Appendix F
Example of the Derivation of AEGL Values Appendix in A Technical Support Document

DERIVATION OF AEGL-1 VALUES

Key study:

None. An AEGL-1 was not recommended because of inadequate data for developing health-based criteria and because exposure-response relationships suggest little margin between exposures resulting in no observable adverse effects and those producing significant toxicity. The absence of an AEGL-1 does not imply that exposure below the AEGL-2 is without adverse effects.

DERIVATION OF AEGL-2 VALUES

Key study:

Weeks et al. 1963

Toxicity endpoint:

Dogs exposed to 1,1-dimethylhydrazine at 360 ppm for 15 min exhibited behavioral changes and muscle fasciculations



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OCR for page 186
Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals Appendix F Example of the Derivation of AEGL Values Appendix in A Technical Support Document DERIVATION OF AEGL-1 VALUES Key study: None. An AEGL-1 was not recommended because of inadequate data for developing health-based criteria and because exposure-response relationships suggest little margin between exposures resulting in no observable adverse effects and those producing significant toxicity. The absence of an AEGL-1 does not imply that exposure below the AEGL-2 is without adverse effects. DERIVATION OF AEGL-2 VALUES Key study: Weeks et al. 1963 Toxicity endpoint: Dogs exposed to 1,1-dimethylhydrazine at 360 ppm for 15 min exhibited behavioral changes and muscle fasciculations

OCR for page 186
Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals Uncertainty factors: An uncertainty factor of 3 for interspecies variability was applied because the toxic response to dimethylhydrazine was similar across the species tested. This was especially true for lethality responses (LC50 values for varying time periods ranging from 5 min to 4 h) among rats, mice, dogs, and hamsters. A comparison of LC50 values for the same exposure durations in these species did not vary more than 3-fold. An uncertainty factor of 10 was retained for intraspecies variability (protection of sensitive populations). A broad spectrum of effects were seen that included behavioral effects, hyperactivity, fasciculations, tremors, convulsions, and vomiting. The mechanism of toxicity is uncertain and susceptibility among individuals regarding these effects may vary. Following identical exposures, the responses of the dogs varied from extreme severity (vomiting, tremors, convulsions, and death) to no observable effects. A factor of 10 was also applied because experiments by Weeks et al. (1963) indicated that dogs that had been previously stressed (auditory stimuli) were more susceptible to the adverse effects of dimethylhydrazine. Calculations: 360 ppm/30=12 ppm C1×t=k 12 ppm×15 min=180 ppm·min Time scaling: C1×t=k (ten Berge et al. 1986) (12 ppm)1×15 min=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 of n=1 was selected. 30-min AEGL-2: C1×30 min=180 ppm·min C=6 ppm 1-h AEGL-2: C1×60 min=180 ppm·min C=3 ppm 4-h AEGL-2: C1×240 min=180 ppm·min

OCR for page 186
Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals   C=0.75 ppm 8-h AEGL-2: C1×480 min=180 ppm·min C=0.38 ppm DERIVATION OF AEGL-3 Key study: Weeks et al. 1963 Toxicity endpoint: 1-h LC50 of 981 ppm in dogs reduced by a factor of three to 327 ppm as an estimate of a lethality threshold. Weeks et al. (1963) provided data showing that 15-min exposure of dogs at 36–400 ppm produced only minor, reversible effects (behavioral changes and mild muscle fasciculations) Uncertainty factors: An uncertainty factor of 3 for interspecies variability was applied because the toxic response to dimethylhydrazine was similar across the species tested. This was especially true for lethality responses (LC50 values for varying time periods ranging from 5 min to 4 h) among rats, mice, dogs, and hamsters. A comparison of LC50 values for the same exposure durations in these species did not vary more than 3-fold. An uncertainty factor of 10 was applied for intraspecies variability (protection of sensitive populations). A broad spectrum of effects were seen that included behavioral effects, hyperactivity, fasciculations, tremors, convulsions, and vomiting. The mechanism of toxicity is uncertain and susceptibility among individuals regarding these effects may vary. Following identical exposures, the responses of the dogs varied from extreme severity (vomiting, tremors, convulsions, and death) to no observable effects. A factor of 10 was also applied because experiments by Weeks et al. (1963) indicated that dogs that had been previously stressed (auditory stimuli) were more susceptible to the adverse effects of dimethylhydrazine. Calculations: 327 ppm/30=10.9 ppm C1×t=k 11.9 ppm×60 min=654 ppm·min

OCR for page 186
Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals Time scaling: C1×t=k (ten Berge et al. 1986) 11.9 ppm1×60 min=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 of n=1 was selected. 30-min AEGL-2: C1×30 min=654 ppm·min C=22 ppm 1-h AEGL-2: C1×60 min=654 ppm·min C=11 ppm 4-h AEGL-2: C1×240 min=654 ppm·min C=2.7 ppm 8-h AEGL-2: C1×480 min=654 ppm·min C=1.4 ppm