Page 160 Cite

Suggested Citation:"Appendix D Acute Exposure Guideline Levels for Selected Chloroformates." National Academies of Sciences, Engineering, and Medicine. 2016. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 20. Washington, DC: The National Academies Press. doi: 10.17226/23634.

×

Appendix D

Acute Exposure Guideline Levels for Selected Chloroformates

DERIVATION SUMMARY METHYL CHLOROFORMATE

AEGL-1 Values for Methyl Chloroformate

The data on methyl chloroformate were insufficient for deriving AEGL-1 values, so no values are recommended.

AEGL-2 Values for Methyl Chloroformate


10 min	30 min	1 h	4 h	8 h

4.0 ppm	2.8 ppm	2.2 ppm	1.4 ppm	0.70 ppm

Data adequacy: In the absence of specific data on methyl chloroformate to derive AEGL-2 values, estimates were made by dividing the AEGL-3 values by 3. This calculation is used to estimate a threshold for irreversible effects if a chemical has a steep concentration-response curve (NRC 2001). The values are supported by the results of repeated-exposure studies. No deaths occurred in rats repeatedly exposed to methyl chloroformate at 3.1 ppm and only histopathologic changes in the nasal turbinates and lesions of the larynx were found. Larynx lesions were the only finding in rats exposed at 1.01 ppm for 6 h/day, 5 days/week for 4 weeks (BASF 1993).

AEGL-3 Values for Methyl Chloroformate


10 min	30 min	1 h	4 h	8 h

12 ppm	8.5 ppm	6.7 ppm	4.2 ppm	2.1 ppm

Key reference: Hoechst. 1986. Chloroformic Acid Methyl Ester. Inhalation Toxicity in the Flow Through System in Male and Female SPF Wistar Rats. 4-hour LC₅₀. Hollander, H., Weigland, W, Mayer, D., Langer, K.H. Hoechst Pharmaceutical Research Toxicology. Report No. 86.0432. April 11, 1986.

Test species/Strain/Sex/Number: Rats; Wistar; 5/sex/group

Exposure route/Concentrations/Durations: Inhalation; 35, 45, 57, or 73 ppm for 4 h

End point/Concentration/Rationale: Lethality; 4-h BMCL₀₅ = 42.4 ppm, estimated threshold for death in rats

Page 161 Cite

Suggested Citation:"Appendix D Acute Exposure Guideline Levels for Selected Chloroformates." National Academies of Sciences, Engineering, and Medicine. 2016. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 20. Washington, DC: The National Academies Press. doi: 10.17226/23634.

×


Effects: LC₅₀ (males) = 51 ppm; LC₅₀ (females) = 53 ppm BMCL₀₅ (males and females) = 42.4 ppm BMC₀₁ (males and females) = 47.8 ppm
Concentration	Male mortality	Female mortality
35 ppm	0/5	0/5
45 ppm	0/5	0/5
57 ppm	5/5	3/5
73 ppm	5/5	5/5
Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 Intraspecies: 3 The effects of the chloroformates result from the direct-acting corrosive effects of the chemicals on the airways, in the absence of other systemic effects. Supporting information for this mode of action comes from observations of nasal irritation and respiratory effects (pulmonary congestion, pulmonary edema, and increased lung weights) in short-term repeated-exposure studies of rats exposed to methyl chloroformate (Gage 1970; HRC 1992; BASF 1993, 1999). Interspecies and intraspecies uncertainty factors of 3 are often used for respiratory irritants because pharmacodynamic variability is probably minimal (within a factor of 3) for irritants and because metabolic (pharmacokinetic) differences among species and individuals are unlikely to play a major role in direct-acting irritation or corrosion at the portal-of-entry (respiratory tract).

Modifying factor: Not applicable

Animal-to-human dosimetric adjustment: Insufficient data

Time scaling: Cⁿ × t = k; default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations (NRC 2001). Time scaling from 4 h to 10 min is supported by a 1-h LC₅₀ study (Industrial Bio-Test Laboratories, Inc. 1975); using a BMCL₀₅ from this study would result in a 10-min AEGL-3 value of 13 ppm, which supports the time-scaled value of 12 ppm calculated from the study by Holendar (1986).

Data adequacy: Acute lethality studies in rats had consistent results that were relevant for calculating AEGL-3 values. The AEGL-3 values are supported by the results of repeated-exposure studies. No deaths occurred in rats exposed to methyl chloroformate at 7.8 ppm for 6 h/day, 5 days/week for 4 weeks (BASF 1999), and no deaths occurred until week 4 in rats exposed at 8.8 ppm for 6 h/day, 5 days/week for 4 weeks (BASF 1993).

