2

Chloroformates Acute Exposure Guideline Levels

1. GENERAL INFORMATION ON SELECTED CHLOROFORMATES

The bases of the AEGL values for the following chloroformates are described in this report: methyl chloroformate, ethyl chloroformate, isopropyl chloroformate, n-propyl chloroformate, allyl chloroformate, n-butyl chloroformate, isobutyl chloroformate, sec-butyl chloroformate, benzyl chloroformate, phenyl chloroformate, 2-ethylhexyl chloroformate, and ethyl chlorothioformate. Information relevant to all 12 compounds is presented first, and is followed by separate sections on the individual chemicals.

1.1. General Physical and Chemical Properties

Selected physicochemical properties of the chloroformates are presented in Table 2-1. Chloroformates are clear, colorless liquids with relatively low freezing points and relatively high boiling points (>100°C). The chloroformates are reactive compounds possessing both acid chloride and alkyl substituents. The alkyl substituent is responsible for the thermal stability of the chloroformate in the following order of decreasing stability: aryl (e.g., benzyl chloroformate, phenyl chloroformate) > primary alkyl (e.g., methyl chloroformate, ethyl chloroformate, n-propyl chloroformate, n-butyl chloroformate) > secondary alkyl (e.g., isopropyl chloroformate, isobutyl chloroformate) > tertiary alkyl (Kreutzberger 2001).

Chloroformates are soluble in organic solvents, and hydrolyze in water. Hydrolysis products of the chloroformates, except ethyl chlorothioformate, are an alcohol (ROH), carbon dioxide, and hydrogen chloride; hydrolysis products of ethyl chlorothioformate are ethyl mercaptan, carbon dioxide, and hydrogen chloride. Specific alcohol hydrolysis products for each chloroformate are listed in Table 2-1. Lower chloroformates (such as methyl and ethyl chloroformate) hydrolyze more rapidly in water at room temperature, and the higher and aromatic chloroformates hydrolyze more slowly at room temperature (Kreutzberger 2001). Measured hydrolysis half-life in water for methyl, ethyl, propyl, isopropyl, and phenyl chloroformate range from 1.4 to 53.2 min (Queen 1967). Rates for the

TABLE 2-1 General Chemical and Physical Properties of Selected Chloroformates^a

Additional chemical and physical data for individual chloroformates are presented in their respective sections.

^aSource is HSDB (2003a,b, 2013, 2014a,b,c,d) except where noted.

^bCalculated from empirical rate constants reported by Queen (1967).

^cKreutzberger (2001).

^dBG Chemie (2005).

^eBohm and Beth-Hubner (2006).

^fO’Neil et al. (2001a,b).

^gIPCS (2005a,b,c).

^hIPCS (2004).

ⁱChemical Book (2016).

^jStauffer Chemical Company (1983).

^kCalculated from empirical rate constant reported by Queen et al. (1970).

^lhttps://cameochemicals.noaa.gov.

other chloroformates were not found. Data on atmospheric hydrolysis, the effect of relative humidity on hydrolysis rates, and persistence in the atmosphere of chloroformates were not available. However, data obtained from a study for structurally-similar and hydrolytically active acetyl chlorides (e.g., chloroacetyl chloride, phosgene, and trichloroacetyl chloride) indicate that gas-phase hydrolysis in an atmosphere of 40% humidity is much less than in water (Butler and Snelson 1979). A comparison of the hydrolysis half-times, vapor pressures, boiling points, flash points, and flammability limits are presented in Table 2-1.

A comparison of the chemical structures are presented in Figure 2-1.

1.2. Production and Use

Chloroformates are produced by the reaction of phosgene with alcohols or phenols. The alkyl chloroformates of low molecular weight alcohols are prepared by reaction of anhydrous alcohols with a molar excess of chlorine-free phosgene at low temperature. Hydrogen chloride is evolved during the reaction and is collected in a tower with recovered excess phosgene (Kreutzberger 2001).

Chloroformates are used as intermediates in the synthesis of pesticides, herbicides, perfumes, pharmaceuticals, foods, polymers, and dyes. They are also used for conversion to peroxydicarbonates, which then serve as free radical initiators for polymerization of vinyl chloride, ethylene, and other unsaturated monomers (Kreutzberger 2001).

1.3. Absorption, Metabolism, Disposition, and Excretion

No specific information about the absorption, metabolism, disposition, and excretion of the chloroformates was found.

