glutaraldehyde alternatives.  3.4.2 Strengths and Limitations of the Survey Tool O n e of the most important strengths of this survey w a s that it w a s the first study to e x a m i n e i s s u e s related to high-level disinfection u s e and d e c i s i o n m a k i n g . T h i s is particularly timely given the recent introduction of new products to the market. It should be e m p h a s i z e d , however, that this w a s an exploratory a n a l y s i s only and no a priori h y p o t h e s e s w e r e being tested here. A reasonably high r e s p o n s e rate w a s a c h i e v e d in this survey. G i v e n recent restructuring in the British C o l u m b i a healthcare s y s t e m that h a s left m a n y hospitals dealing with d e c r e a s e d r e s o u r c e s and m a n y e m p l o y e e s s t r e s s e d for time, and the difficulty identifying k n o w l e d g e a b l e staff to c o m p l e t e the questionnaire, 6 7 % r e s p o n s e c a n be c o n s i d e r e d high. However, the survey suffered from a lack of power to detect relationships between variables. T h e population of British C o l u m b i a hospitals that u s e high-level disinfection is small, and thus the p o w e r to detect significant a s s o c i a t i o n s w a s s m a l l . A s the study w a s d e s i g n e d to b e exploratory, all relationships s e e n w e r e d i s c u s s e d (despite not being statistically significant at conventional cut-points) b e c a u s e they might offer s o m e important insights into the i s s u e s being e x a m i n e d here. For e x a m p l e , the regression a n a l y s i s of factors a s s o c i a t e d with alternative u s e offers s o m e useful understanding of the factors that were c o m m o n to hospitals that had already introduced alternatives and a d d s to the body of descriptive information obtained from the survey. A s d e s c r i b e d earlier, the questionnaire u s e d in the s u r v e y w a s originally d e v e l o p e d to conduct a quick overview of high-level disinfection practices in the province. H a d the full potential of the s u r v e y b e e n realized while it w a s being d e v e l o p e d , the survey would h a v e b e e n d e s i g n e d differently. S o m e of the major differences that could h a v e b e e n i n c o r p o r a t e d — a n d should be a d d e d to a n y s u b s e q u e n t r e s e a r c h — are outlined here. • T h e questionnaire would be d e s i g n e d to obtain a c o m p l e t e list of departments within e a c h hospital and whether e a c h u s e d high-level disinfection. Alternately, this list would be obtained prior to c o m m e n c i n g the survey, and the questionnaire would be directed to the individual departments w h e r e high-level disinfection might be u s e d . T h i s could result in more accurate, detailed r e s p o n s e s , as well a s i n c r e a s e the p o w e r to detect statistically significant relationships. •  Q u e s t i o n s related to the u s e of sterilants and high-temperature pasteurizers would h a v e b e e n omitted.  96  •  •  •  M o r e detailed questions related to e m p l o y e e s would be included, i.e., the total n u m b e r of e m p l o y e e s in e a c h department using high-level disinfection, the n u m b e r directly involved in disinfection, and the b r e a k d o w n between full time and part time e m p l o y e e s . M o r e detailed questions related to decision making would be included, e.g., w h o actually m a k e s the final decisions, w h o h a s input into d e c i s i o n s , w h e r e health information is obtained, w a s the hospital a p p r o a c h e d by a s a l e s representative, h o w did they b e c o m e a w a r e of glutaraldehyde alternatives, were they previously a w a r e of glutaraldehyde health c o n c e r n s , are health effects of potential products r e s e a r c h e d , and what w a s the relative importance of the criteria u s e d to c h o o s e c h e m i c a l s ? Q u e s t i o n s about e m p l o y e e health would be included, e.g., w e r e there reports of health p r o b l e m s before substitution, have there b e e n reports of health problems s i n c e substitution, what products w e r e implicated in relation to health problems, what types of health problems o c c u r r e d , a n d h o w m a n y e m p l o y e e s h a v e b e e n affected?  97  CHAPTER 4. Conclusions and Recommendations 4.1 Synthesis of Predictive Toxicology and Industry Data A review of the regulatory review p r o c e s s e s u s e d in the approval of high-level disinfectants in North A m e r i c a s h o w e d that e m p l o y e e health effects are generally not o n e of the major considerations in approving and regulating n e w products, particularly in C a n a d a . Unlike the c a s e for pesticide products, efficacy, stability, and equipment compatibility all a p p e a r to take p r e c e d e n c e o v e r the health effects from e x p o s u r e to the products. G i v e n this fact, a great deal of the burden for protecting e m p l o y e e health falls to the hospitals, the provincial regulatory a g e n c i e s (Workers' C o m p e n s a t i o n B o a r d in British Columbia), and to a certain d e g r e e the e m p l o y e e s themselves. T h e risks a s s o c i a t e d with glutaraldehyde e x p o s u r e are well k n o w n . B a s e d on its structure and the limited information available, e x p o s u r e to C i d e x OPA® could possibly result in s o m e of the s a m e , or similar, o u t c o m e s . O P A solutions u s e d for high-level disinfection are at a lower concentration than glutaraldehyde solutions ( - 0 . 5 5 % versus -2%), but it is not currently known if this concentration is low e n o u g h to prevent e x p o s u r e s that might result in negative health effects. T h u s , it is essential that an a d e q u a t e detection method for O P A v a p o u r and a e r o s o l be d e v e l o p e d and validated. Despite the limited toxicological data available for peracetic acid, the combination of the available information and the results of the structure-activity relationship analysis indicates that C o m p l i a n c e ™ might h a v e l e s s potential to c a u s e a s t h m a than glutaraldehyde-based products or Cidex® O P A . T h e highly corrosive nature of C o m p l i a n c e ™ , however, requires strict protection against skin contact with the solution. It must be s t r e s s e d , however, that there is no definitive data available about the relative toxicities of any of t h e s e products. Despite the lack of health effects data, the use of C i d e x OPA® is w i d e s p r e a d in British C o l u m b i a hospitals. T h i s indicates a need for further r e s e a r c h to determine whether u s e of the product results in sufficient levels or types of e x p o s u r e to c a u s e health effects, and what t h o s e health effects might be. B e c a u s e r e s e a r c h takes time a n d the products a r e a l r e a d y in use, other risk m a n a g e m e n t strategies a r e n e e d e d until a d e q u a t e health information b e c o m e s available. It is essential that the users of high-level disinfectants be e d u c a t e d about the possible health risks a s s o c i a t e d with the different products and about available control m e a s u r e s to reduce those risks. D e c i s i o n m a k e r s should also be aware that current marketing strategies m a y m a k e unsupported c l a i m s about product safety. At this time, c l a i m s that the n e w products are safer than glutaraldehyde have not been supported by d a t a . T h e fact that no W o r k e r s ' C o m p e n s a t i o n claims have b e e n a c c e p t e d and that there have been no reports of ill health related to O P A in British C o l u m b i a is not an indication that health p r o b l e m s h a v e not or will not occur. T h e three c a s e s reported to S E N S O R in the United States suggest at least the possibility of respiratory  98  sensitization. It often t a k e s a significant period of time before health effects of new c h e m i c a l s are identified, particularly if the o u t c o m e is difficult to d i a g n o s e , a s is the c a s e with o c c u p a t i o n a l a s t h m a . T h e first mention of any respiratory effect from glutaraldehyde e x p o s u r e in the literature did not o c c u r until 1981 (Fisher 1981) and its relation to a s t h m a w a s not confirmed until m u c h later ( C o r r a d o et al. 1986; C h a n Y e u n g et al. 1993), despite the fact that it had b e e n in u s e a s a high-level disinfectant in hospitals s i n c e approximately 1960. Despite efforts to minimize e x p o s u r e in recent years, reports of glutaraldehyde-induced a s t h m a and other respiratory s y m p t o m s continue to o c c u r (Di Stefano et al. 1999; Q u i r c e et al. 1999; V y a s et al. 2000). W o r k e r s ' C o m p e n s a t i o n claims are still rare, however, e v e n though glutaraldehyde is widely a c c e p t e d a s a c a u s e of o c c u p a t i o n a l a s t h m a . Only four claims with specific mention of glutaraldehyde w e r e a c c e p t e d by the British C o l u m b i a W o r k e r s ' C o m p e n s a t i o n Board between 1997 and 2001 (personal communication, M. S a g a r , Healthcare Industry Liaison, B C W C B , J u n e 7, 2002). A systematic study of e x p o s u r e and health would be a more a c c u r a t e m e a n s of determining w h e t h e r there have been negative health o u t c o m e s related to the u s e of O P A or peracetic/hydrogen peroxide solutions.  99  4.2 Recommendations for Policy Makers and Hospital Decision Makers  4.2.1 Health-Based Product  Recommendations  It is difficult at this time to r e c o m m e n d o n e specific type of high-level disinfectant a s the best c h o i c e overall. T h i s preliminary study evaluated the potential health effects of e a c h type of product with specific focus o n respiratory sensitization. Both alternatives to glutaraldehyde e x a m i n e d in this s t u d y — p e r a c e t i c acid/hydrogen peroxide ( C o m p l i a n c e ™ ) a n d O P A (Cidex O P A ® ) — a p p e a r to h a v e lower toxic potential than glutaraldehyde. F o r the r e a s o n s d e s c r i b e d below, C o m p l i a n c e ™ currently a p p e a r s to present the least risk to e m p l o y e e health. T h e active ingredients in C o m p l i a n c e ™ c a n a c t a s skin, eye, m u c o u s m e m b r a n e , and respiratory irritants, all of which c a n result in serious c o n s e q u e n c e s to the user. S e v e r e irritant effects, however, c a n generally be a v o i d e d with effective e x p o s u r e controls. Further study is n e e d e d to e n s u r e that no additional health effects a s yet unidentified are a s s o c i a t e d with hydrogen peroxide/peracetic acid solutions. O P A , which is similar to glutaraldehyde in m a n y respects, is a potential dermal a n d respiratory sensitizer; thus, it m a y c a u s e irreversible a n d potentially life-threatening health effects a m o n g e x p o s e d e m p l o y e e s . Despite this, O P A is e x p e c t e d to be a safer alternative to glutaraldehyde b e c a u s e (1) the active ingredient is u s e d in a m u c h lower concentration, a n d (2) the v a p o u r p r e s s u r e of the raw material is reported to be m u c h lower than that of glutaraldehyde, resulting in lower e x p o s u r e s to the product vapour. T h e relevance of v a p o u r pressure, however, is s o m e w h a t uncertain; the v a p o u r p r e s s u r e of the raw material should be verified a n d the actual v a p o u r p r e s s u r e of the C i d e x OPA® solution n e e d s to be d e t e r m i n e d . Furthermore, low concentration a n d v a p o u r pressure d o not protect against d e r m a l or a e r o s o l e x p o s u r e s , indicating that sensitization would still b e p o s s i b l e . T h e fact that a s t h m a a s s o c i a t e d with O P A a m o n g healthcare workers h a s b e e n reported in the United States exemplifies this possibility. It should be noted, however, that respiratory health is only o n e consideration in c h o o s i n g high-level disinfectants. Other potential e m p l o y e e health effects have not been e x a m i n e d in this study. Furthermore, reusable semicritical d e v i c e s have great potential to s p r e a d n o s o c o m i a l infections including hepatitis, tuberculosis, a n d HIV. Efficacy is therefore a factor that must never b e c o m p r o m i s e d . O t h e r considerations with less serious c o n s e q u e n c e s but that are nonetheless important in the healthcare industry include e a s e of use, cost, a n d equipment compatibility (Fraise 1999).  