DERIVATION SUMMARY FOR ETHYL CHLOROFORMATE

AEGL-1 Values for Ethyl Chloroformate

The data on ethyl chloroformate were insufficient for deriving AEGL-1 values, so no values are recommended.

Page 162 Cite

Suggested Citation:"Appendix D Acute Exposure Guideline Levels for Selected Chloroformates." National Academies of Sciences, Engineering, and Medicine. 2016. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 20. Washington, DC: The National Academies Press. doi: 10.17226/23634.

×

AEGL-2 Values for Ethyl Chloroformate


10 min	30 min	1 h	4 h	8 h

2.9 ppm	2.0 ppm	1.6 ppm	0.40 ppm	0.20 ppm

Data adequacy: In the absence of specific data on ethyl chloroformate to derive AEGL-2 values, estimates were made by dividing the AEGL-3 values by 3. This calculation is used to estimate a threshold for irreversible effects if a chemical has a steep concentration-response curve (NRC 2001). Lethality data on ethyl chloroformate provide evidence of a steep curve. Fisher et al. (1981b) report a 1-h rat LC₅₀ of 189-200 ppm, and that rats exposed at 47 ppm for 1 h were clinically normal and had no mortality.

AEGL-3 Values for Ethyl Chloroformate


10 min	30 min	1 h	4 h	8 h

8.8 ppm	6.1 ppm	4.8 ppm	1.2 ppm	0.60 ppm

Key reference: Vernot, E.H., J.D. MacEwen, C.C. Haun, and E.R. Kinkead. 1977. Acute toxicity and skin corrosion data for some organic and inorganic compounds and aqueous solutions. Toxicol. Appl. Pharmacol. 42:417-424.

Test species/Strain/Sex/Number: Rat, Sprague-Dawley rats, males

Exposure route/Concentrations/Durations: Inhalation for 1 h

End point/Concentration/Rationale: Lethality; LC₀₁ was estimated taking one-third of the LC₅₀ (145 ppm ÷ 3 = 48.3 ppm)

Effects: Male rat LC₅₀ = 145 ppm; female rat LC₅₀ = 170 ppm

Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 Intraspecies: 3 The effects of the chloroformates result from the direct-acting corrosive effects of the chemicals on the airways, in the absence of other systemic effects. Supporting information for this mode of action comes from observations of respiratory effects (e.g., lung congestion, edema, and emphysema) in lethality studies of rats (BASF 1970a,b; Gage, 1970; WARF Institute, Inc. 1978; Fisher et al. 1981). Interspecies and intraspecies uncertainty factors of 3 are often used for respiratory irritants because pharmacodynamic variability is probably minimal (within a factor of 3) for irritants and because metabolic (pharmacokinetic) differences among species and individuals are unlikely to play a major role in direct-acting irritation or corrosion at the portal-of-entry (respiratory tract). Furthermore, interspecies and intraspecies uncertainty factors of 3 were also used in determining the AEGL-3 values for the structural analogs, methyl chloroformate, isopropyl chloroformate, and n-butyl chloroformate, and the resulting AEGL values were considered protective when compared with chemical-specific, repeated-exposure data on these analogs.

Modifying factor: Not applicable

Animal-to-human dosimetric adjustment: Insufficient data

Time scaling: Cⁿ × t = k; default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations (NRC 2001).

Data adequacy: Two acute lethality studies in rats had consistent results and were adequate for deriving AEGL-3 values.

Page 163 Cite

Suggested Citation:"Appendix D Acute Exposure Guideline Levels for Selected Chloroformates." National Academies of Sciences, Engineering, and Medicine. 2016. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 20. Washington, DC: The National Academies Press. doi: 10.17226/23634.

×

DERIVATION SUMMARY FOR ISOPROPYL CHLOROFORMATE

AEGL-1 Values for Isopropyl Chloroformate

The data on isopropyl chloroformate were insufficient for deriving AEGL-1 values, so no values are recommended.

AEGL-2 Values for Isopropyl Chloroformate


10 min	30 min	1 h	4 h	8 h

3.7 ppm	3.7 ppm	3.0 ppm	1.9 ppm	1.3 ppm

Data adequacy: No appropriate data on isopropyl chloroformate were available to derive AEGL-2 values. Thus, the AEGL-2 values were calculated by taking one-third of the AEGL-3 values. This approached is used to estimate a threshold for irreversible effects if a chemical has a steep concentration-response curve (NRC 2001). The values are supported by the study by Gage (1970), which reported only nasal irritation in rats exposed to isopropyl chloroformate at 20 ppm for 6 h/day for 20 days.