1.4. Mechanism of Toxicity

Chloroformates hydrolyze in water or moist air to produce a parent alcohol or mercaptan compound (used in the production of each chloroformate), hydrogen chloride, and carbon dioxide. Thus, exposures to chloroformates are most likely to a mixture of the parent compound and its hydrolysis products. Chloroformates are direct-acting contact irritants, and are corrosive to the eyes, skin, gastrointestinal tract, and the respiratory tract. Inhalation may result in coughing, labored breathing, sore throat, unconsciousness, convulsions, and death. Pulmonary edema frequently occurs, and its symptoms may not manifest for several hours after exposure and may be aggravated by physical exertion. Delayed pulmonary edema resulting in hospitalization and requiring treatment has occurred in people accidentally exposed to unknown concentrations of methyl chloroformate (Schuckmann 1972; Penkovitch and Anikin 1988) and ethyl chloroformate (Bowra 1981). According to AIHA (2006a), a fatality with pulmonary edema occurred after a worker was exposed to methyl chloroformate at an estimated concentration of 40,000 ppm. Ingestion of chloroformates may result in a burning sensation of the digestive tract, nausea, vomiting, and abdominal pain (Kreutzberger 2001).

Table 2-2 provides a comparison of 1-h and 4-h rat LC₅₀ (lethal concentration, 50% lethality) values for the chloroformates and their hydrolysis products. A comparison of the toxicity data suggests that the toxicity of the chloroformates cannot be readily predicted from the toxicity of any particular hydrolysis product and supports the suggestion that the toxicity likely reflects exposure to a mixture of parent compound and hydrolysis products.

1.5. Concurrent-Exposure Issues

No information about exposure to chloroformates in conjunction with other chemicals that might be found concurrently in the workplace or the environment was found.

TABLE 2-2 Rat LC₅₀ Values (ppm) for Selected Chloroformates and Their Hydrolysis Products

^aSee sections on the individual chloroformates for the sources of the LC₅₀ values.

^bHSDB (2003a,b, 2013, 2014a,b,c,d) is source of the alcohol and hydrogen chloride LC₅₀ values.

^cAlcohol, phenol, or mercaptan hydrolysis product is shown in Table 2-1.

1.6. Species Sensitivity

No information about differences in the acute toxicity of the chloroformates between species was available. However, because the chloroformates are highly reactive in nature and are direct-acting irritants, little interspecies variability is expected. RD₅₀ (concentration of a substance that reduces the respiratory rate by 50%) data on methyl, ethyl, propyl, isopropyl, isobutyl, sec-butyl, and phenyl chloroformate suggest that the mouse may be more sensitive than the rat. However, the difference could be an artifact of the stressful testing procedure used with the mice, which were restrained during the exposure period, and not indicative of increased sensitivity to chloroformates.

1.7. Temporal Extrapolation

The concentration-exposure time relationship for many irritant and systemically-acting vapors and gases can be described by the equation Cⁿ × t = k, where the exponent, n, ranges from 0.8 to 3.5 (ten Berge et al. 1986). Insufficient

data were available for deriving an empirical value for n for any of the twelve chloroformates. In the absence of chemical-specific data, a default value of n = 3 was used to extrapolate from longer to shorter durations, and a default value of n = 1 was used to extrapolate from shorter to longer durations, to provide AEGL values that are protective of human health (NRC 2001).

1.8. Data Quality

The literature search, study selection, and evidence integration follows the methods outlined in the AEGLs standing operating procedure (NRC 2001). Although the AEGLs standing operating procedure outlines methods to ensure consistency and transparency, they are not formal systematic review procedures. However, several studies on the chloroformates were conducted by Industrial Bio-Test Laboratories, Inc. (IBT). In 1976 FDA found significant deficiencies and discrepancies in reports and study procedures, which called into question the validity of IBT studies. This led to a number of investigations of IBT by government agencies, the closure of the firm and criminal convictions of some of IBT staff for fraud or falsifying data. In a post hoc audit program of IBT studies conducted by the U.S. Environmental Protection Agency and the Canadian Health and Welfare Department (EPA 1983), 618 of 867 non-acute toxicity studies (including subacute, sub-chronic, carcinogenicity, reproductive toxicity, genotoxicity, and neurotoxicity studies) were reported to be invalid (OECD 2007). Although the focus of this audit was on repeated-dose and long-term studies, in its Manual for Investigation of HPV Chemicals, the Organisation for Economic Co-operation and Development (OECD) reports that significant discrepancies and deficiencies in acute toxicity studies also were found (OECD 2007).