4.2.2 Recommendations  for Decision Makers  S i n c e the introduction of glutaraldehyde alternatives in 1999, d e c i s i o n m a k e r s at the hospital level h a v e b e e n f a c e d with the choice between familiar c h e m i c a l s with  100  known s e v e r e health effects a n d n e w c h e m i c a l s with u n k n o w n effects. T h i s situation will continue e v e n o n c e the potential effects of the products d i s c u s s e d here are more clearly u n d e r s t o o d . N e w products a n d c h e m i c a l s will continue to b e r e l e a s e d , and d e c i s i o n s will h a v e to be m a d e in the face of uncertainty. E v e n at the time of writing, n e w high-level disinfection products are being introduced to the market. F o r example, the S t e r i l o x ™ Liquid C h e m i c a l Disinfectant S y s t e m , w h i c h u s e s a n electrochemically activated brine solution, w a s a p p r o v e d by t h e U S F D A in S e p t e m b e r 2 0 0 2 (Sterilox 2002). D e c i s i o n s a r e particularly difficult to m a k e w h e n the risks a r e not fully understood. Education a n d r e s e a r c h are therefore essential to facilitate the d e c i s i o n p r o c e s s for high-level disinfection in hospitals. A series of r e c o m m e n d a t i o n s h a s b e e n d e v e l o p e d to assist hospital d e c i s i o n m a k e r s facing this issue. • M a k e a n effort to coordinate high-level disinfection activities within the hospital o r b e t w e e n s e v e r a l hospitals. D e s i g n a t e a p e r s o n o r department that will be r e s p o n s i b l e for i s s u e s related to high-level disinfection, a n d try to involve p e r s o n n e l with s p e c i a l i z e d training in o c c u p a t i o n a l health i s s u e s . • Initiate o c c u p a t i o n a l health education programs for d e c i s i o n m a k e r s at all levels (hospital a n d regional) that are responsible for high-level disinfection. Include information related to (1) the health effects potentially a s s o c i a t e d with e a c h type of product, (2) other considerations important for high-level disinfectants s u c h a s efficacy a n d equipment compatibility, a n d (3) s u g g e s t i o n s for how to m a k e d e c i s i o n s with respect to u n k n o w n health risks. • C o n t a c t product manufacturers a n d request reports of toxicology studies. If more p e o p l e a s k for this information, corporations m a y b e c o m e more willing to r e l e a s e their d a t a . • A s k manufacturers to suggest e x p o s u r e limits (and supporting data) for n e w c h e m i c a l s that d o not have existing occupational e x p o s u r e limits. This could be d e m a n d e d a s a condition of purchase. • A s k manufacturers to supply e x p o s u r e data from in-use situations with their product, preferably from independent studies. If no reliable e x p o s u r e monitoring method is known for the c h e m i c a l , a s k for details of a sensitive analytical method. • L o b b y Health C a n a d a to require the a b o v e information a s a condition of approval of n e w disinfectants. • P r e s s u r e Health C a n a d a to release a n y toxicological or health information s u p p l i e d b y manufacturers during the regulatory p r o c e s s . E v e n if the data is c o n s i d e r e d proprietary or contains trade secrets, health information is in the public interest a n d therefore should be r e l e a s e d under the Access to Information Act. Hospital d e c i s i o n m a k e r s a r e l e s s likely to be affected by publication restrictions included in confidentiality a g r e e m e n t s than are r e s e a r c h e r s ; this might be o n e m e a n s by which to obtain the d e s i r e d data. • T r y to find additional s o u r c e s to support manufacturers' c l a i m s . Look for u n b i a s e d s o u r c e s in the literature or c h e c k with other industries. A s k manufacturers to provide e v i d e n c e for a n y health c l a i m s they m a k e .  101  •  • •  •  Look for information related to the u s e of the "new" c h e m i c a l in other industries or in other countries. Contact occupational health a n d safety organizations or professionals in a r e a s w h e r e the c h e m i c a l m a y h a v e b e e n used. A s s e s s w h e t h e r n e w c h e m i c a l s are similar in structure, m o l e c u l a r weight, or reactivity to other c h e m i c a l s with known health effects. T a k e a d v a n t a g e of W e b - b a s e d d i s c u s s i o n groups a n d L I S T S E R V s related to occupational health. T w o useful groups include the globalocchyg-list (http://groups.yahoo.com/group/globalocchyg-list/) a n d the OCC-ENV-MED-L (http://occ-env-med.mc.duke.edu/oem/occ-env-.htm) Follow the precautionary principle (deFur & K a s z u b a 2001). W h e n risks are uncertain, be a s cautious a s if potential o u t c o m e s w e r e k n o w n to be s e v e r e . U s e potentially h a z a r d o u s s u b s t a n c e s a s little a s possible, a n d u s e m a x i m u m controls for ventilation a n d prevention of dermal or respiratory e x p o s u r e s . F o r e x a m p l e , there a r e strict ventilation requirements for the u s e of glutaraldehyde in B C hospitals; t h e s e could be applied to alternatives until r e s e a r c h s h o w s that less stringent requirements a r e n e e d e d to prevent negative health o u t c o m e s . High-level disinfectants s h o u l d be u s e d in e n c l o s e d s y s t e m s a n d automatic w a s h e r s u s e d w h e n e v e r possible. Careful attention should also be given to preventing d e r m a l or a e r o s o l e x p o s u r e s . Protective g o w n s , face m a s k s , and i m p e r m e a b l e g l o v e s that extend over the forearm s h o u l d be worn w h e n working with a n y high-level disinfectant.  Certainly, s o m e of the a b o v e r e c o m m e n d a t i o n s would not be f e a s i b l e for decision makers in individual hospitals. W h e n the degree of uncertainty a n d the potential health risks are high, however, hospitals m a y be able to work together at the regional, provincial, or e v e n national level to obtain the best p o s s i b l e information and put increased p r e s s u r e o n manufacturers to support health claims.  4.2.3 Recommendations  for Policy Makers  Regulators s u c h a s the W o r k e r s ' C o m p e n s a t i o n B o a r d a r e a l s o f a c e d with difficult i s s u e s surrounding the introduction of n e w c h e m i c a l s with u n k n o w n effects. T h e Board m a y be able to e x e r c i s e its influence in obtaining toxicological a n d e x p o s u r e data from manufacturers. Regulatory bodies s u c h a s Health C a n a d a c a n legislate stricter requirements for approval of n e w products. R e q u i r e m e n t s for toxicological data a n d analytical detection methods c a n be a d d e d to the current DIN application for disinfectants. Alternatively, the authority to regulate high-level disinfectants could be transferred to the P e s t M a n a g e m e n t Regulatory A g e n c y , w h i c h already h a s m u c h more stringent health a n d toxicology data requirements for approval of n e w products. Health C a n a d a a n d other government a g e n c i e s c a n a l s o be more proactive in m a k i n g health information available through the Access to Information Act. E v e n t h e s e relatively small c h a n g e s would m a k e the introduction of n e w c h e m i c a l s into the w o r k p l a c e less uncertain a n d a lot less risky for e m p l o y e e s .  102  4.3 Future Work M a n y of the hospitals that participated in the current practices survey requested that they be informed of the findings of this study. It h a s b e e n d e c i d e d that f e e d b a c k might be best given in the form of a w e b p a g e or educational pamphlet distributed through the W o r k e r s ' C o m p e n s a t i o n Board, O H S A H , or other interested organizations s u c h a s the Health S c i e n c e s A s s o c i a t i o n . T h i s pamphlet could incorporate s o m e of the highlights of the survey a n d a s u m m a r y of the predicted toxic effects of currently available c h e m i c a l s , a s well a s a r e c o m m e n d a t i o n for the chemical that presents the least risk to e m p l o y e e health ( b a s e d o n current knowledge). P e r h a p s most valuable, the pamphlet would contain s o m e of the s u g g e s t i o n s listed a b o v e regarding w a y s to deal with the difficult d e c i s i o n s surrounding n e w c h e m i c a l s with unknown health effects. T h e work reported here w a s originally intended a s a preliminary study to d e v e l o p the protocol for an epidemiologic e x p o s u r e - r e s p o n s e study o n the relative effects of O P A and glutaraldehyde u s e in high-level disinfection. B e c a u s e O P A is being widely u s e d in British C o l u m b i a a n d a p p e a r s to have sensitizing potential, this type of study s e e m s useful. B e c a u s e the manufacturer claims that C i d e x OPA® h a s s u c h a low vapour p r e s s u r e a n d is in s u c h a low concentration that the v a p o u r cannot be detected, a valid analytic method must be identified before a study of e x p o s u r e will be feasible. Before a n epidemiological study is initiated, several short feasibility studies have been p r o p o s e d . A series of f o c u s groups with e m p l o y e e s w h o work directly with glutaraldehyde alternatives are planned to gather information about the w a y s t h e s e products are u s e d , h o w e x p o s u r e might occur, a n d whether there h a v e b e e n complaints of ill health. T o determine the potential for e x p o s u r e to O P A v a p o u r from use of the disinfectant product, laboratory simulation studies will be c o n d u c t e d to identify a sensitive a n d reliable method for detecting a n d quantifying the v a p o u r and aerosol, a n d then determine whether the solution is c a p a b l e of producing m e a s u r a b l e concentrations under normal conditions of u s e . If the results of t h e s e additional preliminary studies indicate that further research is n e e d e d , a n e x p o s u r e - r e s p o n s e study will be c o m p l e t e d to m e a s u r e the relative health effects from the u s e of different types of high-level disinfectants. T h i s will involve a prospective a s s e s s m e n t of s y m p t o m s a n d e x p o s u r e a n d a retrospective analysis of s y m p t o m s a n d disinfectant u s e . T h e prospective portion would involve quantifying the p r e v a l e n c e of respiratory, skin, a n d m u c o u s m e m b r a n e irritation a n d other somatic s y m p t o m s a m o n g e m p l o y e e s w h o handle different types of high-level disinfectants. Health effects m a y be m e a s u r e d using s t a n d a r d i z e d questionnaires, pre-/post-shift lung function testing, and possibly skin prick tests to determine atopy. E x p o s u r e to specific c h e m i c a l s would be m e a s u r e d by using p e r s o n a l e x p o s u r e monitoring with attention given to the determinants of e x p o s u r e . T h e retrospective c o m p o n e n t w o u l d involve a n examination of first aid records a n d interviews with long-term e m p l o y e e s . T h i s will be u s e d to estimate p r e v a l e n c e of glutaraldehyde-  103  related incidents resulting in first aid visits or transfers a w a y from s o u r c e s of exposure. T h e results will be a n a l y z e d to determine w h e t h e r there is an e x p o s u r e r e s p o n s e relationship b e t w e e n (1) first aid incidents or e m p l o y e e transfers and e x p o s u r e to specific high-level disinfectants, (2) current s y m p t o m s a n d glutaraldehyde e x p o s u r e , and (3) current s y m p t o m s and e x p o s u r e to glutaraldehyde alternatives. 