AEGL-3 Values for Isopropyl Chloroformate


10 min	30 min	1 h	4 h	8 h

11 ppm	11 ppm	9.1 ppm	5.7 ppm	3.8 ppm

Key reference: Collins, C.J., and B.G. Proctor. 1984. A 5-day Range-Finding Inhalation Toxicity Study of Isopropyl Chloroformate in the Albino Rat. Draft Report. Prepared by Bio-Research Laboratories, Ltd.: Quebec, Canada. Prepared for PPG Industries, Pittsburgh, PA.

Test species/Strain/Sex/Number: Rats; 4 males and 4 females/group

Exposure route/Concentrations/Durations: Inhalation; 25, 50, and 100 ppm (measured concentrations) for 6 h/day for 5 days

End point/Concentration/Rationale: Lethality threshold (42 ppm)

Effects: No deaths at 22 or 42 ppm; 3/4 males and 3/4 females died in the 86-ppm group.

Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 Intraspecies: 3 The effects of the chloroformates result from the direct-acting corrosive effects of the chemicals on the airways, in the absence of other systemic effects. Supporting information for this mode of action comes from observations of nasal irritation and respiratory effects (pulmonary inflammation, pulmonary edema, and emphysema) in short-term repeated exposure rat studies with isopropyl chloroformate (Gage 1970; Collins and Proctor 1984). Interspecies and intraspecies uncertainty factors of 3 are often used for respiratory irritants because pharmacodynamic variability is probably minimal (within a factor of 3) for irritants and because metabolic (pharmacokinetic) differences among species and individuals are unlikely to play a major role in direct-acting irritation or corrosion at the portal-of-entry (respiratory tract). On the basis of these considerations, factors of 3 would represent the potential for any toxicodynamic variability.

Page 164 Cite

Suggested Citation:"Appendix D Acute Exposure Guideline Levels for Selected Chloroformates." National Academies of Sciences, Engineering, and Medicine. 2016. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 20. Washington, DC: The National Academies Press. doi: 10.17226/23634.

×


Modifying factor: Not applicable

Animal-to-human dosimetric adjustment: Insufficient data

Time scaling: Cⁿ × t = k; default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations (NRC 2001). The 10-min AEGL-3 value was set equal to the 30-min AEGL-3 value because of the uncertainty associated with extrapolating a point-of-departure based on a 6-h repeated exposure to a 10-min value.

Data adequacy: The acute toxicity studies on isopropyl chloroformate are sparse, but are supported by a repeated-exposure study.

DERIVATION SUMMARY FOR N-PROPYL CHLOROFORMATE

AEGL-1 Values for n-Propyl Chloroformate

The data on n-propyl chloroformate were insufficient for deriving AEGL-1 values, so no values are recommended.

AEGL-2 Values for n-Propyl Chloroformate


10 min	30 min	1 h	4 h	8 h

3.7 ppm	3.7 ppm	3.0 ppm	1.9 ppm	1.3 ppm

Data adequacy: Sparse data set on n-propyl chloroformate. Chemical-specific data were insufficient to derive AEGL-2 values because of uncertainties in the quality of the available data. However, n-propyl chloroformate is a structural analog of isopropyl chloroformate, and available data suggest that n-propyl chloroformate and isopropyl chloroformate have similar toxicity. Thus, the AEGL-2 values for isopropyl chloroformate were adopted as the AEGL-2 values for n-propyl chloroformate.

AEGL-3 Values for n-Propyl Chloroformate


10 min	30 min	1 h	4 h	8 h

11 ppm	11 ppm	9.1 ppm	5.7 ppm	3.8 ppm

Data adequacy: Sparse data set on n-propyl chloroformate. Chemical-specific data were insufficient to derive AEGL-3 values because of uncertainties in the quality of the available data. However, n-propyl chloroformate is a structural analog of isopropyl chloroformate, and available data suggest that n-propyl chloroformate and isopropyl chloroformate have similar toxicity. Thus, the AEGL-3 values for isopropyl chloroformate were adopted as the AEGL-3 values for n-propyl chloroformate.

DERIVATION SUMMARY FOR ALLYL CHLOROFORMATE

AEGL-1 Values for Allyl Chloroformate

The data on allyl chloroformate were insufficient for deriving AEGL-1 values, so no values are recommended.

Page 165 Cite

Suggested Citation:"Appendix D Acute Exposure Guideline Levels for Selected Chloroformates." National Academies of Sciences, Engineering, and Medicine. 2016. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 20. Washington, DC: The National Academies Press. doi: 10.17226/23634.