OECD (2007) outlined specific criteria for using data generated by IBT, and recommended rejecting a study when either a regulatory or internal audit revealed problems with respect to the reliability of the findings or when the findings of unaudited studies are inconsistent with data collected by reputable laboratories. OECD (2007) further recommended that unaudited studies should not be used as key studies, but instead be used with caution and considered only as weak evidence if supported by data from reputable laboratories. OECD (2007) also noted that if an IBT study is consistent with a well conducted and reliable study, the IBT results may be used to increase confidence in characterization of a substance’s toxicity.

In reviewing IBT studies for this report, the general recommendations of OECD (2007) were followed. First and foremost, no IBT studies were used as the principal or key study in deriving AEGLs for any of the chloroformates. In cases where IBT study reports were available, they were reviewed (but not formally audited), and if the findings were consistent with other studies of reputable validity, the results of the IBT studies are included and referred to as providing supporting evidence.

1.9. Special Considerations

A summary of the AEGL values for the chloroformates reviewed in this document is presented in Table 2-3. AEGL-1 values were not derived for any chloroformate because of insufficient toxicity data. As discussed in Section 1.4 (Mechanism of Toxicity), exposures to the chloroformates are most likely to a mixture of the parent compound and its hydrolysis products. Therefore, using AEGL-values for hydrogen chloride as the basis for establishing AEGL values for the chloroformates was considered inappropriate. Furthermore, AEGL-1 values for hydrogen chloride (shown in Table 2-4) approach or exceed the AEGL-2 and AEGL-3 values for the chloroformates.

No acute inhalation data consistent with the definition of AEGL-2 were available. Therefore, the AEGL-2 values for all chloroformates were calculated by taking a three-fold reduction in the AEGL-3 values. That approach is consistent with recommendations in the Standing Operating Procedures for Developing AEGLs for estimating a threshold for irreversible effects (NRC 2001). AEGL-3 values were based on lethality data on the individual chloroformates, although the toxicity data for chloroformates were sparse. Respiratory effects associated with direct-acting irritation and corrosion (nasal irritation, pulmonary inflammation, pulmonary edema, and emphysema and associated lethality) have been observed in humans and animals for several of the chloroformates. Interspecies and intraspecies uncertainty factors of 3 (for a total uncertainty factor of 10) were used for calculating the AEGL values for the chloroformates. Those values were chosen 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). The AEGL values for n-propyl chloroformate were determined on the basis of structural similarity to isopropyl chloroformate, and the AEGL values for isobutyl chloroformate and sec-butyl chloroformate were determined on the basis of structural analogy to n-butyl chloroformate.

2. METHYL CHLOROFORMATE

2.1. Summary

Data on methy chloroformate were insufficient for deriving AEGL-1 values, so no values are recommended.

No acute inhalation data appropriate for deriving AEGL-2 values for methyl chloroformate were available. Thus, the AEGL-2 values were calculated by taking one-third of the AEGL-3 values. That approached is used to estimate a threshold for irreversible effects if a chemical has a steep concentration-response curve (NRC 2001). Lethality data on methyl chloroformate provide evidence of a steep curve. In studies of rats exposed to methyl chloroformate for 4 h,

TABLE 2-3 AEGL Values for Selected Chloroformates^a

^aTreatment of people exposed to chloroformates should consider that pulmonary edema frequently occurs, but its symptoms may not manifest for several hours after exposure and may be aggravated by physical exertion.

^bNR, not recommended. Absence of an AEGL-1 value does not imply that exposure below the AEGL-2 value is without adverse effects.

TABLE 2-4 AEGL Values for Chloroformate Hydrolysis Products

Hoeschst (Hollander et al. 1986) reported an LC₅₀ of 51-53 ppm, no mortality at 45 ppm, and 80% mortality at 57 ppm. In another study using rats, the 1-h LC₅₀ was 100 ppm, and rats exposed at 26 ppm for 1 h were clinically normal and had no mortality (Fisher et al. 1981a).

