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National Research Council (US) Committee on Acute Exposure Guideline Levels; National Research Council (US) Committee on Toxicology. Nineteenth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A. Washington (DC): National Academies Press (US); 2011.

Cover of Nineteenth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A

Nineteenth Interim Report of the Committee on Acute Exposure Guideline Levels: Part A.

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CHLOROFORMATES

At its meeting held on October 26-29, 2010, the committee reviewed the TSD on 13 selected chloroformates. A presentation on the TSD was made by Julie Klotzbach, of Syracuse Research Corporation. Technical and general comments for the entire document are combined below in “Other Comments.”

This document can be finalized when the committee comments are addressed adequately.

Methyl Chloroformate

The following is excerpted from the Executive Summary of the TSD:

Data were insufficient for derivation of AEGL-1 values for methyl chloroformate…. The AEGL-2 values for methyl chloroformate were based upon a 3-fold reduction in the AEGL-3 values.… The calculated 4-hour BMCL05 value in rats (42.4 ppm) (Hoechst 1986) was used as the point-of-departure for methyl chloroformate AEGL-3 values.

Ethyl Chloroformate

The following is excerpted from the Executive Summary of the TSD:

Data were insufficient for derivation of AEGL-1 values for ethyl chloroformate…. The AEGL-2 values for methyl chloroformate were based upon a 3-fold reduction in the AEGL-3 values.… One-third of the most conservative 1-hour LC50 value in rats (145 ppm × 1/3 = 48 ppm) (Vernot et al. 1977) was used as the point-of-departure for ethyl chloroformate AEGL-3 values.

Propyl Chloroformate

The following is excerpted from the Executive Summary of the TSD:

Data were insufficient for derivation of AEGL-1 values for propyl chloroformate.… The AEGL-2 values for propyl chloroformate were based upon a 3-fold reduction in the AEGL-3 values.… The calculated 1-hour rat BMCL05 of 216 ppm (Bio-Test Laboratories Inc. 1970a) was used for deriving AEGL-3 values.

Isopropyl Chloroformate

The following is excerpted from the Executive Summary of the TSD:

Data were insufficient for derivation of AEGL-1 values for isopropyl chloroformate…. The AEGL-2 values for isopropyl chloroformate were based upon a 3-fold reduction in the AEGL-3 values…. One-third of the 1-hour LC50 value in rats (300 ppm × 1/3 = 100 ppm) (Bio Test Laboratories, Inc. 1970b) was used as the point-of-departure for isopropyl chloroformate AEGL-3 values.

Allyl Chloroformate

The following is excerpted from the Executive Summary of the TSD:

Data were insufficient for the derivation of AEGL-1 values for allyl chloroformate.… The AEGL-2 values for allyl chloroformate were based upon a 3-fold reduction in the AEGL-3 values.… The calculated 1-hour rat BMCL05 of 21 ppm (Stillmeadow Inc. 1987) was used for deriving AEGL-3 values.

n-Butyl Chloroformate

The following is excerpted from the Executive Summary of the TSD:

Data were insufficient for the derivation of AEGL-1 values for n-butyl chloroformate.… The AEGL-2 values for n-butyl chloroformate were based upon a 3-fold reduction in the AEGL-3 values.… One-third of the concentration where 4/10 rats died after a 1-hour exposure to n-butyl chloroformate (200 ppm × 1/3 = 66.7 ppm) (BASF 1970) was used as the point-of-departure for n-butyl chloroformate AEGL-3 values.

Benzyl Chloroformate

The following is excerpted from the Executive Summary of the TSD:

Data were insufficient for the derivation of AEGL-1 values for benzyl chloroformate.… The AEGL-2 values for benzyl chloroformate were based upon a 3-fold reduction in the AEGL-3 values.… The experimental concentration causing no deaths in rats (18.6 ppm) after a 4-hour exposure (BASF 1990a) was used as the point-of-departure for benzyl chloroformate AEGL-3 values.

Phenyl Chloroformate

The following is excerpted from the Executive Summary of the TSD:

Data were insufficient for the derivation of AEGL-1 values for phenyl chloroformate.… The AEGL-2 values for phenyl chloroformate were based upon a 3-fold reduction in the AEGL-3 values.… The 4-hour rat BMCL05 of 3.6 ppm from the combined BASF (1990b) and Hoechst (1989) studies was used as the point-of-departure for phenyl chloroformate AEGL-3 values.

2-Ethylhexyl Chloroformate

The following is excerpted from the Executive Summary of the TSD:

Data were insufficient for the derivation of AEGL-1 values for 2-ethylhexyl chloroformate.… The AEGL-2 values for 2-ethylhexyl chloroformate were based upon a 3-fold reduction in the AEGL-3 values.… The 4-hour male rat BMCL05 of 18.1 ppm from the BASF (1985) study was used as the point-of-departure for 2-ethylhexyl chloroformate AEGL-3 values.