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O c c u p a t i o n a l Health a n d Safety R e g u l a t i o n . G e n e r a l H a z a r d R e q u i r e m e n t s . R i c h m o n d , C a n a d a : W o r k e r s ' C o m p e n s a t i o n B o a r d of British C o l u m b i a . W C B . (1999b). M e t h o d 5 2 7 0 . A l d e h y d e s in air. Laboratory a n d T e c h n i c a l S e r v i c e s M a n u a l . R i c h m o n d , C a n a d a : W o r k e r s ' C o m p e n s a t i o n B o a r d of British Columbia. W C B . (2000). M e t h o d 5280. G l u t a r a l d e h y d e in air. Laboratory a n d T e c h n i c a l S e r v i c e s M a n u a l . R i c h m o n d , C a n a d a : W o r k e r s ' C o m p e n s a t i o n B o a r d of British Columbia. W e n S u n , H., F e i g a l , R. J . , & M e s s e r , H. H. (1990). Cytoxicity of glutaraldehyde and f o r m a l d e h y d e in relation to time of e x p o s u r e a n d concentration. Pediatric Dentistry 12, 3 0 3 - 3 0 7 .  114  Werley, M. S., Burleigh-Flayer, H. D., & Ballantyne, B. (1995). Respiratory peripheral s e n s o r y irritation and hypersensitivity studies with glutaraldehyde vapor. Toxicology and Industrial Health 11,: 4 8 9 - 5 0 1 . W h i t e h o u s e , J . D., S e x t o n , D. J . , & Kirkland, K. B. (1998). Infection control: past, present, a n d future i s s u e s . C o m p r e h e n s i v e T h e r a p y 24, 7 1 - 7 7 .  11  APPENDIX I. Correspondence with Health Canada Access to Information Office  116  THE UNIVERSITY  OF B R I T I S H  COLUMBIA  School of Occupational & Environmental Hygiene 3rd Floor - 2206 East Mall Vancouver, BC Canada V6T 1Z3 www.soeh.ubc.ca (604) 822-9595 te/ (604) 822-9588 fax  D e c e m b e r 26, 2001  ATI Coordinator Health C a n a d a B r o o k e Claxton Building ( 0 9 0 9 D ) Room 967D Ottawa, Ontario K 1 A 0 K 9 R e : ATI R e q u e s t D e a r ATI Coordinator, U n d e r the A c c e s s to Information Act, I request a c c e s s to the following d o c u m e n t s : - the full DIN application m a d e by J o h n s o n a n d J o h n s o n M e d i c a l P r o d u c t s for "Cidex O P A S o l u t i o n " (DIN n u m b e r 0 2 2 3 9 7 3 2 ) - the N e w Drug S u b m i s s i o n application for C i d e x O P A , if o n e w a s m a d e - any and all r e c o r d s or c o m m u n i c a t i o n s including but not limited to audits and reports, e s p e c i a l l y toxicological information, related to C i d e x O P A a n d its active ingredient, orffto-phthalaldehyde -  the full DIN application m a d e by Metrex R e s e a r c h C o r p o r a t i o n for " C o m p l i a n c e " (DIN n u m b e r 0 2 2 4 0 4 6 8 ) the N e w Drug S u b m i s s i o n application for C o m p l i a n c e , if o n e w a s m a d e any and all r e c o r d s or c o m m u n i c a t i o n s including but not limited to audits and reports, e s p e c i a l l y toxicological information, related to C o m p l i a n c e and its active ingredients, h y d r o g e n peroxide and peracetic acid.  I would like to receive the r e c o r d s a s photocopies of original d o c u m e n t s . I h a v e e n c l o s e d the required $ 5 application fee, m a d e p a y a b l e to the R e c e i v e r G e n e r a l of C a n a d a , with this request. I a s k that all other f e e s be w a i v e d . I request that you avail yourself of your power, u n d e r S e c t i o n 11 (6) of the Act, to w a i v e fees, s i n c e I a m a university r e s e a r c h e r a n d m y request is m a d e in the public interest, with the aim of informing the public. I look forward to your reply within 30 days, a s the law requires.  117  THE U N I V E R S I T Y OF BRITISH  COLUMBIA  School of Occupational & Environmental Hygiene 3rd Floor - 2206 East Mall Vancouver, BC Canada V6T 1Z3 www.soeh.ubc.ca (604) 822-9595 te/ (604) 822-9588 fax  May 2, 2002  Christiane Lortie Access to Information and Privacy Centre Address Locator 1912C1 Tunney's Pasture Ottawa, O N K 1 A 0 K 9  Dear Ms. Lortie; This is in response to the information supplied from an Access to Information request for information relating to the high-level disinfection products Cidex O P A Solution and Compliance (File number A-2001-1129 / cl). The request was originally made by Karen Rideout, a graduate student working under my supervision. We were specifically interested in receiving the toxicity testing information included in this submission. Unfortunately, all material relating to toxicity was redacted from the files we received. I wish to make an additional request for the following material: • •  •  Complete ingredient listing for Compliance Complete ingredient listing for Cidex O P A (names o f five o f the eight "other" ingredients were provided in the original request in Part 2, Line 51 o f the "Drug Submission Application") N o material relating to toxicological testing o f either product was provided. Was any toxicological data required by Health Canada as part o f the D I N application or New Drug Submission application? I f so, please provide all such material in your response.  I would like to clarify my reasons for requesting this material. I am a researcher at the University o f British Columbia conducting a research project entitled " M a k i n g Healthcare a Healthier Place to Work—Chemical High-level Disinfection in Acute Care." It involves a comparative risk assessment o f all available products for chemical high-level disinfection. Our goal is to compare the relative impact of high-level disinfectant products on the health of employees who handle the products. The project is funded by the Canadian Institutes o f Health Research and has the support o f the Workers' Compensation Board o f B C , the Occupational Health and Safety Agency for Healthcare in B C , healthcare management associations, and labour union members.  121  LOI SUR L'ACCES A L'INFORMATION  Third Party Information Third party information  20. (1) Subject to this section, the head of a government institution shall refuse to disclose any record requested under this Act that contains  61  Renseignements de tiers 20. (1) Le responsable d'une institution fiderale est tenu, sous reserve des autres dispositions du present article, de refuser la communication de documents contenant:  (a) trade secrets of a third party;  Renseignements de tiers  a) des secrets industriels de tiers;  (b) financial, commercial, scientific or technical information that is confidential information supplied to a government institution by a third party and is treated consistently in a confidential manner by the third party;  b) des renseignements financiers, commerciaux, scientifiques ou techniques fournis a une institution federal e par un tiers, qui sont de nature confidentielle et qui sont traites comme tels de facon constante par ce tiers;  (c) information the disclosure of which could reasonably be expected to result in material financial loss or gain to, or could reasonably be expected to prejudice the competitive position of, a third party; or  c) des renseignements dont la divulgation risquerait vraisemblablement de causer des pertes ou profits financiers appreciates a un tiers ou de nuire a  (d) information the disclosure of which could reasonably be expected to interfere with contractual or other negotiations of a third party.  d) des renseignements dont la divulgation risquerait vraisemblablement d'entraver des negotiations menees par un tiers en vue de contxats ou a d'autres fins.  sa comp6titivit6;  131  APPENDIX II.  Correspondence with the Information Commissioner of Canada  faculty of Graduate Studies  THE UNIVERSITY OF BRITISH  COLUMBIA  School of Occupational & Environmental Hygiene 3rd Floor - 2206 East Mall Vancouver, BC Canada V6T 1Z3 www.soeh.ubc.ca (604) 822-9595 te/ (604) 822-9588 fax  Mr. J o h n R e i d T h e Information C o m m i s s i o n e r of C a n a d a P l a c e d e Ville, T o w e r B 112 Kent Street, 2 2 Floor Ottawa, O N K 1 A 1 H 3 n d  N o v e m b e r 18, 2 0 0 2  D e a r Mr. R e i d , I wish to register a complaint under the A c c e s s to Information A c t regarding a request I m a d e for information about a high-level disinfectant product l i c e n s e d though the T h e r a p e u t i c Products Directorate of Health C a n a d a . In D e c e m b e r of 2 0 0 1 , I requested all submitted toxicological information related to C i d e x O P A Solution, DIN N u m b e r 0 2 2 3 9 7 3 2 (ATI File N u m b e r 2 0 0 1 - 1 1 2 9 ) . I received s o m e d o c u m e n t s in M a r c h 2002, but no toxicological d a t a w a s provided I a p p e a l e d this r e s p o n s e in May, a n d re-filed my request in S e p t e m b e r (ATI File N u m b e r A - 2 0 0 2 - 0 0 6 7 2 / lc). In a n O c t o b e r 17 t e l e p h o n e conversation with Linda C h o q u e t t e in the A c c e s s to Information Office, I w a s informed that s o m e toxicological data w a s s e v e r e d by the third party (the manufacturer) a s per S e c t i o n 20 of the A c c e s s to Information Act. I would like to clarify that my complaint is not with the w a y in w h i c h my request w a s handled, a s I h a v e found the A c c e s s to Information Office staff to b e very helpful. Furthermore, it a p p e a r s that Section 20 of the A c t d o e s in fact apply to the records that w e r e refused to me. T h e r e a s o n for this complaint relates to the p u r p o s e for which I r e q u e s t e d this information. I feel that it is in the public interest to r e l e a s e this information to me, despite the requirements of Section 20.1 a m a r e s e a r c h e r at the University of British C o l u m b i a conducting a research project entitled Making Healthcare a  Healthier Place to Work—Chemical High-Level Disinfection in Acute Care. It  138  APPENDIX III. Correspondence with United States Food and Drug Administration Regarding Freedom of Information Requests for Cidex OPA®  141  acuity of Graduate Studies  THE U N I V E R S I T Y OF BRITISH  COLUMBIA  School of Occupational & Environmental Hygiene 3rd Floor - 2206 East Mall Vancouver, BC Canada V6T 1Z3 www.soeh.ubc.ca (604) 822-9595 tel (604) 822-9588 fax  May 2, 2002 Food and Drug Administration Division of Freedom of Information, HFI-35 5600 Fishers Lane Rockville, MD 20857 To whom it may concern: This is in response to the information supplied from a Freedom of Information Act request for information relating to the 510(k) notification for Cidex OPA Solution (K99-1487), reference number 01021459. The request was originally made by Karen Rideout, a graduate student working under my supervision. We were specifically interested in receiving the toxicity testing information included in this submission. Unfortunately, all material relating to toxicity was redacted from the files we received. I wish to make an additional request for the following material: • • •  Complete ingredient listing. Section 14. Toxicity Data (pages 151 -195). (Indicated on page 26 of the 510(k) notification document). Appendix 18: Toxicity Testing.  Because the material received was from a variety of documents, it may be difficult to determine exactly to what I am referring. I have therefore included copies of the pages referring to this material for reference and clarification. I would like to clarify my reasons for requesting this material. I am a researcher at the University of British Columbia conducting a research project entitled "Making Healthcare a Healthier Place to Work—Chemical High-level Disinfection in Acute Care." It involves a comparative risk assessment of all available products for chemical high-level disinfection. Our goal is to compare the relative impact of high-level disinfectant products on the health of employees who handle the products. The project is funded by the Canadian Institutes of Health Research and has the support of the Workers' Compensation Board of BC, the Occupational Health and Safety Agency for Healthcare in BC, healthcare management associations, and labour union members.  144  Advanced Sterilization Products  510(k) Notification CLDEX® OPA Solution  2. 510(k) Checklist from Draft Guidance Document for LCS/HLD 1.  Cover Letter (Signed and Dated)  F i r s t  2.  Table of Contents  p a  3.  Indications for Use Form  Page 28  4.  Truthful and Accurate Statement (Signed and Dated)  Page 27  5.  SlOfk) Summary  6.  Comparison of Germicide to Predicate  Page 34  7  Physical and Chemical Properties  Page 50  8.  Stability Data  .Page 61  9.  Labeling  .Page 68  10.  Potency Test Data  Page 105  11.  Simulated-use Test Data  Page 126  12.  