×

AEGL-2 Values for Allyl Chloroformate


10 min	30 min	1 h	4 h	8 h

1.3 ppm (6.4 mg/m³)	0.87 ppm (4.3 mg/m³)	0.70 ppm (3.4 mg/m³)	0.18 ppm (0.88 mg/m³)	0.09 ppm (0.44 mg/m³)

Data adequacy: In the absence of specific data on allyl chloroformate to derive AEGL-2 values, estimates were made by dividing the AEGL-3 values by 3. This calculation is used to estimate a threshold for irreversible effects if a chemical has a steep concentration-response curve (NRC 2001). Lethality data on allyl chloroformate provide evidence of a steep curve. The incidence of mortality in rats exposed to ally chloroformate for 1 h was 0/10 at 33.7 ppm, 6/10 at 65 ppm, and 10/10 at 175.7 ppm (Stillmeadow Inc. 1987).

AEGL-3 Values for Allyl Chloroformate


10 min	30 min	1 h	4 h	8 h

3.8 ppm	2.6 ppm	2.1 ppm	0.53 ppm	0.26 ppm

Key reference: Stillmeadow Inc. 1987. Rat Acute Inhalation Toxicity: Allyl Chloroformate. Stillmeadow, Inc. Biological Testing Laboratory: Houston, TX. Project No. 4438-86. Report Submitted to PPG Industries, Inc., Chicago, IL. February 19, 1987. OTS0536028.

Test species/Strain/Sex/Number: Rat; Sprague Dawley; 5 males and 5 females per group

Exposure route/Concentrations/Durations: Inhalation; 33.7, 65.0, 77.7, 134.5, 175.7, and 233.3 ppm for 1 h

End point/Concentration/Rationale: Lethality threshold; 1-h BMCL₀₅ = 21 ppm
Effects: Mortality rates were 0/10 at 33.7 ppm; 6/10 at 65.0 ppm; 7/10 at 77.7 ppm; 9/10 at 134.5 ppm; 10/10 at 175.7 ppm; and 10/10 at 233.3 ppm. The data were used to calculate the following: LC₅₀ = 65.1 ppm; BMCL₀₅ = 21 ppm; and BMC₀₁ = 25.7 ppm.

Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 Intraspecies: 3 The effects of the chloroformates result from the direct-acting corrosive effects of the chemicals on the airways, in the absence of other systemic effects. Supporting information for this mode of action comes from observations of nasal irritation and respiratory effects (pulmonary inflammation, pulmonary edema, and emphysema) observed in humans and animals for several chloroformates evaluated in this report. Interspecies and intraspecies uncertainty factors of 3 are often used for respiratory irritants because pharmacodynamic variability is probably minimal (within a factor of 3) for irritants and because metabolic (pharmacokinetic) differences among species and individuals are unlikely to play a major role in direct-acting irritation or corrosion at the portal-of-entry (respiratory tract). On the basis of these considerations, factors of 3 would represent the potential for any toxicodynamic variability. Furthermore, interspecies and intraspecies uncertainty factors of 3 were also used in determining the AEGL-3 values for the structural analogs, methyl chloroformate, isopropyl chloroformate, and n-butyl chloroformate, and the resulting AEGL values were considered protective when compared with chemical-specific, repeated-exposure data on these analogs.

Page 166 Cite

Suggested Citation:"Appendix D Acute Exposure Guideline Levels for Selected Chloroformates." National Academies of Sciences, Engineering, and Medicine. 2016. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 20. Washington, DC: The National Academies Press. doi: 10.17226/23634.

×


Modifying factor: Not applicable

Animal-to-human dosimetric adjustment: Insufficient data

Time scaling: Cⁿ × t = k; default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations (NRC 2001).

Data adequacy: Only one study of allyl chloroformate was available.

DERIVATION SUMMARY FOR N-BUTYL CHLOROFORMATE, ISOBUTYL CHLOROFORMATE, AND SEC-BUTYL CHLOROFORMATE

AEGL-1 Values for n-Butyl, Isobutyl, and sec-Butyl Chloroformate

The data on n-butyl, isobutyl, and sec-butyl chloroformate were insufficient for deriving AEGL-1 values, so no values are recommended.

AEGL-2 Values for n-Butyl, Isobutyl, and sec-Butyl Chloroformate


10 min	30 min	1 h	4 h	8 h

4.0 ppm	2.8 ppm	2.2 ppm	0.57 ppm	0.28 ppm

Data adequacy: Data on n-butyl, isobutyl, and sec-butyl chloroformate were inadequate for deriving AEGL-2 values.

For n-butyl chloroformate, AEGL-2 values were estimated by dividing the AEGL-3 values by 3. The values are supported by results of repeated-exposure studies by HRC (1990), which found no effects in rats exposed to n-butyl chloroformate at 1.8 ppm for 6 h/day, 5 days/week for 4 weeks, or at 2.9 ppm for 6 h/day for 5 days.