Ethyl Chlorothioformate

The following is excerpted from the Executive Summary of the TSD:

Data were insufficient for the derivation of AEGL-1 values for ethyl chlorothioformate.… The AEGL-2 values for ethyl chlorothioformate were based upon a 3-fold reduction in the AEGL-3 values.… An estimated 4-h rat lethality threshold of 15 ppm (1/3 the 4-hour LC50: 1/3 × 45 ppm = 15 ppm) (Stauffer 1983) was used for deriving AEGL-3 values for ethyl chlorothioformate.

AEGL-Specific Comments

The committee approved the AEGL-1, AEGL-2, and AEGL-3 derivations for the selected chloroformates.

Other Comments

The references are somewhat dated (e.g., 5 years or older) and many appear to be indirect sources (e.g., HSDB, in which original data sources are older still). The authors should check the current literature to ensure that statements in the document are still valid—see Section I.8, pages I-11 to I-12; Section II.7, pages II-19 to II-21; Section III.7, pages III-13 to III-14; Section IV.7, p. IV-12; Section V.7, pages V-15 to V-16; Section VI.7, p. VI-10; Section VII.7, pages VII-13 to VII-14; Section VIII.7, pages VIII-10 to VIII-11; Section IX.7, p. IX-13; Section X.7, p. X-10; Section XI.7, pages X-11 to X-12. It would be useful to conduct a quick check of the current literature to ensure that the TSD reflects current knowledge, and that statements within each chapter are still valid.

A summary table should be added to the introductory chapter (Chapter 1: General Information for Selected Chloroformates) that lists all 12 chemicals in this class and the corresponding AEGL values for the time exposures. The authors should include relevant AEGLs to place values for chloroformates in context with chemicals for which toxicity comparisons have been made, as indicated by the fate discussion in the literature. For example, the discussion should include AEGL values and other relevant information on phosgene, since chloroformates are formed from the reaction of phosgene with alcohols (page 12, line 11). The authors should also consider adding relevant information about hydrogen chloride (HCl) and other relevant chemicals, since chloformates hydrolyze to HCl and other parent compounds in water or moist air (page 12, lines 29-30). This information could be inserted in a new section for “Special Considerations” (often included in TSDs, e.g., see Section 4 of the TSD for mercury vapor). Also see the comment about providing these values in the combined summary table for the AEGLs. This consideration of fate products (notably HCl) may also have implications for a potential AEGL-1; see the first sentence and table in each of the executive summaries for Chapters II-XI, as well as companion text and tables for the AEGL-1 within topical sections of each chapter (e.g., Sections II.3.3, III.3.3, IV.3.3, and so on; Sections II.6, III.6, IV.6, and so on; and Appendixes A and B in each chapter: “Derivation of AEGL-1 Values” and “Derivation Summary,” respectively).

Section I.1 (General Chemical and Physical Properties), pages. I-4 to I-10: This section contains very little text. More information would be useful to provide context for the summary tables and derivation of AEGLs in the subsequent chapters. In particular, it would be useful to include specific information on the fate of chloroformates (including persistence and half-life) to frame additional context regarding toxicity information for fate products that could also be present with the parent chemical within 8 h of a release. It would also be useful to highlight this specific information in Section I.5, pg. I-11 (concurrent exposure issues). Furthermore, it would be useful to check reported vapor pressures (per temperature) against nominal concentrations considered for AEGL derivations (e.g., for isopropyl chloroformate); see Section I.1, Table I-4, page I-6; and Section V.2.6, page V-11, Table V-4, and the text associated with that summary.

Page I-4, Section 1.1: Given the unusual nature of this document in addressing so many chloroformates and given the repetition of the same basic categories in the tables, the authors should consider presenting a combined table that identifies key properties across these compounds (e.g., for evaporation, flash points). It could also be informative to present such properties as a bar graph to highlight key similarities and differences.

Pages I-4 to I-10, Sections 1.1 to 1.4: These sections contain main summary tables. Additional (short) text would be useful to provide context for the summary tables. In particular, the authors should include specific information on the fate of chloroformates to frame additional context regarding toxicity information for fate products that could also be present with the parent chemical within 8 h of a release.

Section I.6, page I-11, lines 9-15: As indicated per the check of more recent literature (see the comment above), the committee suggests revisiting statements regarding the toxic effect not being expected to vary greatly between species or individuals; for example, consider animal data for isopropyl chloroformate (Section V.2, pg. V-11, Table V-4, and the text that precedes this summary).

Page I-10, lines 23-29; and Section I.7, page I-11, lines 19-27: It would seem useful to explicitly address the issue of delayed onset of pulmonary effects (and need for treatment to address severity as indicated, per human data from more recent literature; see comment above). This issue would also be useful to keep in mind in the parallel discussions for specific AEGL derivations (e.g., for Chapter XI [ethyl chlorothioformate], Section XI.4.3, pages XI-9 to XI-10).

Page III-7, lines 17-18: As indicated by the check of more recent literature (see comment above), the committee suggests addressing potential implications for humans of carcinogenicity information for ethyl chloroformate.