In-Use Test Data  Page 131  13.  Residue Data  Page 140  14.  Toxicity Data  Page 151  15.  Material/Device Compatibility Data  Page 196  16.  Chemical Indicator Labeling  Page 90  17.  Chemical Indicator Performance Data  Page 229  S  P a  S  P a  e  S  c  1  c  2  3  1  146  Advanced Sterilization Products  510(k) Notification CIDEX* OPA Solution  Table 5: c i d e x ® o p a Solution Formulation  Formjr EPA Registration Number :707S-17 *Or equivalent supplier  Appendix 2 addresses manufacturing information on these raw materials  147  Appendix 18: Toxicity Testing i 13  57 89  .  109  :  123 157 170  ;  .  259 345  1  391 400  i  419 448 519  575 596 631 658  148  APPENDIX IV. Toxicity Comparison Tables: Glutaraldehyde (Cidex®) vs. Ortho-phthalaldehyde (Cidex OPA®), Obtained from Freedom of Information Request to the Food and Drug Administration  150  510(k) Notification CIDEX* OPA Solution  Advanced Sterilization Products  3. Comparison of Toxicology a. TOXICITY TESTING SUMMARY: RAW MATERIAL Table 9; Raw Material Toxicity Comparison Characteristic/Criteria glutaraldehyde 50%  OPA >99%  Subchronic Oral Toxicity Study in Rats with orr/io-phthalaldehyde Summarized on page 164 Study found in Appendix 18  Rat - (via drinking water) N O E L range: 5-7 mg/kg/day  Rat - (via oral gavage) NOEL range: 5 mg/kg/day  Acute Oral Toxicity Study in Rat with orthophthalaldehyde Summarized on page 166 Study found in Appendix 18  Rat-LDK, 733 mg/kg  Rat - LD 121 mg/kg Category  Mutagenicity - Gene Mutation in Bacteria (Ames Assay) with ortAo-phthalaldehyde Summarized on page 175 Study found in Appendix 18  Mixed responses  Negative  DNA Damage/Repair in vitro in Rat Primary Hepatocytes with orr/io-phthalaldehyde Summarized on page 178 Study found in Appendix 18  Mixed responses  Negative  Mutagenicity - Gene Mutation in Mammalian Cells in vitro with ortAo-phthalaldehyde Summarized on page 180 Study found in Appendix 18  Not Tested  Negative  Sister Chromatid Exchange Assay in vitro in Chinese Hamster Ovary Cells with orthophthalaldehyde Summarized on page 182 Study found in Appendix 18  Mixed responses  Weakly positive  Mutagenicity - Acute in vivo Cytogenetics Assay in Rats with ort/io-phthalaldehyde Summarized on page 177 Study found in Appendix 18  Negative  Negative  Developmental Toxicity (Teratology) Study in Rats with ort/io-phthalaldehyde Rat - N O E L range: 50-100 Summarized on page 185 mg/kg/day Study found in Appendix 18  50  n  Rat - NOEL: 20 mg/kg/day  151.  510(k) Notification CIDEX* OPA Solution  Advanced Sterilization Products  b. TOXICITY TESTING SUMMARY: SOLUTION Table 10:  CIDEX* OPA Solution Toxicity Comparison  Characteristic/Criteria Primary Dermal Irritation Study in Rabbits with Aqueous ortho-  CIDEX* Activated Dialdehyde Solution  CIDEX OPA Solution 9  Rabbit - Category HI/TV minor erythema and edema (1)  Rabbit - Category IV Non-irritating  Guinea Pig - Sensitizer  Guinea Pig - Non sensitizer  Not tested  Rabbit - LD50 >2000 mg/kg  Not tested  Rat - LD50 >5000 mg/kg  phthalaldehyde Solution Summarized on page 171 Study found in Appendix 18  Rabbit - Category I/TJ Severe corneal injury, iritis (2) Category IV  Rabbit - Category III Moderate irritant  Acute Inhalation Summarized on page 172  Four Hour L C (96ug/L)  Not tested because of very low vapor pressure  phthalaldehyde Solution Summarized on page 151 Study found in Appendix 18 Epicutaneous Skin Sensitization Test in Guinea Pigs with Aqueous ortho-  phthalaldehyde Solution Summarized on page 152 Study found in Appendix 18 Acute Dermal Toxicity Study in New Zealand White Rabbits with ortho-  phthal aldehyde Summarized on page 158 Study found in Appendix 18 Acute Single Dose Oral Toxicity in Rat with Aqueous ortho-  phthalaldehyde Solution Summarized on page 169 Study found in Appendix 18 Primary Eye Irritation Study in Rabbits with Aqueous ortho-  J0  - 23.5 ppm v/v  152  APPENDIX V. Correspondence with the United States Food and Drug Administration Regarding Freedom of Information Request for Compliance™  153  Faculty of Graduate Studies  THE U N I V E R S I T Y OF BRITISH C O L U M B I A School of Occupational & Environmental Hygiene 3rd Floor - 2206 East Mall Vancouver, BC Canada V6T 1Z3 www.soeh.ubc.ca (604) 822-9595 tel (604) 822-9588 fax  May 2,2002 Food and Drug Administration Division of Freedom of Information, HFI-35 5600 Fishers Lane Rockville, MD 20857 To whom it may concern: This is in response to the information supplied from a Freedom of Information Act request for information relating to the 510(k) notification for Endo-Spor Plus (K972708), reference number 01021458. The request was originally made by Karen Rideout, a graduate student working under my supervision. We were specifically interested in receiving the toxicity testing information included in this submission. Unfortunately, all material relating to toxicity was redacted from the files we received. I wish to make an additional request for the following material: • •  Complete ingredient listing. Attachments 24 through 29, referred to on page 75 (Table I)  Because the material received was from a variety of documents, it may be difficult to determine exactly to what I am referring. I have therefore included copies of the pages referring to this material for reference and clarification. I would like to clarify my reasons for requesting this material. I am a researcher at the University of British Columbia conducting a research project entitled "Making Healthcare a Healthier Place to Work—Chemical High-level Disinfection in Acute Care." It involves a comparative risk assessment of all available products for chemical high-level disinfection. Our goal is to compare the relative impact of high-level disinfectant products on the health of employees who handle the products. The project is funded by the Canadian Institutes of Health Research and has the support of the Workers' Compensation Board of BC, the Occupational Health and Safety Agency for Healthcare in BC, healthcare management associations, and labour union members. I have no commercial interest in any of this information. I am making similar requests for toxicity information for all other recently marketed products, and I am making requests to all 156  51000 CHECKLIST FOR ENDO-SPOR PLUS™ LIQUID CHEMICAL STERTJLANT (Continued) Yes Present Omission Justified 1. Cover Letter  Yes  2.  Yes  Table of Contents  No Inadequate Omitted  Comments  3. SMDA Information  Yes  See Tab C  4. Comparison of GermicidetoPredicate  Yes  See Tab D No  5. EPA Data  Not Required See Tab E  6. Physical and Chemical Properties  Yes  See Tab F  7.  Yes  See Tab O  8. Efficacy Data  Yes  See Tab H  9.  Yes  See Tab I  Yes  See Tab I  Labeling  Residue Data  10. Toxicity Data  See TabJ  1 1 . Compatibility Data 12. Indicators  Yes  Adequate justification as to why an indicator is not required. See Tab K  13. Contacts and Addresses  Yes  See Cover Letter  158  A cotton tipped swab was pre-moistened with deionized water and rubbed over the entire external surface of each endoscope. The swab (cotton tip only) was placed into 15 ml deionized water and analyzed for the presence of residue. The scrubbing segment of each procedure was repeated four times for a total of five scrubs and the swabs were pooled. The reprocessing was repeated for a total of two times to prove repeatability of the tests. The active ingredient level was measured using recognized methods by qualified analytical chemistry personnel. As a control, one endoscope was processed as described above, but deionized water was used in place of the disinfectant. The test is considered acceptable for evaluation of test results if the control instrument leaves no residue. The results of this testing showed no hydrogen peroxide and no peracetic acid detected in the test endoscopes or in the control endoscopes. There was no hydrogen peroxide and no peracetic acid detected in the rinse water of the test endoscopes or in the rinse water of the control endoscopes. When tested for residues, the Endo-Spor Plus™ sterilant/disinfectant leaves no discernible residues on flexible fiberoptic endoscopes. 2. Toxicity Testing (See Attachments 24 through 29) Testing was performed to determine the potential toxicological affects of exposure to Endo-Spor Plus™ liquid chemical germicide. The individual tests performed and a discussion of the results follow. 1- Primary Dermal Irritation (See Attachment 24) Primary Dermal Irritation Testing was performed to determine the dermal irritation potential of the Hydrogen Peroxide/Per ace tic Acid solution to the intact skin of the rabbit using a single, semi-occlusive patch test procedure. This testing was performed by 1 in compliance with 40 CFR 158.135 and 158.70, paragraph C Pesticide Assessment Guidelines Subdivision F:Hazard Evaluation Human and Domestic Animals, Series 81-5. The test results showed that the Endo-Spor Plus™ solution was not a primary dermal irritant. The protocol data, and final report is included as Attachment 24.  -75-  159  APPENDIX VI. Compliance™ Toxicity Summaries Obtained from Freedom of Information Request to the United States Food and Drug Administration  161  2- Toxicity Testing (See Attachments 24 through 29) Testing was performed to determine the potential toxicological affects of exposure to Endo-Spor Plus™ liquid chemical germicide. The individual tests performed and a discussion of the results follow. 1.  Primary Dermal Irritation (See Attachment 24) Primary Dermal Irritation Testing was performed to determine the derma] irritation potential of the Hydrogen Peroxide/Peracetic Acid solution to the intact skin of the rabbit using a single, semi-occlusive patch test procedure. This testing was performed by | in compliance with 40 CFR 158.135 and 158.70, paragraph C Pesticide Assessment Guidelines Subdivision RHazard Evaluation Human and Domestic Animals, Series 81-5. The test results showed that the Endo-Spor Plus" solution was not a primary dermal irritant. The protocol data, andfinalreport is included as Attachment 24.  -75-  162  2.  Acute Dermal Toxicity (See Attachment 25) Acute Dermal Toxicity testing was performed to determine the acute dermal toxicity of the Hydrogen Peroxide/Peracetic Acid solution in rabbits at the dose of two grams per kilogram of body weight This testing was performed by\ I in compliance with 40 CFR 158.135 and 158.70, paragraph C Pesticide Assessment Guidelines Subdivision F:Hazard Evaluation Human and Domestic Animals, Series 81-2. The test results showed that the dermal LD50 of Endo-Spor Plus™ solution in rabbits was considered to be greater than two grams per kilogram. The protocol data, and final report is included as Attachment 25.  3.  Ocular Irritation Test (See Attachment 26) Ocular Irritation Testing was performed to determine the ocular irritation potential of the Hydrogen Peroxide/Peracetic Acid solution following instillation in the eyes of rabbits. This testing was performed byj | in compliance with 40 CFR 158.135 and 158.70, paragraph C Pesticide Assessment Guidelines Subdivision F:Hazard Evaluation Human and Domestic Animals, Series 81-4. The test results showed that the Endo-Spor Plus™ solution produced irreversible irritation in the eyes of two of six rabbits. A warning will be added to the Endo-Spor Plus™ labeling warning against the corrosiveness and recommending the use of persona] protective equipment for protection of eyes, face and hands. The protocol data, and final report is included in as Attachment 25.  4.  Acute Oral Toxicity (See Attachment 27) Acute Oral Toxicity testing was performed to determine the acute oral toxicity of the Hydrogen Peroxide/Peracetic Acid solution at the dose level of five grams per kilogram of body weight. This testing was performed by\ I in compliance with 40 CFR 1 C O lie J tea iir\ — — - • Assessment Guidelines 158.135 and 158.70, paragraph C Pesticide Subdivision FrHazard Evaluation Human and Domestic Animals, Series 81-1.  -76-  163  The test results showed that the oral LDjg of the Endo-Spor Plus™ solution in rabbits was considered to be greater than five grams per kilogram. Thefinalreport including protocol, and data is included as Attachment 27. 5.  