Because isobutyl and sec-butyl chloroformate are structural analogs to n-butyl chloroformate, the AEGL-2 values for n-butyl chloroformate were adopted for them. Additionally, mouse RD₅₀ data suggest that two chemicals have similar toxicity; the RD₅₀ values from studies in male Swiss-Webster mice were 97 ppm for isobutyl chloroformate and 117 ppm for sec-butyl chloroformate (Carpenter 1982d).

AEGL-3 Values for n-Butyl, Isobutyl, and sec-Butyl Chloroformate


10 min	30 min	1 h	4 h	8 h

12 ppm	8.4 ppm	6.7 ppm	1.7 ppm	0.83 ppm

Key reference: BASF. 1970. BASF AG, Gewerbehygienisch-Pharmakologisches Institut. N-Butylchlorokohlensaureester-Gewerbetoxikologische Vorprufung. Unpublished Report No. XIX 352.

Test species/Strain/Sex/Number: Rat; Sprague Dawley; 5 males and 5 females per group

Exposure route/Concentrations/Durations: Inhalation; n-butyl chloroformate at 200 ppm for 1 h

Page 167 Cite

Suggested Citation:"Appendix D Acute Exposure Guideline Levels for Selected Chloroformates." National Academies of Sciences, Engineering, and Medicine. 2016. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 20. Washington, DC: The National Academies Press. doi: 10.17226/23634.

×


End point/Concentration/Rationale: Threshold for death was estimated by dividing 200 ppm by 3 (66.7 ppm)

Effects: 4/10 rats died

Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 Intraspecies: 3 The effects of the chloroformates result from the direct-acting corrosive effects of the chemicals on the airways, in the absence of other systemic effects. Supporting information for this mode of action comes from observations of nasal irritation and respiratory effects (pulmonary inflammation, pulmonary edema, and emphysema) observed in humans and animals for several chloroformates evaluated in this report. Interspecies and intraspecies uncertainty factors of 3 are often used for respiratory irritants because pharmacodynamic variability is probably minimal (within a factor of 3) for irritants and because metabolic (pharmacokinetic) differences among species and individuals are unlikely to play a major role in direct-acting irritation or corrosion at the portal-of-entry (respiratory tract). On the basis of these considerations, factors of 3 would represent the potential for any toxicodynamic variability.

Modifying factor: Not applicable

Animal-to-human dosimetric adjustment: Insufficient data

Time scaling: Cⁿ × t = k; default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations (NRC 2001).

Data adequacy: Data on n-butyl chloroformate were sparse. Values are supported by results from repeated-exposure studies conducted by HRC (1990); no rats died when exposed to n-butyl chloroformate 5.1 ppm for 6 h/day, 5 days/week for 4 weeks or at 28.4 ppm for 6 h/day for 5 days.

Even less data were available on isobutyl and sec-butyl chloroformate. Because the two compounds are structural analogs of n-butyl chloroformate, the AEGL-3 values for n-butyl chloroformate were adopted for isobutyl chloroformate and sec-butyl chloroformate. Additionally, mouse RD₅₀ data suggest that two chemicals have similar toxicity; the RD₅₀ values from studies in male Swiss-Webster mice were 97 ppm for isobutyl chloroformate and 117 ppm for sec-butyl chloroformate (Carpenter 1982d).

DERIVATION SUMMARY BENZYL CHLOROFORMATE

AEGL-1 Values for Benzyl Chloroformate

The data on benzyl chloroformate were insufficient for deriving AEGL-1 values, so no values are recommended.

Page 168 Cite

Suggested Citation:"Appendix D Acute Exposure Guideline Levels for Selected Chloroformates." National Academies of Sciences, Engineering, and Medicine. 2016. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 20. Washington, DC: The National Academies Press. doi: 10.17226/23634.

×

AEGL-2 Values for Benzyl Chloroformate


10 min	30 min	1 h	4 h	8 h

1.2 ppm	1.2 ppm	0.97 ppm	0.63 ppm	0.31 ppm

Data adequacy: In the absence of specific data on benzyl chloroformate to derive AEGL-2 values, estimates were made by dividing the AEGL-3 values by 3. This calculation is used to estimate a threshold for irreversible effects if a chemical has a steep concentration-response curve (NRC 2001). Lethality data on benzyl chloroformate provide evidence of a steep curve. Mortality rates in rats exposed to benzyl chloroformate for 4 h were 0/10 at 18.6 ppm and 5/10 at 84.6 ppm (BASF 1990); clinical signs in surviving rats resolved (were reversible).

