H. Frederick Frasch National Institute for Occupational Safety and Health Morgantown WV, USA

Transcription

1 H. Frederick Frasch National Institute for Occupational Safety and Health Morgantown WV, USA

2 H. Frederick Frasch National Institute for Occupational Safety and Health Morgantown WV, USA

3 Over 80,000 chemicals are in industrial use with an estimated additional 700 new chemicals being introduced annually. In the US, 20.6% of adult workers (~30,000,000) report frequent occupational skin contact with chemicals during the 12 months preceding the interview. The 2010 National Health Interview Survey Occupational Health Supplement (

4 DAD = E f abs DAD E f abs Dermal absorbed dose (mass/---) Exposure (mass/---) Absorbed fraction Compare DAD with AOEL (Acceptable Operator Exposure Level )

5 The Acceptable Operator Exposure Level (AOEL) is applied in the assessment and review of pesticides and biocides within Europe. The AOEL is based on the highest level at which no adverse effect is observed in tests in the most sensitive relevant animal species or, if appropriate data are available, in humans.

6 DAD = E f abs DAD E f abs f abs = Dermal absorbed dose (mass/---) Exposure (mass/---) Absorbed fraction absorbed mass mass/area applied load mass/area (may include skin depot) (% absorption = f abs x 100%)

7 f abs = absorbed mass mass/area applied load mass/area

8 Guidance on Dermal Absorption. EFSA Panel on Plant Protection Products and their Residues (PPR). EFSA Journal 2012; 10(4): 2665.

9 Review of available data on pesticide formulations indicates that: the rate of absorption is generally inversely related to the concentration of the active substance. Exceptions may include irritant and volatile compounds, and the presence of coformulants that strongly affect absorption. dermal absorption of > 27% is only seen with formulations having active substance contents of < 4% (see opinion section ). for diluted products and in use dilutions, dermal absorption studies do not support a default value below 75% (see opinion section ).

10 Review of available data on pesticide formulations indicates that: the rate of absorption is generally inversely related to the concentration of the active substance. Exceptions may include irritant and volatile compounds, and the presence of coformulants that strongly affect absorption. dermal absorption of > 27% is only seen with formulations having active substance contents of < 4% (see opinion section ). for diluted products and in use dilutions, dermal absorption studies do not support a default value below 75% (see opinion section ).

11 Review of available data on pesticide formulations indicates that: the rate of absorption is generally inversely related to the concentration of the active substance. Exceptions may include irritant and volatile compounds, and the presence of coformulants that strongly affect absorption. dermal absorption of > 27% is only seen with formulations having active substance contents of < 4% (see opinion section ). for diluted products and in use dilutions, dermal absorption studies do not support a default value below 75% (see opinion section ).

12 Review of available data on pesticide formulations indicates that: the rate of absorption is generally inversely related to the concentration of the active substance. Exceptions may include irritant and volatile compounds, and the presence of coformulants that strongly affect absorption. dermal absorption of > 27% is only seen with formulations having active substance contents of < 4% (see opinion section ). for diluted products and in use dilutions, dermal absorption studies do not support a default value below 75% (see opinion section ).

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14 The analysis supports dermal absorption defaults of 6% for liquid concentrates, 2% for solid concentrates, and 30% for all spray dilutions, irrespective of the active substance concentration. M Aggarwal et al., Regulatory Toxicology and Pharmacology 68: , (190 GLP and OECD compliant human in vitro) It confirmed previously proposed default values irrespective of active substance loading. M Aggarwal et al., Regulatory Toxicology and Pharmacology 72: 58-70, (Additional 171 studies 361 total)

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16 6% 6% 30%

17 The assessment of the scientific quality of studies indicated that they fulfil the regulatory standards and that the provided consistent and solid datasets should be analysed applying the appropriate (model-based) statistical protocol in order to revise the current guidance EFSA guidance on dermal absorption. The draft EFSA revised guidance on dermal absorption is planned to be published on the EFSA website for public consultation by the end of the year. You will have the opportunity to provide comments that should be taken into account by EFSA.

