Appendix I
Example of the AEGL Derivation Summary Appendix in A Technical Support Document

DERIVATION SUMMARY FOR ACUTE EXPOSURE GUIDELINE LEVELS FOR DIMETHYLHYDRAZINE

(CAS No. 57–14–7; 1,1-Dimethylhydrazine)

(CAS No. 540–73–8; 1,2-Dimethylhydrazine)

AEGL-1 Values

30 min

1 h

4 h

8 h

Not recommended

Not recommended

Not recommended

Not recommended

Reference: Not applicable

Test Species/Strain/Number: Not applicable

Exposure Route/Concentrations/Durations: Not applicable

Effects: Not applicable

Endpoint/Concentration/Rationale: Not applicable



The National Academies | 500 Fifth St. N.W. | Washington, D.C. 20001
Copyright © National Academy of Sciences. All rights reserved.
Terms of Use and Privacy Statement



Below are the first 10 and last 10 pages of uncorrected machine-read text (when available) of this chapter, followed by the top 30 algorithmically extracted key phrases from the chapter as a whole.
Intended to provide our own search engines and external engines with highly rich, chapter-representative searchable text on the opening pages of each chapter. Because it is UNCORRECTED material, please consider the following text as a useful but insufficient proxy for the authoritative book pages.

Do not use for reproduction, copying, pasting, or reading; exclusively for search engines.

OCR for page 196
Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals Appendix I Example of the AEGL Derivation Summary Appendix in A Technical Support Document DERIVATION SUMMARY FOR ACUTE EXPOSURE GUIDELINE LEVELS FOR DIMETHYLHYDRAZINE (CAS No. 57–14–7; 1,1-Dimethylhydrazine) (CAS No. 540–73–8; 1,2-Dimethylhydrazine) AEGL-1 Values 30 min 1 h 4 h 8 h Not recommended Not recommended Not recommended Not recommended Reference: Not applicable Test Species/Strain/Number: Not applicable Exposure Route/Concentrations/Durations: Not applicable Effects: Not applicable Endpoint/Concentration/Rationale: Not applicable

OCR for page 196
Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals Uncertainty Factors/Rationale: Not applicable Modifying Factor: Not applicable Animal to Human Dosimetric Adjustment: Not applicable Time Scaling: Not applicable Data Adequacy: Numeric values for AEGL-1 are not recommended because (1) data are not available, (2) data indicate that toxic effects may occur at or below the odor threshold, (3) an inadequate margin of safety exists between the derived AEGL-1 and the AEGL-2, or (4) the derived AEGL-1 is greater than the AEGL-2. Absence of an AEGL-1 does not imply that exposure below the AEGL-2 is safe. NOTE: If an AEGL-1 value is not recommended, there should be a short discussion of the rationale for that choice. The rationale should include as appropriate a discussion that numeric values for AEGL-1 are not recommended because (1) relevant data are lacking, (2) the margin of safety between the derived AEGL-1 and AEGL-2 values is inadequate, or (3) the derived AEGL-1 is greater than the AEGL-2. Absence of an AEGL-1 does not imply that exposure below the AEGL-2 is safe. AEGL-2 Values 30 min 1 h 4 h 8 h 6.0 ppm 3.0 ppm 0.75 ppm 0.38 ppm Reference: Weeks, M.H., G.C.Maxey, M.E.Sicks, and E.A.Greene. 1963. Vapor toxicity on UDMH in rats and dogs from short exposures. Am. Ind. Hyg. Assoc. J. 24:137–143 Test Species/Strain/Sex/Number: mongrel dogs, 2–4/group, sex not specified Exposure Route/Concentrations/Durations: Inhalation; 1,200–4,230 ppm for 5 min; 360, 400, or 1,530 ppm for 15 min; 80–250 ppm for 60 min Effects: Exposure (15 min) Effect 360 ppm muscle fasciculations in 1 of 4 dogs (determinant for AEGL-2) 400 ppm behavioral changes in 2 of 4 dogs 1,530 ppm tremors, convulsions, vomiting in 2 of 2 dogs Endpoint/Concentration/Rationale: 15-min exposure at 360 ppm considered a threshold for potentially irreversible effects or effects that would impair escape. At this exposure, muscle fasciculations were observed in 1 of 4 exposed dogs, and at 400 ppm, behavioral changes were observed.