Skin Sensitization (See Attachment 28) Split Adjuvant Guinea Pig sensitization on Hydrogen Peroxide/Peracetic Acid solution was performed to determine if the formulation will cause an allergic contact dermatitis (sensitization^ in guinea pigs. This was performed by^ \ in compliance with 40 CFR 158.135 and 158.70, paragraph C Pesticide Assessment Guidelines Subdivision F:Hazard Evaluation Human and Domestic Animals, Series 81-6, pages 59-62. The test results showed that the Endo-Spor Plus™ solution did not produce an allergic contact dermatitis following challenge in guinea pigs. The final report including protocol, and data is located in Attachment 28.  6.  Mutagenicity Test (See Attachment 29) The Ames Spot Test using Endo-Spor Plus™ solution was performed to determine if the formulation is mutagenic at the histidine locus in the Salmonella typhimurium strains. This testing was performed by | {in accordance with the Ames technique with and without activation with rat liver induced S-9 mix. The test results showed that a l%Endo-Spor Plus™ solution did not produce a mutagenic effect in the Ames Spot Test employing five tester strains of auxotrophic Salmonella typhimurium (his-). The final report including the test protocol, summary and result is located in Attachment 2.  7.  Literature Search (See Attachments 78 and 79) A literature search gastrointestinal lesions and hydrogen peroxide/ peracetic acid by CottreU, Ltd. The results of that literature search for gastrointestinal lesions are included with thisfilingas Attachment 78 and for hydrogen peroxide/peracetic acid as Attachment 79.  -77-  164  APPENDIX VII. Correspondence with National Technical Information Service Regarding Request for E P A Fact Sheet on 1,2-benzenedicarboxaldehyde (OPA)  165  APPENDIX Vlll. Affirmation of Non-multinational Status Form  172  Affirmation of Non-Multinational Status F o r m  This affirmation is required by the E P A interim procedures to implement Section 10 (g) of the Federal Insecticide, Fungicide, and Rodenticide Act. I have requested access to information submitted by an applicant or registrant under the Federal Insecticide, Fungicide, and Rodenticide Act (7 U.S.C. 136 et seq.) to the Environmental Protection Agency. I hereby affirm that: (1) I am not a business, or other entity engaged in the production, sale, or distribution of pesticides in countries other than the United States or in addition to the United States; and I am not an employee or agent of any such business or entity; (2) I do not seek access to the information for purposes of delivering it or offering it for sale to any such business or entity or its employees or agents; (3) I will not purposefully deliver the information (or negligently cause it to be delivered) to any such entity or to any of its employees or agents. I am aware that I may be subject to criminal penalties under 18 U.S.C. 1001 if I have made any statement of material facts knowing that such statement is false or if I willfully conceal any material fact.  Date  Signature  Name Address Organization  Check one: I am not requesting access on behalf of someone else. I am requesting access of behalf of someone else. My client is: Client  Organization  R E T U R N THIS F O R M T O :  Public Information and Records Integrity Branch (7502C), Office of Pesticide Programs, U. S. Environmental Protection Agency, Ariel Rios Building, 1200 Pennsylvannia Avenue, N.W., Washington, D.C. 20460  173  APPENDIX IX. Correspondence with US EPA Regarding Freedom of Information Request for Cidex OPA Antimicrobial  APPENDIX X. Fax from Advanced Sterilization Products Regarding Air Monitoring of Cidex OPA® Solution  08/18/01  MON 1 4 : 1 4  F A X 1 905  946  2027  0010  CSSE A D V A N C E D S T E R T U Z A T I O N P R O D U C T S a  ^OU4i»tm«*Jptm*^  company  Division of Ethicon, Inc.  AIR MONITORING OF CIDEX OPA® SOLUTION  Currently Advanced Sterilization Products (ASP) does not have a method for measuring the vapor of CTDEX OPA Solution. The raw material (>99% ortho-phthalaldehyde, has a very low vapour pressure, making vapor determination in the solution (0.55% ortho-phthalaldehyde) difficult. We are working in conjunction with Union Carbide to try to determine the vapour pressure of C I D E X OPA Solution. Using standard Industrial Hygiene methods such as N I O S H Method 500 (particulates not otherwise regulated), using a glass fiber filter, with the particulates being extracted with acctonnitrile and analyzed with H P L C , no ortho-phthalaldehyde vapour was detected in quantifiable concentrations in the air over either the solid or the 0.55% solution. This method normally detects concentrations o f organics down to the sub-ppm level. In addition, for experimental purposes, a G C / M S Headspace Analysis was conducted on the 0.55% C I D E X OPA Solution. Similarly, ortho-phthalaldehyde was not detected in this sampling even at an elevated temperature of 25°C. ASP w i l l continue to pursue other analytical methodologies that may enable us to quote a quantifiable level for the vapour pressure of C I D E X OPA Solution; however this is not available at this time.  180 TUN  1R  PAPH  APPENDIX XI. Correspondence with Advanced Sterilization Products Regarding Requests for Cidex OPA® Data  181  THE U N I V E R S I T Y OF BRITISH  COLUMBIA  School of Occupational & Environmental Hygiene 3rd Floor - 2206 East Mall Vancouver, BC Canada V6T 1Z3 www.soeh.ubc.ca (604) 822-9595 te/ (604) 822-9588 fax  David J. Fraser Director, Marketing & Sales Advanced Sterilization Products 200 Whitehall Drive Markham, ON L3R 0T5 September 18, 2002 Dear Mr. Fraser, I am writing in relation to an ongoing project examining the relative toxicities of available high-level disinfectant chemicals. As you know, I am a researcher at the University of British Columbia conducting a research project entitled "Making Healthcare a Healthier Place to Work—Chemical High-level Disinfection in Acute Care." It involves a comparative risk assessment of all available products for chemical high-level disinfection. Our goal is to compare the relative impact of high-level disinfectant products on the health of employees who handle the products. The project is funded by the Canadian Institutes of Health Research and has the support of the Workers' Compensation Board of BC, the Occupational Health and Safety Agency for Healthcare in BC, healthcare management associations, and labour union members. I would like to thank you at this time for the information regarding Cidex-OPA you have already provided to through the British Columbia Workers' Compensation Board. However, this information has not been sufficient for me to adequately compare the potential health effects of this product with those of other high-level disinfectants, and there is a lack of published material relating to the toxicity of ortho-phthalaldehyde (OPA) in solution form. As you may be aware, I submitted a Freedom of Information request to the United States Food and Drug Administration for information about C i d e x - O P A . My intent was to obtain the names of all ingredients not listed on the product label and the results of the toxicity testing performed by your company, as submitted in your 510(k) notification (K991487). I did receive some information from this request, but all ingredient and toxicity data was deleted. I was informed by the FDA that they cannot release this type of information to me without the company's permission.  182  APPENDIX XII.  Toxicity Summaries for Compliance™ Obtained from Metrex  Toxicity Studies  Oral Toxicity Dermal Toxicity/lrritation/Sensitization Ocular Irritation "Primary Dermal Irritation Test" Sponsor: Cottrell, Ltd. Gibraltar Laboratories, Inc. June 24, 1996. Lab ID# G-91579 Conclusion: Under the conditions of this test, Compliance is not a primary dermal irritant. "Acute Dermal Toxicity Test" Sponsor: Cottrell, Ltd. Gibraltar Laboratories, Inc. July 9, 1996. Lab ID# G-91854. Conclusion: Under the conditions of this test, the dermal L D was considered to be greater than 2g/kg.  5 0  of Compliance in rabbits  "Ocular Irritation Test" Sponsor: Cottrell, Ltd. Gibraltar Laboratories, Inc. July 8, 1996. Lab ID# G-91825. Conclusion: Under the conditions of this test, Compliance produced irreversible irritation in the eyes of two of six rabbits. "Acute Oral Toxicity Test" Sponsor: Cottrell, Ltd. Gibraltar Laboratories, Inc. August 2, 1996. Lab ID# G-91853. Conclusion: Under the conditions of this test, the oral L D of Compliance in rats was considered to be greater than 5g/kg. 5 0  "Split Adjuvant Guinea Pig Sensitization Test" Sponsor: Cottrell, Ltd. Gibraltar Laboratories, Inc. July 12, 1996. Lab ID# G-91931. Conclusion: Compliance did not produce an allergic contact dermatitis following challenge in guinea pigs. "Ames Spot Tesf' Sponsor: Cottrell, Ltd. Gibraltar Laboratories, Inc. July 24, 1996. Lab ID# G-92009. Conclusion: A one percent solution of Compliance did not produce a mutagenic effect in the A m e s Spot Test employing five tester strains of auxotrophic Salmonella  typhimurium.  185  APPENDIX XIII. Correspondence with Metrex/Sybron Dental Specialties Regarding Requests for Compliance™ Data  186  T H E U N I V E R S I T Y OF BRITISH  COLUMBIA  School of Occupational & Environmental Hygiene 3rd Floor - 2206 East Mall Vancouver, BC Canada V6T 1Z3 www.soeh.ubc.ca (604) 822-9595 te/ (604) 822-9588 fax  Colleen Boswell Director, Corporate Compliance Sybron Dental Specialties, Inc. 1717 West Collins Avenue Orange, CA 92867 September 18,2002 Dear Ms. Boswell, I am writing in relation to an ongoing project examining the relative toxicities of available high-level disinfectant chemicals. I am a researcher at the University of British Columbia conducting a research project entitled "Making Healthcare a Healthier Place to Work— Chemical High-level Disinfection in Acute Care." It involves a comparative risk assessment of all available products for chemical high-level disinfection. Our goal is to compare the relative impact of high-level disinfectant products on the health of employees who handle the products. The project is funded by the Canadian Institutes of Health Research and has the support of the Workers' Compensation Board of BC, the Occupational Health and Safety Agency for Healthcare in BC, healthcare management associations, and labour union members. As you may know, I submitted a Freedom of Information request to the United States Food and Drug Administration for information about your Metrex product Compliance (EndoSpor Plus). My intent was to obtain the names of all ingredients not listed on the product label and the results of the toxicity testing performed by your company, as submitted in your 510(k) notification (K972708). I did receive some information from this request, but all ingredient and toxicity data was deleted. I was informed by the FDA that they cannot release this type of information to me without the company's permission. I would like to request this information from you at this time. In the material provided to me by the FDA, the toxicity data I am interested in is Attachments 24 through 29, referred to on page 75 (Table I) in the 510(k). I would also like to reassure you that I have no commercial interest in this information. 1 am making similar requests for toxicity and ingredient information for all recently marketed products. In order to evaluate and compare products with respect to potential impact on the health of people using them, it is essential that I have access to toxicity and health information for all products.  