18 The analysis supports dermal absorption defaults of 6% for liquid concentrates, 2% for solid concentrates, and 30% for all spray dilutions, irrespective of the active substance concentration. M Aggarwal et al., Regulatory Toxicology and Pharmacology 68: , (190 GLP and OECD compliant human in vitro) It confirmed previously proposed default values irrespective of active substance loading. M Aggarwal et al., Regulatory Toxicology and Pharmacology 72: 58-70, (Additional 171 studies 361 total)

19 The analysis supports dermal absorption defaults of 6% for liquid concentrates, 2% for solid concentrates, and 30% for all spray dilutions, irrespective of the active substance concentration. M Aggarwal et al., Regulatory Toxicology and Pharmacology 68: , (190 GLP and OECD compliant human in vitro) It confirmed previously proposed default values irrespective of active substance loading. M Aggarwal et al., Regulatory Toxicology and Pharmacology 72: 58-70, (Additional 171 studies 361 total)

20 The analysis supports dermal absorption defaults of 6% for liquid concentrates, 2% for solid concentrates, and 30% for all spray dilutions, irrespective of the active substance concentration. M Aggarwal et al., Regulatory Toxicology and Pharmacology 68: , (190 GLP and OECD compliant human in vitro) It confirmed previously proposed default values irrespective of active substance loading. M Aggarwal et al., Regulatory Toxicology and Pharmacology 72: 58-70, (Additional 171 studies 361 total)

21 Concentration = mass/volume Load = mass/area of exposure or.. volume/area of exposure Mass Load = Concentration x Volume Load -For any given concentration, mass can be varied depending on volumetric load. -For any given load, mass can be varied depending on concentration.

22 Concentration = mass/volume Load = mass/area of exposure or.. volume/area of exposure Mass Load = Concentration x Volume Load -For any given concentration, mass load will vary with volumetric load. -For any given volume load, mass load will vary with concentration.

23 DAD = E f abs DAD E f abs f abs = Dermal absorbed dose (mass/---) Exposure (mass/---) Absorbed fraction absorbed mass mass/area applied load mass/area

24 In addition to the concentrated product, the greatest dilution (lowest concentration) of the product recommended for use should be tested. An application that mimics human exposure, normally 1-5 mg/cm 2 of skin for a solid and up to 10 ml/cm 2 for liquids, should be used.

25 Concentration = mass/volume Load = mass/area of exposure or.. volume/area of exposure Mass Load = Concentration x Volume Load -For any given concentration, mass load will vary with volumetric load. -For any given volume load, mass load will vary with concentration.

26 Dilution Rate Percent absorbed 0 dilution (neat product) x aqueous dilution 67

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28 Dilution f abs Maximum Exposure (mg/kg/day) DAD (mg/kg/day) AOEL (mg/kg/day) OK?

29 1.0 Dilution rates Concentrate (0 dilution) Dilute (1000x) Absorbed fraction of applied mass Time (h) 0.01

30 Applied load: 10 L/cm 2 (11.2 mg/cm 2 ) 0.6 Absorbed fraction of applied mass Time (h) 0.01

31 0.6 Applied load: 10 L/cm 2 (11.2 mg/cm 2 ) 1 L/cm 2 (1.12 mg/cm 2 ) Absorbed fraction of applied mass Time (h) 0.01

32 0.6 Applied load: 10 L/cm 2 (11.2 mg/cm 2 ) 1 L/cm 2 (1.12 mg/cm 2 ) 0.1 L/cm 2 (0.112 mg/cm 2 ) Absorbed fraction of applied mass Time (h) 0.01

33 0.6 Applied load: 10 L/cm 2 (11.2 mg/cm 2 ) 1 L/cm 2 (1.12 mg/cm 2 ) 0.1 L/cm 2 (0.112 mg/cm 2 ) 0.01 L/cm 2 ( mg/cm 2 ) 0.55 Absorbed fraction of applied mass Time (h) 0.01

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35 Captan residues on patches and gloves worn by strawberry pickers 10 Exposure (mean, SD) (mg/cm 2 ) Chest Sleeve Back Thigh Shin Glove Sample area WL Winterlin et al. J Agric Food Chem 32: , 1984.

36 Cyclohexane soluble matter skin surface loads over 8 h shift in rubber manufacturing production workers Exposure (geometric mean, SD) (mg/cm 2 ) Neck/Jaw Shoulder Upper arm Wrist Groin Ankle Sample area R Vermeulen J Heideman RP Boss H Kromhout. Ann Occup Hyg 44: , 2000.

37 1,6-hexamethylene diisocyanate (HDI) monomer and oligomer exposure. Tape stripped from hands and arms of automotive refinishing workers Exposure (mean,maximum) (mg/cm 2 ) HDI Uretidone Biuret Isocyanurate Monomer (HDI) and polymers KW Fent, K Jayaraj, LM Ball, LA Nylander-French. J Environ Monit 10: , 2008.