OCR for page 196
Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals Uncertainty Factors/Rationale: Total uncertainty factor: 30 Interspecies: 3—The toxic response to dimethylhydrazine (LC50 values) was similar across species. The 4-h LC50 values for mouse, rat, and hamster differ by a factor of approximately 2 and were consistent with the dog data when extrapolated from 1 h using n=1. The more susceptible species, the dog, was used to derive the AEGL-2 values. Intraspecies: 10—A broad spectrum of effects were seen, including behavioral effects, hyperactivity, fasciculations, tremors, convulsions, and vomiting. The mechanism of toxicity is uncertain and susceptibility among individuals regarding these effects may vary. This variability was especially demonstrated in dogs wherein responses varied from one of extreme severity (vomiting, tremors, convulsions, and death) to no observable effects. Therefore, a factor of 10 was applied. A factor of 10 was also applied because experiments by Weeks et al. (1963) indicated that dogs had been previously stressed (auditory stimuli), which may have affected their response to dimethylhydrazine. Based upon these data, it was assumed that humans may be equally variable in their response to dimethylhydrazine. Modifying Factor: None Animal to Human Dosimetric Adjustment: None applied, insufficient data Time Scaling: Cn×t=k, where n=1 and k=180 ppm·min; LC50 data were available for 5-, 15-, 30-, 60-, and 240-min exposures in rats and 5-, 15-, and 60-min in dogs. Exposure-response data indicated a near linear concentration-response relationship (n=0.84 for rats; n=0.80 for dogs). For time-scaling, a linear relationship was assumed and a value where n=1 was selected. Data Adequacy: Information regarding the human experience for acute inhalation exposure to dimethylhydrazine are limited to qualitatively case reports indicating nasal and respiratory tract irritation, breathing difficulties, and nausea. Data in animals have shown concentration-dependent effects ranging from respiratory tract irritation, pulmonary edema and neurologic effects to lethality. Because the nonlethal effects in humans and animals are qualitatively similar, the animal data were considered relevant and appropriate for development of AEGL values. The AEGL values for dimethylhydrazine reflect the steep exposure-response relationship suggested by available data.

OCR for page 196
Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals AEGL-3 Values 30 min 1 h 4 h 8 h 22 ppm 11 ppm 2.7 ppm 1.4 ppm Reference: Weeks, M.H., G.C.Maxey, M.E.Sicks, and E.A.Greene. 1963. Vapor toxicity of UDMH in rats and dogs from short exposures. Am. Ind. Hyg. Assoc. J. 24:137–143 Test Species/Strain/Sex/Number: mongrel dogs, 3–4/group; sex not specified Exposure Route/Concentrations/Durations: Inhalation; exposure to various concentrations (80–22,300 ppm) for 5, 15, or 60 min Effects: 1-h LC50 981 ppm (reduction by 1/3 was basis for AEGL-3 derivation) 15-min LC50 3,580 ppm 5-min LC50 22,300 ppm Endpoint/Concentration/Rationale: 1-h LC50 (981 ppm) reduced by 1/3 was considered an estimate of the lethality threshold (327 ppm). Based on the available exposure-response data for this chemical (Jacobson et al. 1955), a 3-fold reduction in LC50 values results in exposures that would not be associated with lethality. Uncertainty Factors/Rationale: Total uncertainty factor: 30 Interspecies: 3—The toxic response to dimethylhydrazine (LC50 values) was similar across species. The 4-h LC50 values for mouse, rat, and hamster differ by a factor of approximately 2 and were consistent with the dog data when extrapolated from 1 h using n=1. The more susceptible species, the dog, was used to derive the AEGL-3 values. Intraspecies: 10—A broad spectrum of effects were seen, including behavioral effects, hyperactivity, fasciculations, tremors, convulsions, and vomiting. The mechanism of toxicity is uncertain, and susceptibility among individuals regarding these effects may vary. This variability was especially demonstrated in dogs wherein responses varied from one of extreme severity (vomiting, tremors, convulsions, and death) to no observable effects. Therefore, a factor of 10 was used. A factor of 10-fold was also used because experiments by Weeks et al. (1963) indicated that dogs previously stressed by auditory stimuli may have a potentiated response to dimethylhydrazine. Based upon these data, it was assumed that humans may be equally variable in their response to dimethylhydrazine subsequent to similar stresses. Modifying Factor: None Animal to Human Dosimetric Adjustment: None applied, insufficient data

OCR for page 196
Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals Time Scaling: Cn×t=k, where n=1 and k=654 ppm·min; LC50 data were available for 5-, 15-, 30-, 60-, and 240-min exposures in rats and 5-, 15-, and 60-min in dogs. Exposure-response data indicated a near linear concentration-response relationship (n=0.84 for rats; n=0.80 for dogs). For time-scaling, a linear relationship was assumed and a value where n=1 was selected by the National Advisory Committee. Data Adequacy: Information regarding the lethality of dimethylhydrazine in humans were not available. Lethality data for several animal species allowed for a defensible development of the AEGL-3 values but uncertainties remain regarding individual variability in the toxic response to dimethylhydrazines.