AEGL-3 Values for Benzyl Chloroformate


10 min	30 min	1 h	4 h	8 h

3.7 ppm	3.7 ppm	2.9 ppm	1.9 ppm	0.93 ppm

Key reference: BASF. 1990. Study on the Acute Inhalation Toxicity LC₅₀ of Benzyl Chloroformate as a Vapor in Rats, 4-Hour Exposure. Project No. 13I0674/887075. Unpublished report, BASF Aktiengesellschaft, Experimental Toxicology and Ecology: Ludwigshafen, Germany. February 15, 1990.

Test species/Strain/Sex/Number: Rat; Sprague Dawley; 5 males and 5 females per group

Exposure route/Concentrations/Durations: Inhalation; 18.6 or 84.6 ppm for 4 h

End point/Concentration/Rationale: No deaths occurred at 18.6 ppm

Effects: No deaths at 18.6 ppm; 5/10 rats died at 84.6 ppm

Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 Intraspecies: 3 The effects of the chloroformates result from the direct-acting corrosive effects of the chemicals on the airways, in the absence of other systemic effects. Supporting information for this mode of action comes from observations of nasal irritation and respiratory effects (pulmonary inflammation, pulmonary edema, and emphysema) observed in humans and animals for several chloroformates evaluated in this report. Interspecies and intraspecies uncertainty factors of 3 are often used for respiratory irritants because pharmacodynamic variability is probably minimal (within a factor of 3) for irritants and because metabolic (pharmacokinetic) differences among species and individuals are unlikely to play a major role in direct-acting irritation or corrosion at the portal-of-entry (respiratory tract). Furthermore, interspecies and intraspecies uncertainty factors of 3 were also used in determining the AEGL-3 values for the structural analogs, methyl chloroformate, isopropyl chloroformate, and n-butyl chloroformate, and the resulting AEGL values were considered protective when compared with chemical-specific, repeated-exposure data on these analogs.

Modifying factor: Not applicable

Animal-to-human dosimetric adjustment: Insufficient data

Page 169 Cite

Suggested Citation:"Appendix D Acute Exposure Guideline Levels for Selected Chloroformates." National Academies of Sciences, Engineering, and Medicine. 2016. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 20. Washington, DC: The National Academies Press. doi: 10.17226/23634.

×


Time scaling: Cⁿ × t = k; default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations (NRC 2001). The 30-min AEGL-3 value was adopted for the 10-min AEGL-3 value because of the uncertainty associated with extrapolating a point-of-departure based on a 4-h exposure to a 10-min value.

Data adequacy: Sparse data set.

DERIVATION SUMMARY PHENYL CHLOROFORMATE

AEGL-1 Values for Phenyl Chloroformate

The data on phenyl chloroformate were insufficient for deriving AEGL-1 values, so no values are recommended.

AEGL-2 Values for Phenyl Chloroformate


10 min	30 min	1 h	4 h	8 h

0.24 ppm	0.24 ppm	0.19 ppm	0.12 ppm	0.06 ppm

Data adequacy: In the absence of specific data on phenyl chloroformate to derive AEGL-2 values, estimates were made by dividing the AEGL-3 values by 3. This calculation is used to estimate a threshold for irreversible effects if a chemical has a steep concentration-response curve (NRC 2001). This approach is justified based on the steep concentration curve with regard to lethality; mortality rates in rats exposed to phenyl chloroformate for 4 h were 2/10 at 15.6 ppm, 7/10 at 44.5 ppm, and 9/10 at 74.9 ppm (Hoechst 1989; BASF 1990b); clinical signs resolved (were reversible) at 15.6 ppm (BASF 1990b).

AEGL-3 Values for Phenyl Chloroformate


10 min	30 min	1 h	4 h	8 h

0.72 ppm	0.72 ppm	0.57 ppm	0.36 ppm	0.18 ppm

Key references: BASF. 1990. Study on the Acute Inhalation Toxicity LC₅₀ of Phenyl Chloroformate as a Vapor in Rats, 4-Hour Exposure. Project No. 13I0675/887076. Unpublished report, BASF Aktiengesellschaft, Experimental Toxicology and Ecology: Ludwigshafen, Germany. January 18, 1990.

Hoechst. 1989. Chloroformic Acid Phenyl Ester. Aerosol Inhalation Toxicity in Male and Female SPF Wistar Rats. 4-Hour LC₅₀. Hofmann, T. Hoechst Pharmaceutical Research Toxicology. Report No. 89.0761. April 26, 1989.

Test species/Strain/Sex/Number: Rat; Sprague Dawley; 5 males and 5 females per group

Exposure route/Concentrations/Durations: Inhalation; 1.76, 15.6, 44.5, 74.9, 97,156, 159.2, and 311 ppm for 4 h

End point/Concentration/Rationale: Lethality threshold, BMCL₀₅ =3.6 ppm

Page 170 Cite

Suggested Citation:"Appendix D Acute Exposure Guideline Levels for Selected Chloroformates." National Academies of Sciences, Engineering, and Medicine. 2016. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 20. Washington, DC: The National Academies Press. doi: 10.17226/23634.