38 Imidacloprid exposure during stapling ornamental plants 100 Exposure (median, maximum) (mg/cm 2 ) Hands Sample area Face C Aprea et al. J Expo Sci Environ Epidemiol 19: , Good News: even if we assume 100% absorption, absorbed dose < acceptable daily intake. FOR THIS CASE.

39 Lubricant and fuel exposures to hands and forearms of consumers Exposure (geometric mean, 90 th %) (mg/cm 2 ) Diesel "Easy" "Hard" Bicycle Exposure situation KS Galea, A Davis, D Todd, L MacCalman, C McGonagle, JW Cherrie. J Expo Sci Environ Epidemiol 24: , 2014.

40 0.6 Applied load: 10 L/cm 2 (11.2 mg/cm 2 ) 1 L/cm 2 (1.12 mg/cm 2 ) 0.1 L/cm 2 (0.112 mg/cm 2 ) 0.01 L/cm 2 ( mg/cm 2 ) 0.55 Absorbed fraction of applied mass Time (h) 0.01

41 0.6 Applied load: 10 L/cm 2 (11.2 mg/cm 2 ) 1 L/cm 2 (1.12 mg/cm 2 ) 0.1 L/cm 2 (0.112 mg/cm 2 ) 0.01 L/cm 2 ( mg/cm 2 ) 0.55 Absorbed fraction of applied mass Time (h) 0.01

42 0.6 Applied load: 10 L/cm 2 (11.2 mg/cm 2 ) 1 L/cm 2 (1.12 mg/cm 2 ) 0.1 L/cm 2 (0.112 mg/cm 2 ) 0.01 L/cm 2 ( mg/cm 2 ) 0.55 Absorbed fraction of applied mass Time (h) 0.01

43 Dilution f abs Maximum Exposure (mg/kg/day) DAD (mg/kg/day) AOEL (mg/kg/day) OK?

44 Dilution Rate f abs Maximum Exposure (mg/kg/day) DAD (mg/kg/day) AOEL (mg/kg/day) OK?

45 25 Acetochlor Testosterone 20 Percent absorbed Load (mg/cm 2 ) RC Wester, HI Maibach. J Invest Dermatol 67: , RC Wester, JL Melendres, HI Maibach. Food Chem Toxicol 34: , 1996.

46 100 Percent absorbed Atrazine Carbaryl Carbofuran Captan Chlordecone Dinoseb DSMA Folpet MSMA Nicotine PCB Permethrin Load (mg/cm 2 ) PV Shah et al. J Toxicol Environ Health 21: ,1987.

47 Percent absorbed MB Napropamide Maneb Permethrin Fipronil Tralomethrin Amitraz Load (mg/cm 2 ) T Thongsinthusak, JH Ross, MH Dong. Significance of dermal dose levels in dermal absorption studies of pesticides. California EPA (1999).

48 Active ingredient (concentrate) EFSA (absorbed %) Experimental (absorbed %) Acetochlor Captan Carbofuran Napropamide Fold difference * Scientific Report submitted to EFSA: Proposal for a revision of the guidance document on dermal absorption (Annex 4), 2010.

49 Active ingredient (concentrate) EFSA (absorbed %) Experimental (absorbed %) Acetochlor Captan Carbofuran Napropamide Fold difference * Scientific Report submitted to EFSA: Proposal for a revision of the guidance document on dermal absorption (Annex 4), 2010.

50 Operator No PPE With PPE Tractor mounted sprayer (orchard) Tractor mounted field crop sprayer Hand held knapsack sprayer Conclusion on pesticide peer review: peer review of the pesticide risk assessment of the active substance captan. EFSA Scientific Report 296, 1-90, 2009

51 Operator No PPE With PPE Tractor mounted sprayer (orchard) * Tractor mounted field crop sprayer ** Hand held knapsack sprayer ** PPE: *Gloves plus protective garment/sturdy footwear **Gloves Conclusion on pesticide peer review: peer review of the pesticide risk assessment of the active substance captan. EFSA Scientific Report 296, 1-90, 2009.