187  T H E U N I V E R S I T Y OF BRITISH  COLUMBIA  School of Occupational & Environmental Hygiene  3rd Floor - 2206 East Mall Vancouver, BC Canada V6T 1Z3 www.soeh.ubc.ca (604) 822-9595 tel (604) 822-9588 fax  A.J. LaSota Vice President Metrex Research Corporation 1717 West Collins Avenue Orange, C A 92867  October 22, 2002  Dear Mr. LaSota, I am writing in relation to an ongoing project examining the relative toxicities of available high-level disinfectant chemicals. I am a researcher at the University of British Columbia conducting a research project entitled "Making Healthcare a Healthier Place to Work— Chemical High-level Disinfection in Acute Care." It involves a comparative risk assessment of all available products for chemical high-level disinfection. Our goal is to compare the relative impact of high-level disinfectant products on the health of employees who handle the products. The project is funded by the Canadian Institutes of Health Research and has the support of the Workers' Compensation Board of B C , the Occupational Health and Safety Agency for Healthcare in BC, healthcare management associations, and labour union members. As you may know, I submitted a Freedom of Information request to the United States Food and Drug Administration (FDA) and an Access to Information request to Health Canada for information about your product Compliance (Endo-Spor Plus). M y intent was to obtain the names of all ingredients not listed on the product label and the results of the toxicity testing performed by your company, as submitted in your 510(k) notification (K972708) to the FDA and in your New Drug Submission and Drug Identification Number (DIN) Application to Health Canada. I did receive some information from these requests, but all ingredient and toxicity data was withheld. I was informed by both the F D A and Health Canada that they cannot release this type of information to me without the company's permission. I would like to request this information from you at this time. In the material provided to me by the FDA, the toxicity data I am interested in is Attachments 24 through 29, referred to on page 75 (Table I) in the 510(k). In the material I received from Health Canada, no reference to toxicity testing was made. I would also like to reassure you that I have no  189  A p p p e n d i x XIV. M S D S for O P A Raw Material  sensation, c o u g h i n g , w h e e z i n g , laryngitis, shortness o f breath, headache, nausea and v o m i t i n g . H i g h concentrations m a y cause l u n g damage.  Ingestion: C a u s e s i r r i t a t i o n to the g a s t r o i n t e s t i n a l tract. S y m p t o m s m a y i n c l u d e n a u s e a , v o m i t i n g a n d d i a r r h e a .  Skin Contact: C a u s e s i r r i t a t i o n to s k i n . S y m p t o m s i n c l u d e redness, i t c h i n g , a n d p a i n . M a y c a u s e a l l e r g i c s k i n r e a c t i o n s .  E y e Contact: Causes irritation, redness, and pain.  Chronic Exposure: N o information found.  Aggravation of Pre-existing Conditions: N o information found.  4. First Aid Measures Inhalation: R e m o v e to f r e s h a i r . I f n o t b r e a t h i n g , g i v e a r t i f i c i a l r e s p i r a t i o n . I f b r e a t h i n g i s d i f f i c u l t , g i v e o x y g e n . G e t m e d i c a l attention.  Ingestion: G i v e large a m o u n t s o f w a t e r to d r i n k . N e v e r g i v e a n y t h i n g b y m o u t h to a n u n c o n s c i o u s p e r s o n . G e t m e d i c a l attention.  Skin Contact: I m m e d i a t e l y f l u s h s k i n w i t h p l e n t y o f w a t e r f o r at  least 15  minutes. R e m o v e contaminated c l o t h i n g and shoes. G e t m e d i c a l  attention. W a s h c l o t h i n g before reuse. T h o r o u g h l y c l e a n shoes before reuse.  E y e Contact: I m m e d i a t e l y f l u s h e y e s w i t h p l e n t y o f w a t e r f o r at l e a s t 15 m i n u t e s , l i f t i n g u p p e r a n d l o w e r e y e l i d s o c c a s i o n a l l y . G e t medical attention.  5. Fire Fighting Measures Fire: A s w i t h m o s t o r g a n i c s o l i d s , fire i s p o s s i b l e a t e l e v a t e d t e m p e r a t u r e s o r b y c o n t a c t w i t h a n i g n i t i o n s o u r c e .  Explosion: F i n e dust d i s p e r s e d i n a i r i n s u f f i c i e n t c o n c e n t r a t i o n s , a n d i n the presence o f a n i g n i t i o n s o u r c e is a potential dust e x p l o s i o n hazard.  Fire Extinguishing Media: Water spray, dry chemical, alcohol foam, or carbon dioxide.  Special Information: I n t h e e v e n t o f a fire, w e a r f u l l p r o t e c t i v e c l o t h i n g a n d N I O S H - a p p r o v e d s e l f - c o n t a i n e d b r e a t h i n g a p p a r a t u s w i t h f u l l facepiece operated i n the pressure d e m a n d or other positive pressure m o d e .  6. Accidental Release Measures R e m o v e a l l s o u r c e s o f i g n i t i o n . V e n t i l a t e a r e a o f l e a k o r s p i l l . W e a r a p p r o p r i a t e p e r s o n a l p r o t e c t i v e e q u i p m e n t as s p e c i f i e d i n S e c t i o n 8. S p i l l s : C l e a n u p s p i l l s i n a m a n n e r t h a t d o e s n o t d i s p e r s e d u s t i n t o t h e a i r . U s e n o n - s p a r k i n g t o o l s a n d equipment. R e d u c e airborne dust and prevent scattering by m o i s t e n i n g w i t h water. P i c k up spill for recovery or d i s p o s a l and place i n a closed container.  7. Handling and Storage K e e p i n a t i g h t l y c l o s e d container, stored i n a c o o l , d r y , ventilated area. Protect against p h y s i c a l d a m a g e . Isolate f r o m i n c o m p a t i b l e s u b s t a n c e s . C o n t a i n e r s o f this m a t e r i a l m a y be h a z a r d o u s w h e n e m p t y s i n c e they r e t a i n p r o d u c t r e s i d u e s (dust, s o l i d s ) ; o b s e r v e a l l w a r n i n g s and p r e c a u t i o n s listed for the p r o d u c t .  196  8. Exposure Controls/Personal Protection Airborne Exposure Limits: None established. Ventilation System: A system of local and/or general exhaust is recommended to keep employee exposures as low as possible. Local exhaust ventilation is generally preferred because it can control the emissions of the contaminant at its source, preventing dispersion of it into the general work area. Please refer to the ACGIH document, Industrial Ventilation, A Manual of Recommended Practices, most recent edition, for details. Personal Respirators (NIOSH Approved): For conditions of use where exposure to the dust or mist is apparent, a half-face dust/mist respirator may be worn. For emergencies or instances where the exposure levels are not known, use a full-face positive-pressure, air-supplied respirator. WARNING: Air-purifying respirators do not protect workers in oxygen-deficient atmospheres. Skin Protection: Wear impervious protective clothing, including boots, gloves, lab coat, apron or coveralls, as appropriate, to prevent skin contact. Eye Protection: Use chemical safety goggles and/or full face shield where dusting or splashing of solutions is possible. Maintain eye wash fountain and quick-drench facilities in work area.  9. Physical and Chemical Properties Appearance: Light yellow crystalline solid. Odor: No information found. Solubility: Negligible. Specific Gravity: No information found. pH: No information found. % Volatiles by volume @ 21C (70F): 0  Boiling Point: No information found. Melting Point:  56C(133F)  Vapor Density (Air=l): No information found. Vapor Pressure (mm Hg): No information found. Evaporation Rate (BuAc=l): No information found.  10. Stability and Reactivity Stability: Stable under ordinary conditions of use and storage. Hazardous Decomposition Products: Carbon dioxide and carbon monoxide may form when heated to decomposition. Hazardous Polymerization: Will not occur. Incompatibilities: Strong oxidizers. Conditions to Avoid: Heat, incompatibles.  197  11. Toxicological Information No LD50/LC50 information found relating to normal routes of occupational exposure. \Cancer L i s t s \ NTP C a r c i n o g e n Known Anticipated  Ingredient o-Phthalaldehyde  (643-79-8)  No  IARC C a t e g o r y  No  None  12. Ecological Information Environmental Fate: No information found. Environmental Toxicity: No information found.  13. Disposal Considerations Whatever cannot be saved for recovery or recycling should be managed in an appropriate and approved waste disposal facility. Processing, use or contamination of this product may change the waste management options. State and local disposal regulations may differ from federal disposal regulations. Dispose of container and unused contents in accordance with federal, state and local requirements.  14. Transport Information Not regulated.  15. Regulatory Information \Chemical  Inventory  Status  - P a r t 1\  Ingredient o-Phthalaldehyde \Chemical  TSCA (643-79-8) Inventory  \Federal,  Status  - P a r t 2\  (643-79-8) State  Ingredient o-Phthalaldehyde \Federal,  CERCLA (643-79-8)  No  Yes  Korea  DSL  NDSL  Phil.  No  Yes  No  Yes  No  4 International Regulations  Ingredient o-Phthalaldehyde  No  Yes  Australia  —Canada—  4 I n t e r n a t i o n a l R e g u l a t i o n s - P a r t 1\ -SARA 302RQ TPQ List  (643-79-8) State  Japan  Yes Yes  Ingredient o-Phthalaldehyde  EC  SARA 313 Chemical  No - P a r t 2\ -RCRA261.33 No  Catg.  No  -TSCA8(d) No  198  Appendix XV. M S D S for C i d e x O P A  (  0TE2%  MATERIAL S A F E T Y DATA  MS-09588-0-001  SHEET  Page 2 E F F E C T I V E : 12/01/02 REVISION: C C O 15501-10  CIDEX® OPA SOLUTION  L I K E L Y R O U T E O F E X P O S U R E : Inhalation, skin/eye contact. INHALATION: Breathing vapors may be irritating to the nose, throat, or respiratory system. May cause coughing, chest discomfort and tightness, difficulty with breathing or headache. Symptoms subside when exposure ends. Preexisting bronchitis or asthma conditions can be aggravated by exposure to this product. Heating of the solution will increase its potential for irritation. C O N T A C T WITH SKIN or E Y E S : Persons with potential exposure should not wear contact lenses. Direct eye contact with the product m a y cause stinging, excess tearing, and redness. Skin contact may cause staining ,especially after prolonged exposure. Repeated skin contact may cause dermatitis. I N G E S T I O N : Ingestion may cause irritation or chemical burns of the mouth, throat, esophagus and stomach.Symptoms may include vomiting, diarrhea, and nausea.  H A Z A R D O U S MATERIAL INFORMATION S Y S T E M  HEALTH  (BLUE)  FLAMMABILITY REACTIVITY  (  RED  )  ( Y E L L O W )  PROTECTIVE EQUIPMENT  B  RESPIRATORY  INJECTION: Injection of this material would lead to pain, mild irritation, and swelling at the site of injection.  SEE SECTION 8  I  SEE SECTION S  For routine applications.  PART II  What should I do if a hazardous situation occurs?  4. FIRST-AID M E A S U R E S SKIN E X P O S U R E : W a s h affected area immediately with plenty of soap and water for at least 15 minutes. If a skin reaction should occur, seek medical advice. E Y E E X P O S U R E : G o to the nearest eyewash station and rinse immediately with plenty of water for at least 15 minutes. Seek medical advice. INHALATION: If inhaled, remove person exposed to fresh air, and seek medical advice. I N G E S T I O N : If swallowed, do not induce vomiting. Seek medical advice immediately. C A L L P H Y S I C I A N O R YOUR LOCAL POISON CONTROL CENTER FOR MOST CURRENT INFORMATION.  5. FIRE-FIGHTING M E A S U R E S  NFPA RATING  F L A S H POINT: Not applicable.  FLAMMABILITY  F L A M M A B L E LIMITS fin air by volume. %); Not Applicable FIRE EXTINGUISHING M A T E R I A L S : Select fire extinguishing media appropriate for the surrounding area.  REACTIVITY  HEALTH  S P E C I A L FIRE-FIGHTING P R O C E D U R E S : Wear self contained breathing apparatus, eye protection and protective clothing to prevent contact with skin and eyes. OTHER  202  4 t f S k  MATERIAL S A F E T Y DATA S H E E T  CIDEX® OPA SOLUTION  MS-09588-0-001 Page 3 E F F E C T I V E : 12/01/02 REVISION: C C O 15501-10  6. ACCIDENTAL RELEASE MEASURES R E L E A S E R E S P O N S E : Responders should wear appropriate personal protective equipment (for example, chemical goggles, gloves, apron or lab coat) during the clean up of spills. S e e Section 13 for disposal. For spill neutralization, sprinkle approximately 25 grams of glycine (free base) powder per gallon of estimated CIDEX® O P A Solution spill. With a mop or other tool, thoroughly blend the glycine into the spill. Allow 5 minutes for deactivation of o-phthalaldehyde. Close storm-water drains and take other measures to protect human health and the environment, as necessary. Place all neutralized spill residue and disposable clean-up materials in an appropriate container and seal. Rinse area and tools with soap and water solution and follow with a water rinse. Dispose of in accordance with applicable U . S . Federal, state, or local regulations, or appropriate standards of Canada (see Section 13, Disposal Considerations).  PART III  How can I prevent hazardous situations from occurring?  