×


Effects:
Concentration	Mortality
1.76 ppm	0/10
15.6 ppm	2/10
44.5 ppm	7/10
74.9 ppm	9/10
97 ppm	9/10
156 ppm	10/10
159.3 ppm	10/10
311 ppm	10/10

Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 Intraspecies: 3 The effects of the chloroformates result from the direct-acting corrosive effects of the chemicals on the airways, in the absence of other systemic effects. Supporting information for this mode of action comes from observations of nasal irritation and respiratory effects (pulmonary inflammation, pulmonary edema, and emphysema) observed in humans and animals for several chloroformates evaluated in this report. Interspecies and intraspecies uncertainty factors of 3 are often used for respiratory irritants because pharmacodynamic variability is probably minimal (within a factor of 3) for irritants and because metabolic (pharmacokinetic) differences among species and individuals are unlikely to play a major role in direct-acting irritation or corrosion at the portal-of-entry (respiratory tract). Furthermore, interspecies and intraspecies uncertainty factors of 3 were also used in determining the AEGL-3 values for the structural analogs, methyl chloroformate, isopropyl chloroformate, and n-butyl chloroformate, and the resulting AEGL values were considered protective when compared with chemical-specific, repeated-exposure data on these analogs.

Modifying factor: Not applicable

Animal-to-human dosimetric adjustment: Insufficient data

Time scaling: Cⁿ × t = k; default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations (NRC 2001). The 30-min AEGL-3 value was adopted for the 10-min AEGL-3 value because of the uncertainty associated with extrapolating a point-of-departure based on a 4-h exposure to a 10-min value.

Data adequacy: Sparse data set.

Derivation Summary 2-Ethylhexyl Chloroformate

AEGL-1 Values for 2-Ethylhexyl Chloroformate

The data on 2-ethylhexyl chloroformate were insufficient for deriving AEGL-1 values, so no values are recommended.

Page 171 Cite

Suggested Citation:"Appendix D Acute Exposure Guideline Levels for Selected Chloroformates." National Academies of Sciences, Engineering, and Medicine. 2016. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 20. Washington, DC: The National Academies Press. doi: 10.17226/23634.

×

AEGL-2 Values for 2-Ethylhexyl Chloroformate


10 min	30 min	1 h	4 h	8 h

1.2 ppm	1.2 ppm	0.97 ppm	0.60 ppm	0.30 ppm

Data adequacy: In the absence of specific data on 2-ethylhexyl chloroformate to derive AEGL-2 values, estimates were made by dividing the AEGL-3 values by 3. This calculation is used to estimate a threshold for irreversible effects if a chemical has a steep concentration-response curve (NRC 2001). This approach is justified based on the steep concentration curve with regard to lethality; mortality rates in rats exposed to 2-ethylhexyl chloroformate for 4 h were 0/20 at 22.8 ppm, 5/20 at 26.6 ppm, 9/20 at 34.3 ppm, and 20/20 at 46.9 ppm (BASF 1985).

AEGL-3 Values for 2-Ethylhexyl Chloroformate


10 min	30 min	1 h	4	8 h

3.6 ppm	3.6 ppm	2.9 ppm	1.8 ppm	0.91 ppm

Key reference: BASF. 1985. Acute Inhalation Toxicity LC₅₀ for a 4-Hour Exposure (Rats), Vapor Test of 2-Ethylhexyl Chloroformate. Unpublished report, BASF Aktiengesellschaft, Experimental Toxicology and Ecology: Ludwigshafen, Germany. February 8, 1985.

Test species/Strain/Sex/Number: Rats; Wistar; 10 males and 10 females per group

Exposure route/Concentrations/Durations: Inhalation; 22.8, 26.6, 34.3, and 46.9 ppm for 4 h

End point/Concentration/Rationale: Lethality threshold, BMCL₀₅ = 18.1 ppm

Effects:
Concentration	Male Mortality	Female Mortality	Male and Female Mortality
22.8 ppm	0/10	0/10	0/20
26.6 ppm	4/10	1/10	5/20
34.3 ppm	7/10	2/10	9/20
46.9 ppm	10/10	10/10	20/20

Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3 Intraspecies: 3 The effects of the chloroformates result from the direct-acting corrosive effects of the chemicals on the airways, in the absence of other systemic effects. Supporting information for this mode of action comes from observations of nasal irritation and respiratory effects (pulmonary inflammation, pulmonary edema, and emphysema) observed in humans and animals for several chloroformates evaluated in this report. Interspecies and intraspecies uncertainty factors of 3 are often used for respiratory irritants because pharmacodynamic variability is probably minimal (within a factor of 3) for irritants and because metabolic (pharmacokinetic) differences among species and individuals are unlikely to play a major role in direct-acting irritation or corrosion at the portal-of-entry (respiratory tract). Furthermore, interspecies and intraspecies uncertainty factors of 3 were also used in determining the AEGL-3 values for the structural analogs, methyl chloroformate, isopropyl chloroformate, and n-butyl chloroformate, and the resulting AEGL values were considered protective when compared with chemical-specific, repeated-exposure data on these analogs.

Page 172 Cite

Suggested Citation:"Appendix D Acute Exposure Guideline Levels for Selected Chloroformates." National Academies of Sciences, Engineering, and Medicine. 2016. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 20. Washington, DC: The National Academies Press. doi: 10.17226/23634.

×


Modifying factor: Not applicable

Animal-to-human dosimetric adjustment: Insufficient data

Time scaling: Cⁿ × t = k; default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations (NRC 2001). The 30-min AEGL-3 value was adopted for the 10-min AEGL-3 value because of the uncertainty associated with extrapolating a point-of-departure based on a 4-h exposure to a 10-min value.

Data adequacy: Sparse data set.

Derivation Summary Ethyl Chlorothioformate

AEGL-1 Values for Ethyl Chlorothioformate

The data on ethyl chlorothioformate were insufficient for deriving AEGL-1 values, so no values are recommended.

AEGL-2 Values for Ethyl Chlorothioformate


10 min	30 min	1 h	4 h	8 h

1.0 ppm	1.0 ppm	0.80 ppm	0.50 ppm	0.25 ppm

Data adequacy: In the absence of specific data on ethyl chlorothioformate to derive AEGL-2 values, estimates were made by dividing the AEGL-3 values by 3. This calculation is used to estimate a threshold for irreversible effects if a chemical has a steep concentration-response curve (NRC 2001). This approach is justified based on the steep concentration curve with regard to lethality; mortality rates in rats exposed to ethyl chlorothioformate for 4 h were 4/20 at 33 ppm, 14/20 at 59 ppm, and 20/20 at 65 ppm (Stauffer Chemical Company 1983).

AEGL-3 Values for Ethyl Chlorothioformate


10 min	30 min	1 h	4 h	8 h

3.0 ppm	3.0 ppm	2.4 ppm	1.5 ppm	0.75 ppm

Key reference: Stauffer Chemical Company. 1983. Acute Inhalation Toxicity of Ethyl Chlorothioformate in Rats (T-10710). Environmental Health Center Inhalation Facility. Stauffer Chemical Company: Farmington, CT. OTS0538464.

Test species/Strain/Sex/Number: Rat; Sprague Dawley; 10 males and 10 females per group

Exposure route/Concentrations/Durations: Inhalation; 0, 33, 59, 65, 69, or 124 ppm for 4 h (estimated lethality threshold of 1/3 the 4-hour rat LC₅₀ of 45 ppm (1/3 × 45 ppm = 15 ppm) is the point-of-departure for AEGL-3)

End point/Concentration/Rationale: 4-h lethality threshold estimated by dividing the LC₅₀ of 45 ppm by 3, for a point-of-departure of 15 ppm.

Effects: LC₅₀ = 51 ppm (males); 41 ppm (females); 45 ppm (males and females)

Page 173 Cite

Suggested Citation:"Appendix D Acute Exposure Guideline Levels for Selected Chloroformates." National Academies of Sciences, Engineering, and Medicine. 2016. Acute Exposure Guideline Levels for Selected Airborne Chemicals: Volume 20. Washington, DC: The National Academies Press. doi: 10.17226/23634.

×


Uncertainty factors/Rationale: Total uncertainty factor: 10 Interspecies: 3, because ethyl chlorothioformate and other chloroformates are respiratory irritants and pharmacodynamic variability between species is probably minimal (within a factor of 3). Intraspecies: 3, because the observed LC₅₀s for ethyl chlorothioformate and ethyl chloroformate were similar

Modifying factor: No applicable

Animal-to-human dosimetric adjustment: Insufficient data

Time scaling: Cⁿ × t = k; default values of n = 3 for extrapolating to shorter durations and n = 1 for extrapolating to longer durations (NRC 2001). The 30-min AEGL-3 value was adopted for the 10-min AEGL-3 value because of the uncertainty associated with extrapolating a point-of-departure based on a 4-h exposure to a 10-min value.

Data adequacy: Database included only lethality studies in rats.