52 Operator No PPE With PPE Tractor mounted sprayer (orchard) 1, Tractor mounted field crop sprayer Hand held knapsack sprayer

53 Concentration: Low f abs /f abs,max High Load ( L/cm 2 )

54 Concentration: Low f abs /f abs,max High Load ( L/cm 2 )

55 Concentration: Low f abs /f abs,max High Load ( L/cm 2 )

56 Concentration: Low f abs /f abs,max High Load ( L/cm 2 )

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58 The draft EFSA revised guidance on dermal absorption is planned to be published on the EFSA website for public consultation by the end of the year. You will have the opportunity to provide comments that should be taken into account by EFSA.

59 Annette Bunge (Colorado School of Mines) Jerry Kasting (University of Cincinnati) John Kissel (University of Washington) Ana Barbero (NIOSH)

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61 Diethyl phthalate neat J SS ( g/cm 2 /h): DEP: 4.5 % absorption Load (mg/cm 2 )

62 Diethyl phthalate neat Vanillylnonanamide in PG Parathion neat J SS ( g/cm 2 /h): DEP: 4.5 VAN: 2.5 PAR: 0.7 % absorption Load (mg/cm 2 ) GB Kasting. J Phar Sci 90: , MA Miller and GB Kasting. J Toxicol Environ Health A 73:

63 % absorption Diethyl phthalate neat Vanillylnonanamide in PG Parathion neat 15 organic compounds in water 3 organophosphate flame retardants J SS ( g/cm 2 /h): DEP: 4.5 VAN: 2.5 PAR: : FR's: Load (mg/cm 2 ) HE Buist et al. Regul Toxicol Pharmacol 57: , MA-E Abdallah, G Pawar, S Harrad. Toxicol Appl Pharmacol 291: 28-37, 2016.

64 N d e rm m a s s a p p lie d lo a d a re a s te a d y -s ta te flu x e x p o s u re d u ra tio n m a s s a re a tim e tim e J Kissel. J Expo Sci Environ Epidemiol 21: , 2011.

65 Diethyl phthalate neat Vanillylnonanamide in PG Parathion neat 15 organic compounds in water 3 organophosphate flame retardants % absorption N derm = load/(j SS x t exp )

66 Diethyl phthalate neat Vanillylnonanamide in PG Parathion neat 15 organic compounds in water 3 organophosphate flame retardants % absorption / = load/(j SS x lag time) GB Kasting. J Phar Sci 90: , 2001.

67 Diethyl phthalate Vanillylnonanamide Parathion 15 Organics 3 Flame retardants % absorption Load/(J SS x (t exp 2 /lag time))

68 % absorption = log(x) r 2 = 0.74 Diethyl phthalate Vanillylnonanamide Parathion 15 Organics 3 Flame retardants regression % absorption Load/(J SS x (t exp 2 /lag time))

69 f abs = absorbed mass mass/area applied load mass/area

70 150 Applied load: Absorbed mass ( g/cm 2 ) L/cm 2 1 L/cm time (h)

71 150 Applied load: Absorbed mass ( g/cm 2 ) L/cm 2 1 L/cm 2 y x y constant steady-state flux x time (h)

72 If the load is large enough such that concentration is maintained ( 90%), steady-state flux will be maintained (over the duration of the exposure). For infinite dose condition, fractional absorption is a deceptive number. Why? Fractional absorption will change simply by changing the load. 0 < f abs 0.1

73 If the load is large enough such that concentration is maintained ( 90%), steady-state flux will be maintained (over the duration of the exposure). For any given concentration, there is a load for which this condition is met. Why? Fractional absorption will change simply by changing the load. 0 < f abs 0.1

74 If the load is large enough such that concentration is maintained ( 90%), steady-state flux will be maintained (over the duration of the exposure). For infinite dose condition, fractional absorption is a deceptive number. Why? Fractional absorption will change simply by changing the load. 0 < f abs 0.1

75 If the load is large enough such that concentration is maintained ( 90%), steady-state flux will be maintained (over the duration of the exposure). For infinite dose condition, fractional absorption is a deceptive number. Why? Fractional absorption will change simply by changing the load. 0 < f abs 0.1

76 If the load is large enough such that concentration is maintained ( 90%), steady-state flux will be maintained (over the duration of the exposure). For infinite dose condition, fractional absorption is a deceptive number. Why? Fractional absorption will change simply by changing the load. 0 < f abs 0.1

77 150 Applied load: Absorbed mass ( g/cm 2 ) L/cm 2 1 L/cm 2 y x y constant steady-state flux x time (h)

78 0.6 Applied load: 10 L/cm 2 (11.2 mg/cm 2 ) 1 L/cm 2 (1.12 mg/cm 2 ) Absorbed fraction of applied mass Time (h) 0.01