7. HANDLING and STORAGE W O R K A N D H Y G I E N E P R A C T I C E S : All employees working with this product must be properly trained. , avoid getting this product O N Y O U or IN Y O U . W a s h thoroughly after handling this product. Avoid breathing mists and sprays of this product. U s e in a well-ventilated location. Remove contaminated clothing immediately. S T O R A G E A N D H A N D L I N G P R A C T I C E S : Store containers in a cool, dry location (15-30°C, 59-86°F), away from direct sunlight, or sources of intense heat. Store away from incompatible materials (see Section 10, Stability and Reactivity). Keep container tightly closed when not in use.Empty containers may contain residual amounts of this product; and must be triple rinsed prior to disposal.  8. EXPOSURE CONTROLS - PERSONAL PROTECTION VENTILATION A N D E N G I N E E R I N G C O N T R O L S : Use adequate ventilation as defined by local building codes, facility protocols or worker exposure legislation. If existing ventilation is not adequate, product should be used with a local exhaust hood, or in ductless fume hoods/portable ventilation system. R E S P I R A T O R Y P R O T E C T I O N : None normally required for routine use. E Y E P R O T E C T I O N : Safety glasses/goggles as authorized in 29 C F R 1910.133, applicable U.S. State regulations, or the appropriate standards of Canada. H A N D P R O T E C T I O N : Latex, P V C or nitrile rubber gloves for routine use. Latex gloves should be changed frequently (every 10-15 minutes) during use of product. Use double gloves for spill response (latex covered by nitrile rubber) and follow Accidental Release Measures provided in Section 6 of this M S D S . B O D Y P R O T E C T I O N : U s e safety glasses / chemical goggles/gloves, apron or lab coat.  9. PHYSICAL and CHEMICAL PROPERTIES E V A P O R A T I O N R A T E m - B u A c = 1): Similar to water. S P E C I F I C G R A V I T Y (water = 1): 1.0003 g/cc M E L T I N G / F R E E Z I N G POINT: 0°C (32°F) SOLUBILITY IN W A T E R : Soluble. BOILING POINT: 100°C (212°F) pH (0.1 M Solution): 7.2-7.8 ODOR: Practically odorless(mild antiseptic odour) V A P O R P R E S S U R E : Not detectable at 25°C F O R M : Liquid F L A S H POINT: Not applicable. C O L O R : Clear, light blue. H O W T O D E T E C T THIS S U B S T A N C E (warning properties): T h e color m a y be a distinguishing characteristic for this product, if spilled. The product stains proteins on surfaces to grey/black. 1  10. STABILITY and REACTIVITY 1 (detection limit=2ppb)  203  0Jmm\  MATERIAL S A F E T Y DATA SHEET  CIDEX® OPA SOLUTION  MS-09588-0-001 Page 4 E F F E C T I V E : 12/01/02 REVISION: C C O 15501-10  STABILITY: Stable. INCOMPATIBILITY: Strong acids, strong bases and strong oxidizers.  PART IV  /s there any other useful information about this material?  11. TOXICOLOGICAL INFORMATION TOXICITY DATA: Eye exposure (rabbit) = slightly irritating, but reversible in seven days (oral, rat) > 5000 mg/kg LD50 (skin, rabbit) > 2000 mg/kg L D 5 0  S U S P E C T E D C A N C E R A G E N T : This product's components are not found on the following lists: U.S. F E D E R A L O S H A Z LIST, N T P , I A R C , and C A L / O S H A . SENSITIZATION T O T H E P R O D U C T : Non sensitizer based on current data REPRODUCTIVE TOXICITY INFORMATION Mutagenicity: Rat (acute in vivo cytogenetics assay with O P A >99%) - Negative (Gene mutation in mammalian cells in vitro with O P A >99%) - Negative Ames A s s a y (gene mutation in bacteria with O P A >99%) - Negative (Sister chromatid exchange assay in vitro with Chinese hamster ovary cells O P A >99%) - weakly positive. Teratology: Rat N O E L : 20 mg/kg/day No controlled clinical study data is available. M E D I C A L CONDITIONS A G G R A V A T E D B Y E X P O S U R E : Preexisting asthma, bronchitis, or dermatitis and other skin disorders can be aggravated by exposure to this product. RECOMMENDATIONS T O PHYSICIANS: use of gastric lavage.  Probable mucosal damage from oral exposure may contraindicate the  12. ECOLOGICAL INFORMATION E N V I R O N M E N T A L STABILITY: T h e components of this product will slowly decompose into inorganic and organic compounds.  13. DISPOSAL CONSIDERATIONS W a s t e disposal must be in accordance with appropriate U.S. Federal, state, and local regulations or with regulations of Canada. Spent CIDEX® O P A Solution may be disposed down the drain, where authorized.  14. TRANSPORTATION INFORMATION THIS M A T E R I A L IS N O T H A Z A R D O U S . P E R T H E U.S. D E P A R T M E N T O F T R A N S P O R T A T I O N (49 C F R 172.101). MARINE POLLUTANT: C F R 172.101.  No component of this product is designated as a Marine Pollutant, per Appendix B to 49  TRANSPORT CANADA. TRANSPORTATION OF DANGEROUS G O O D S REGULATIONS: NOT CONSIDERED A S DANGEROUS GOODS.  THIS M A T E R I A L IS  15. REGULATORY INFORMATION U . S . S A R A R E P O R T I N G R E Q U I R E M E N T S : The components of this product are not subject to the reporting requirements of Sections 302, 304, and 313 of Title III of the Superfund Amendments and Reauthorization Act. U . S . T S C A I N V E N T O R Y S T A T U S : The components of this product are listed on the T S C A I n v e n t o r y ? ^  4 7 T S f c  MATERIAL S A F E T Y DATA SHEET  CIDEX® O P A S O L U T I O N  MS-09588-0-001 Page 5 EFFECTIVE:  12/01/02  REVISION: C C O 15501-10  C A L I F O R N I A S A F E D R I N K I N G W A T E R A N D T O X I C E N F O R C E M E N T A C T ( P R O P O S I T I O N 65): No component of this product is on the California Proposition 65 lists. ADDITIONAL CANADIAN R E G U L A T I O N S : C A N A D I A N D S L / N D S L I N V E N T O R Y S T A T U S : The components of this product are listed on the D S L Inventory. C A N A D I A N W H M I S S Y M B O L S : Class D2B: Other Toxic Effects  16. OTHER INFORMATION PREPARED BY:  Advanced Sterilization Products 33 Technology Drive Irvine, C A 92618 D A T E O F PRINTING: October 25, 1999 The information contained herein is based on data considered accurate. However, no warranty is expressed or implied regarding the accuracy of these data or the results to be obtained from the use thereof. Advanced Sterilization Products assumes no responsibility for injury to the vendee or third persons proximately caused by the material if reasonable safety procedures are not adhered to as stipulated in the data sheet. Additionally, Advanced Sterilization Products assumes no responsibility for injury to vendee or third persons proximately caused by abnormal use of the material even if reasonable safety procedures are followed. Furthermore, vendee assumes the risk in his use of the material.  205  A p p e n d i x XVI. M S D S for C o m p l i a n c e  Effective Date: June 2001 Page 2 of 4  Compliance  FIRE O R EXPLOSION  F L A S H POINT: METHOD:  non-flammable  HAZARD  L O W E R E X P L O S I V E LIMIT:  not applicable  U P P E R E X P L O S I V E LIMIT:  AUTO-IGNITION T E M P E R A T U R E :  not applicable not applicable  not applicable  M E A N S O F E X T I N C T I O N : not applicable  Normal fire-fighting procedures may be used. Use caution when approaching fire exposed containers.  S P E C I A L FIRE FIGHTING P R O C E D U R E S :  HAZARDOUS COMBUSTION PRODUCTS: EXPLOSION DATA:  not applicable  not applicable  S E N S I T I V I T Y t o M E C H A N I C A L I M P A C T : none known S E N S I T I V I T Y t o S T A T I C D I S C H A R G E : none known REACTIVITY DATA  STABILITY A T R O O M T E M P E R A T U R E :  stable solution  Incompatible with cyanides, nitric acid, potassium permanganate, reducing agents, heavy metals (i.e., iron, copper, chromium, cobalt and caustic). Although inhibited, other than short-term contact with copper, zinc, and brass causes corrosion. INCOMPATIBLE MATERIALS:  C O N D I T I O N S o f R E A C T I V I T Y : not applicable HAZARDOUS DECOMPOSITION PRODUCTS: TOXICOLOGICAL  not applicable PROPERTIES  O C C U P A T I O N A L E X P O S U R E LIMITS: ACGIH TLV-TWA*  Hydrogen Peroxide  NOTE:  *  1.4 mg/m  3  Threshold Limit Value - Ceiling of American Conference of Governmental Industrial Hygienists is concentration that can not be exceeded during any part of working exposure.  208  Effective Date: June 2001 Page 3 of 4  Compliance  E F F E C T S O F A C U T E E X P O S U R E T O P R O D U C T (Routes of entry): INHALATION:  Low or mild irritation of the nose, throat and lungs.  EYE CONTACT:  Serious eye irritant. May cause irreversible tissue damage.  S K I N C O N T A C T / A B S O R P T I O N : Mild to moderate irritation. Whitening of the skin may occur which is expected to return to normal within approximately 1 hour. No skin absorption has been reported in humans. INGESTION:  May irritate or burn mucosal membrane.  EFFECTS OF CHRONIC E X P O S U R E TO PRODUCT: SENSITIZATION T O P R O D U C T :  Not a dermal irritant.  Non-sensitizing.  CARCINOGENICITY: TERATOGENICITY:  R E P R O D U C T I V E TOXICITY:  evidence of carcinogenicity, teratogenicity, or reproductive toxicity. PREVENTIVE  No reported  MEASURES  H A N D L I N G P R O C E D U R E S a n d E Q U I P M E N T : Avoid personal contact. Prevent skin and eye contact. Do not breathe fumes, vapours or spray mist released from this product. Do not use this product at elevated temperatures. Do not allow this product to freeze. Washing facilities should be readily available when using this product. Wash thoroughly after handling and before eating, drinking or smoking. Food should not be used in area where this product is stored or handled. PERSONAL PROTECTIVE EYES:  EQUIPMENT  Wear safety glasses or face shields.  Wear protective gloves. Earliest Compliance permeation times: Butyl rubber (>8 hrs), double-gloved latex (6 hrs), double-gloved nitrile (4 hrs), single-gloved latex (1.5 hrs) or singlegloved nitrile (1 hr). SKIN:  Use in a well-ventilated area. Adequate ventilation to maintain recommended exposure limit. RESPIRATORY:  E N G I N E E R I N G C O N T R O L S : General mechanical and local exhaust ventilation to maintain airborne concentrations below occupational exposure limits. If ventilation is insufficient, wear suitable respiratory protection.  Keep containers tightly closed. Store in its original sealed container, at room temperature (15°C - 30°C), in a dry, well ventilated area. Do not allow this product to freeze. Do not store with incompatible materials. Protect containers from damage. STORAGE REQUIREMENTS:  S P I L L o r L E A K P R O C E D U R E : Ventilate area; wear protective gloves and eye gear. Wipe with sponge, mop or towel. Flush with large quantities of water. Collect liquid and discard it.  Container must be triple rinsed and disposed of in accordance with local, provincial or federal regulations. Used solution should be disposed of in accordance with local, provincial or federal regulations.  WASTE DISPOSAL:  209  APPENDIX XVII. Letter Mailed to Chief Executive Officers of Health Authorities and Healthcare Unions  A P P E N D I X XVIII. Questionnaire C o v e r Letter  APPENDIX XIX. Current Practices Survey Questionnaire  217  > s o -o  A  g  ja  «  >-o  <N  x> a § « CU fi <w CJ • = .  o co a cu c> u  c E o  « H  cu cu  .bo  2  •g  3  o,  H .o  c«  c«  SP  a  g  B  e •« o  CO cs  M  B  •a  CO  CU CU  a> cu "eu CJ  hi  , ftl w  8  cu  a  a, a. CJ c 3 o ft a < E cu CU M  CU  -s:  cu  O  •2  e>.  qu ne CU  B  cu  "  o  CJ  o u  5 c. c ft, a  OJ)  pie mei are  cu cu "&  CO  3  M  S«  .  pfl  JS cu  cu »3  ft  ® 2 "° cu JH 3 ft Si S S a ft 3 ft "3 < E .2 M  cu  K  CO  CU  s  *-> s  .2  a CO  ft -2  to co  -a  t5  ft  ft  £  -S  3 o  .S  v. 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E o u  Sol  .2  l-S«2 . u I-a .£  £ «  S  "  2  *  M**  B  e e o  ©  •3 ° es w  9  U  er a < «. <u es a  tt .2« *-° u  1-2 S  Ig € f« j I a a. a  (S  0>  ...  4»  3 °  CL ~T u. >• 3  a. «  cu  P3 fl  < B <B CJ S  .2 .a B "5 ft tc *3 o u.  ? -2s +u*  >,  ft i3 g  fl  eS  <u  I—I  V>  O  (*« cu o b  </) s  < M  ft  B  a)  S  cr a)  e  u  o  © fl  4>  fl  ft Q  0  eS  4)  s£  fl "« es  5 u 5* fl  •a  IO  u  x ©  ft ftl 6 cu  ©  es  CJ  ft  "3 O  <u  fl "a u  o ^  fl  < ft+  u  -4-» ai  8  o  o  £1 cu  3  - a fl  •R t o  ft  4>  00  i  B  41  4) ft  u.  s  V  o  Vi  a  =  B V  5 < * * es ft •  fi  «  H z  ©  ^  B  a> z  1  es PB  W H  221  Cardiology  Department  Yes No  HLD Used?  