Page IV-8, lines 27-36: Consider using this information from standard ocular irritant testing to inform the irritant end point, as potentially providing context not only for the AEGL-1 but also for the AEGL-2. Also, consider an adjustment for this relatively reactive compound (propyl), noting that a modifying factor was used for the AEGL-3 but not the AEGL-2. (Regarding consistency in applying modifying factors within and across derivations, see the following comment.)

Page IV-11, lines 11-13; and page IV-19, AEGL-3 derivation table: The modifying factor entry is 2, with a “justification” that would also apply to a number of other compounds and other AEGLs (e.g., AEGL-2) where it has not been used. For example, consider Chapter VIII (benzyl chloroformate) and derivation summary tables on pages VIII-16 and VIII-17. We suggest checking the consistency in how the modifying factor was or was not applied across these compounds, while ensuring adherence to the SOP, and we suggest explaining the inconsistencies or revising the applications to achieve consistency. Perhaps consider adding language to the introductory chapter to address this issue (e.g., in Section I.4).

Regarding other available benchmarks, a number of sections indicate that no (other) values have been established, a possibility that does not appear to reflect current information; for example, see page II-19, lines 13-14 (methyl); page III-13, line 10 (ethyl); page VII-10, line 16 (isobutyl and sec-butyl); page VIII-10, line 15 (benzyl); page IX-12, line 21 (phenylpage) page X-10, line 20 (2-ethylhexyl); page XI-11, line 14 (ethyl chlorothioformate). We suggest checking emergency response planning guidelines (ERPGs) (e.g., for methyl and ethyl chloroformate) and workplace environmental exposure limits (WEELs) (e.g., for benzyl, phenyl, isobutyl, sec-butyl, and 2-ethylhexyl chloroformate and for ethyl chlorothioformate) for additional information and whether the scientific bases of these benchmarks can be provided for potential insights.

Comment References

  • BASF. 1970. n-Butylchlorokohlensaureester-Gewerbetoxikologische Vorprufung Report No. XIX352. BASF Aktiengesellschaft, Gewerbehygienisch-Pharmakologisches Institut.
  • BASF. 1985. Acute Inhalation Toxicity LC50 for a 4-hour Exposure (Rats), Vapor Test of 2-Ethylhexyl Chloroformate. BASF Aktiengesellschaft, Experimental Toxicology and Ecology, Ludwigshafen, Germany. February 8, 1985.
  • BASF. 1990. a. Study on the Acute Inhalation Toxicity LC50of Benzyl Chloroformate as a Vapor in Rats, 4-hour Exposure. Project No 13I0674/887075. BASF Aktiengesellschaft, Experimental Toxicology and Ecology, Ludwigshafen, Germany. February 15, 1990.
  • BASF. 1990. b. Study on the Acute Inhalation Toxicity LC50of Phenyl Chloroformate as a Vapor in Rats, 4-hour Exposure. Project No 13I0675/887076. BASF Aktiengesellschaft, Experimental Toxicology and Ecology, Ludwigshafen, Germany. January 18, 1990.
  • Bio-Test Laboratories, Inc. 1970. a. Acute Toxicity Studies on n-Propyl Chloroformate. IBT No. A8345. Report to PPG Industries, Inc., Pittsburg, PA:
  • Bio-Test Laboratories, Inc. 1970. b. Acute Vapor Inhalation Toxicity Study with IPCF in Albino Rats. IBT No. N9129. Report to PPG Industries, Inc., Pittsburg, PA.
  • Hoechst. 1986. Chloroformic Acid Methyl Ester. Inhalation Toxicity in the Flow through System in Male and Female SPF Wistar Rats: 4-hour LC50. Report No. 86.0432. Hoechst Pharmaceutical Research Toxicology. April 11, 1986.
  • Hoechst. 1989. Chloroformic Acid Phenyl Ester. Aerosol Inhalation Toxicity in Male and Female SPF Wistar Rats: 4-hour LC50. Report No. 89.0761. Hoechst Pharmaceutical Research Toxicology. April 26, 1989.
  • Stauffer. 1983. Initial Submission: Acute Inhalation Toxicity of Ethyl Chlorothioformate in Rats with Cover Letter Dated 08/28/92. Report No. T-10712. Stauffer Chemical Company, Farmington, CT. Submitted by ICI Americas, Inc., to U.S. Environmental Protection Agency, Washington, DC. Microfiche No. OTS05384564.
  • Stillmeadow. 1987. Rat Acute Inhalation Toxicity: Allyl Chloroformate. Project No. 4438-86. Stillmeadow, Inc., Houston, TX, February 19, 1987. Submitted by PPG Industries, Inc., Chicago, IL, to U.S. Environmental Protection Agency, Washington, DC. Microfiche No. OTS0536028.
  • 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(2):417-423. [PubMed: 595018]
Copyright 2011 by the National Academy of Sciences. All rights reserved.
Bookshelf ID: NBK209465

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