Glutaraldehyde Cidex® 3  h— CD  O  o l  Glutacide® MetriCide® Wavicide® Ortho-phthalaldehyde Cidex® OPA Glutaraldehyde + Phenol ColdSpor Hydrogen peroxide Compliance™ Sterrad System® Ethylene oxide Steris System® Water Pasteurmatic System® Other (specify)  If appropriate, specify which type or formulation of the product that you use.  Name of HLD products or equipment used (Check all that apply).  X  222  Approximately how many pieces of equipment requiring HLD are cleaned in this department per month?  Approximately how much of this product is used per month (specify litres (1) or gallons (g))?  Please complete whichever column below is easier for you.  s g _© , "3 8  bo  «cu m a B  "i  E *  s  f  j a  M  <~ 2  o _ flfl  "S  4  SL JS « s 3 2 IM  u  >d »  a  3  Oi  D.  CU  5  Cu fl  3  <u s  cn  ,u. I f .2  "H.  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Glutaraldehyde Cidex® Endo-cide™ Glutacide® MetriCide® Wavicide® Ortho-phthalaldehyde Cidex® OPA Glutaraldehyde + Phenol ColdSpor Hydrogen peroxide Compliance™ Sterrad System® Ethylene oxide Steris System® Water Pasteurmatic System® Other (specify)  If appropriate, specify which type or formulation of the product that you use.  Name of HLD products or equipment used (Check all that apply).  X  224  Approximately how many pieces of equipment requiring HLD are cleaned in this department per month?  Approximately how much of this product is used per month (specify litres (1) or gallons (g))?  Please complete whichever column below is easier for you.  Sterile Processing (SPD)/ Central Sterilization (CSD)  Department  Yes  No  HLD Used?  Glutaraldehyde Cidex® 2 t<D  TD C  32 O 6  w Glutacide® MetriCide® Wavicide® Ortho-phthalaldehyde Cidex® OPA Glutaraldehyde + Phenol ColdSpor Hydrogen peroxide 2  t-  U O C 03  o Sterrad System® Ethylene oxide Steris System® Water Pasteurmatic System® Other (specify)  If appropriate, specify which type or formulation of the product that you use.  Name of HLD products or equipment used (Check all that apply).  X  225  Approximately how many pieces of equipment requiring HLD are cleaned in this department per month?  Approximately how much of this product is used per month (specify litres (1) or gallons (g))?  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If you currently use glutaraldehyde for high level chemical disinfection in any department in your facility, please answer the following questions. If not, please skip to Question 3 on the next page. Are you thinking about using a different chemical for high level disinfection in any department in the next year? Yes • (Go to Question 2a)  No •  (Go to Question 2b)  2a. If yes, in which department do you plan to use the new chemical (check all that apply)? Name of product (Please give complete brand name) Gastroenterology Ultrasound ENT Cardiology Respiratory Operating Room CSD/SPD Other (specify):  Yes Yes Yes Yes Yes Yes Yes  • • • • • • •  No No No No No No No  • • • • • • •  Why are you considering the change?  When do you expect to make the change?  2b. If no, have you ever considered or tried an alternative product? Yes •  No •  If you answered yes above, which product did you try?  In what department(s) did you try the alternative product?  Why did you decide not to change?  227  3. If you currently use one of the newer glutaraldehyde alternatives, e.g., Cidex OPA or Compliance, for high level chemical disinfection in any department in your facility, please answer the following questions. How long has this facility been using the glutaraldehyde alternative?  What chemical(s) were used for HLD before using the alternative?  Why did you choose to use a glutaraldehyde alternative in your facility?  Do you plan to continue using glutaraldehyde alternatives for high level chemical disinfection? Yes •  No •  Why or why not?  Is there any other information regarding the use of high level disinfectants that you would like to tell us about at this time?  228  APPENDIX XX. Telephone Follow-up Guide for Current Practices Survey  C h e m i c a l H i g h - L e v e l D i s i n f e c t i o n in A c u t e C a r e• — T e l e p h o n e F o l l o w - u p t o Q u e s t i o n n a i r e  Facility Name: Contact Name: Job Title: Phone: 1.  If there are blank or missing pages, what does this mean — do these departments not do CHLD, do they not exist at this centre, or was the information not available? If n/a, can we get that information?  2.  How many people work in each department that uses high-level disinfectant chemicals? How many people are potentially exposed in each of these departments? Employed  Potentially Exposed  Gastroenterology Ultrasound/Medical Imaging ENT Cardiology Respiratory/Bronchoscopy OR SPD/CSD 3.  If they answered Question 3, page 11 (using glutaraldehyde alternative), - How did you choose this product/chemical?  - Who made/was involved in making the decision to change chemicals?  230  APPENDIX XXI: Complete Tables of Reasons for Choosing Disinfectants Table A 1 . Reasons for not introducing glutaraldehyde substitutes (n=18). Reason Cost Health concerns No advantage over glutaraldehyde Damage to equipment New equipment made change unnecessary Staining Efficacy of old product Lack of information Hospital policy  nj%) 6 (33%) 4 (22%) 3 (17%) 3 (17%) 2 (11 %) 1 (6%) 1 (6%) 1 (6%) 1 (6%)  Table A 2 . Reasons for considering glutaraldehyde substitution (n=7). Reason Health concerns Cost Shelf/Reuse life Previous product not available Employee health problems Less fumes Trial results  n_(%) 4 (57%) 1 (14%) 1 (14%) 1 (14%) 1(14%) 1 (14%) 1 (14%)  Table A 3 . Reasons for introducing glutaraldehyde substitutes (n=26). Reason Health concerns Employee health problems Processing time Odour Decrease exposure Efficacy Regional change Previous product not available Patient safety Equipment compatibility Used elsewhere Vapour concentration Decrease preparation time Fumes Sales representative recommended Minimize mixing errors Decrease volume used No mixing - can use part bottle Available in hospital stores  n (%) 12 (46%) 5(19%) 5 (19%) 5 (19%) 2 (8%) 2 (8%) 2 (8%) 2 (8%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%)  Table A4. Reasons for continuing tb use alternatives (n=24). Reason  Health concerns Only known alternative Employee health problems Regional change Ease of use Cost Processing time Odour Equipment compatibility Patient safety  n  {%)  8 (33%) 5(21%) 2 (8%) 2 (8%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%)  Table A 5 . Criteria for choosing specific alternatives (n=26). How C h o s e n  Sales rep recommended Only known alternative Processing time Cost Health concerns Decrease exposure Efficacy Odour In-service education Guess Shelf/reuse life Equipment manufacturer recommended Used elsewhere Vapour concentration Region decided Fumes Minimize mixing errors Don't know Previous product not available Decrease volume used User friendly Seminar Trial results  n  (%)  10 (38%) 5 (19%) 5 (19%) 4 (15%) 3 (12%) 3 (12%) 3 (12%) 3 (12%) 2 (8%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%) 1 (4%)  232  c o "35  10 CD i_  Ui 0> Q_ u  to Ui  o tl)  ro 'C  rs >  'E z> CO  cz g  to ra  c  >  E  CD  O  ro  c  'I  CD  TJ TJ  -4—  1  c ra O c  IX  < ><  X >< Q Z LU CL CL <  E  'co >.. Rl z ro o. £ CO 1 2 5 o 0 aj 'c •o o CO rs o o  CD  Q  _1,  CD T3  Q X  I  ,_l  T3 CD >  o > cz  x  o JZ CD O  a) ro ai  ro  O  ii  4—'  o >? c Z!  CD  o c CD CO CD  0 CO  ro  •g  031 Z i | CO  o c E cz Io  O  CD  CP  iOL  — 4 cCD  0  E c/) •c ro o o. c CO CD I , X Q CO o CD s  3  E  •d  I  ro > ro CO  *i_  CD  >  JZ  CD <  UJ _J CQ < I-  _J  T3 _J  CL CO  I i_  X  0 J3 TO  o  I-a  1  J<  o ro o a. o c CD o c ro Q o CO  03 O  0  o c  CD  CD  rovi hsd  (0 (0  Q) N  CO  0 3  I-a  o o i_ io 3 tz c o CD o  CD  o  CQ  to c o ro 'o o  E  ro  CD  CO  cz o g , o l"o c o CO  QJ  ll  £  CD  cz o o CD  ro CM  O JZ  O  oJ  cz o  CO  CO  CO  CD  co| ZJ eg 0  ro "O  M —  CO  9i  El El  0 "O CO ZJ  o 233  or  ohsdept  region  a. in  dminfcon  dmauthor  dmother  dmoutsid  interior  northern  vanisle  fraser  vancoast  province  Ui  dmsenadm  CD  dmdepuse  0057  1732  0746  4653  0040  2122  0533  0427  4558  4829  8722  0611  2644  5121  0361  2073  4782  0533 6715 0016 5487 1906  1389  0175  0833  o 6344  0041  o  7638  0504  o  7314  0845  o  0208 o  0002  3717  o  4826  1273 0897  o  0032 o  3271  0924  o  1983  1510 6243  o  2759  0022  o  1819 o  0001  0340 4276  o o o o o o o o o 2160  0352  o 2199  0385  0859 2673 2769 0456 3254 1764 8657 1087 8403 1087 1167  4160  03  0418  9702  1087 8140  o o o  7238  1678  o  1634  5286  o  6250  0156  o  6057  4869  o  2285  4007  o  8893  9122  o  4022  6810  o  5427  6572  o  0591  0859  o  1617  1294  o  4228  2605  o  2141  2369  um  0010  6695  0156  oq o o  o o oo o  0355  6962 0051  o  0607  0035  o o  0018  2844  2141  o o  7758  8928  or  o o o 2057 3863  2721  o o o o o o o o o  3551  1087  o  1768  8403  6942 6677 8167 0041 3899 2449 3899 5561  3933 8244 2498 2138 5861 3566 8031 0652 0116  0485 2274  2983 0071 2983 4764  o o o  1087  2721  0002  4085  9126  o  o  0156  o  6886  o  o  5366  5286  9430 o o  8236  3213  4808  mother dmoi itsul  o o 0373  7909  o o  1282  o  0389  o o  5286  1941  1114  o o  2607  o  4879  3113  0959  ithor  o  1840  o  1764  o  4007  o  4160  o  0147  o  0759  o  6942  1510  o o  0007  o  o  0795  9126  o 1541  3021  o 7183  6842  o 0702  5861  o 3110  7800  o 0780  5808 4879  dms afety dmde puse dmsenadm drhin fcon  ire.  0904  7632  ohs dopt D)  dmsafety  0001 o  0045  gion 0)  um  0850  <0. 0001  ZIS  towncat  tow neat  ds  ecat  •D  o  >'fc TJ'  o o o  o o o o o o o o o  o o o o o o o o o o  o o  o o  o o o o o o o o o o o  o o o o o o o o o o o  o o o o o o o  o  V  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  V  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  o  234  CD  o o c  0  k_  L_  o o c o  CO L_  CL  CD <JJ  00  <  LU  _1  CQ < 0)  R=0.4148 p=0.0025 R=0.0559 p=0.6967 R=0.1271 p=0.3742  .0 CD  cn  d i-  CM CM  T-  II  II  L O O  d o cn r-10 — r  R=0.1656 p=0.2454 R=0.1740 p=0.2222 R=-0.1123 p=0.4329 R=0.1956 p=0.1682 R=-0.2643 p=0.0609 R=-0.0524 p=0.5520 R=0.1173 p=0.4123  um  R=0.4596 p=0.0007  R=0.2627 p=0.0626  ge  CO  O  d  11 C D  CC II  d r- cn  T-  d  II L O  CC ci  d n  R=0.2124 p=0.1346 R=-0.2405 p=0.0892 R=0.0621 p=0.6649 R=-0.0576 p=0.6883  R=-0.0773 p=0.5896 R=0.0971 p=0.4977 R=-0.0391 p=0.7853 R=0.0763 p=0.5949 R=-0.0570 p=0.6914 R=0.1445 p=0.3117 R=0.0154 p=0.9148 R=0.2468 p=0.0808 R-0.1419 p=0.3207 R=0.2536 p=0.0726 R=-0.0505 p=0.7249 R=0.1996 p=0.1603  R=0.0551 p=0.7012 R=0.2486 p=0.0786 R=-0.3416 p=0.0141 R=-0.1139 p=0.4261 R=0.1177 p=0.4109  R=-0.2331 p=0.0997 R=-0.2229 R=-0.11952 p=0.4035 p=0.1159 R=-0.0551 p=0.7012 R=0.0601 R=-0.1612 p=0.6752 p=0.2586  R=0.0100 p=0.9444  dmsafety dmdepuse dmsenadm dminfcon jdmauthor d-uuthpr  o  CC  CO  O  CC  O CD CD  CC  Tt Tt Tt  d d n ll  CL  cc °-  CO C D CO C M 00 t- C O  oo  d d ll ll  CC CL  R=0.0484 p=0.7361  R=0.1740 p=0.2222 R=0.4093 p=0.0029 R=0.3388 p=0.0150 R=-0.0210 p=0.8837 R=0.1139 p=0.4261 R=-0.2405 p=0.0892 R=0.1553 p=0.2764 R=-0.1523 p=0.2862 R=0.2799 p=0.0467 R=-0.1377 p=0.3353  J_  CC cu  R=0.0131 p=0.9271 R=0.3400 p=0.0146 R=0.2792 p=0.0473 R=-0.2241 p=0.1140 R=0.3835 p=0.0055 R=0.0271 p=0.8501 R=-0.1055 p=0.4611 R=0.0120! p=0.9335  R=-0.0258 p=0.8573 R=-0.0491 p=0.7322 R=0.2180 p=0.1244 R=-0.0352 p=0.8063 R=0.4551 p=0.0008 R=0.0230 p=0.8730 R=-0.3573 p=0.0101 R=0.3231 p=0.0207 R=0.1959 p=0.1684  or  CD CD  IT) C D CM  R=-0.4963 p=0.0002 R=0.3366 p=0.0157 R=0.1106 p=0.4396 R=0.1006 p=0.4822  o  R=0.5529 p<0.0001 R=0.7088 p<0.0001 R=0.0993 p=0.4880 R=0.2179 p=0.1246 R=0.2327 p=0.1004 R=0.1748 p=0.2198 R=0.4693 p=0.0005  it ohsavail  cz  region  o  towncat  CO  sizecat  CD > CD "D  11  R=0.7871 towncat p<0.0001 R=0.4654 region p=0.0006 R=0.6547 p<0.0001 ohsavail R=0.0700 or p=0.6255 R=0.2347 p=0.0973 R=0.2456 um p=0.0824 R=0.1619 sp p=0.2562 R=0.4620 dmsafety p=0.0006 R=0.2456 dmdepuse p=0.0824 R=-0.3324 dmsenadm p=0.0172 R=0.3509 dminfcon p=0.0116 R=-0.0850 dmauthor p=0.5532 R=0.1641 dmother p=0.2499 R=0.0685 dmoutsid p=0.6331  ds  CO Q) .O  i~T- cn i-t - L O oo o co cn cn cn  r-d d dn nd i! " CC CL  O  T t C O r-~ LO T t f-~  Tt  a  T" |^ T- 00  d d n ll  CM  00  CL  1^ T t  CD  r—  Tt  o d d ll ll  O  o  CC  CL  cn o  o cn d d d d ll n  CC  CC CL  CL  T3  LO C D CO O Tt  oo T- T t d d II u  CL  cu  235  

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