Using lethality data from Hoechst (Hollander et al. 1986), a 4-h BMCL₀₅ (benchmark concentration, 95% lower confidence limit with 5% response) of 42.4 ppm was calculated (see Appendix A) and used as the point-of-departure for deriving AEGL-3 values for methyl chloroformate. That concentration is considered a threshold for lethality and is supported by data that no deaths occurred in rats exposed to methyl chloroformate at 45 ppm for 4 h (Hollander et al. 1986). The effects of the chloroformates result from the direct-acting corrosive effects on the airways, in the absence of other systemic effects. Supporting information for this mode of action comes from observations in rats of nasal irritation and respiratory effects (e.g., pulmonary congestion, pulmonary edema, and increased pulmonary weights) in short-term repeated-exposure studies of methyl chloroformate (Gage 1970; Kenny et al. 1992; BASF 1993, 1999a). 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). Thus, interspecies and intraspecies uncertainty factors of 3 would represent the potential for any toxicodynamic variability, resulting in a total uncertainty factor of 10 applied to the estimated threshold for lethality (42.4 ppm). Time scaling was performed using the equation Cⁿ × t = k (ten Berge et al. 1986). Data on methyl chloroformate were insufficient for calculating an empirical value for the exponent n, so default values of n = 3 when extrapolating from longer to shorter durations (10 min, 30 min, and 1 h) and n = 1 when extrapolating from shorter to longer durations (8 h) were used. Time scaling from 4 h to 10 min is supported by a 1-h LC₅₀ study (IBT 1975); utilizing the BMCL₀₅ from this study yields a 10-min AEGL-3 value of 13 ppm, which supports the time-scaled value of 12 ppm calculated from the study by Hoechst (Hollander et al. 1986).

The AEGL values for methyl chloroformate are presented in Table 2-5.

TABLE 2-5 AEGL Values for Methyl Chloroformate^a

^aTreatment of people exposed to chloroformates should consider that pulmonary edema frequently occurs, but its symptoms may not manifest for several hours after exposure and may be aggravated by physical exertion.

^bNR, not recommended. Absence of an AEGL-1 value does not imply that exposure below the AEGL-2 value is without adverse effects.

2.2. Chemical and Physical Properties

Methyl chloroformate hydrolyzes in water to form methanol, carbon dioxide, and hydrogen chloride. Selected chemical and physical properties of methyl chloroformate are presented in Table 2-6.

2.3. Human Toxicity Data

2.3.1. Acute Lethality

No data on human deaths from exposure to methyl chloroformate were found.

2.3.2. Nonlethal Toxicity

2.3.2.1. Case Reports

A healthy 41-year-old chemical production worker inhaled 2-3 breaths of an atmosphere containing methyl chloroformate in the vicinity of leaking equipment (Schuckmann 1972). The concentration of methyl chloroformate in the discharge was not reported. The worker left the contaminated area immediately because of a penetrating odor and coworkers’ warnings. About an hour after exposure, he experienced slight ocular irritation and an irritating cough and reported to the medical facility at the factory. Auscultation of lungs was largely unremarkable; isolated respiratory sounds were found in the upper

TABLE 2-6 Chemical and Physical Properties of Methyl Chloroformate

lobes. The next day (about 24 h later), a follow-up examination was performed. The worker reported increasing cough since early morning and presented with abnormal respiratory sounds in the upper lung lobes during auscultation. A codeine preparation (Codipront) was prescribed and a follow-up examination was scheduled for the next day. However, the worker returned in the afternoon of the same day because of increasingly severe signs and symptoms as the day progressed, as evidenced by extensive abnormal sounds in the upper lung lobes, moderate dyspnea, and a temperature of 37.2°C. The worker was kept for observation overnight, with an oxygen supply, a bronchodilator (Brondilat), and 40 mg Urbason intravenously. During the night the symptoms receded and the worker slept well to the early morning hours. The cough resumed and auscultation showed slight dry rales in the right lower lung lobe. The worker was sent home after treatment with Omnicillin and Codipront. Examination performed the next day revealed no notable complaints. The following day,

however, the worker complained of a severely irritating cough and dyspnea; slight cyanosis of the lips was also observed. Auscultation of the lungs, revealing rales in all lung areas, confirmed the subjective findings. The worker was then admitted to the factory’s medical facility and stayed there for about three days. Urbason, Brondilat, and Hostacyclin were administered during this time period. The symptoms started to recede, although a morning cough persisted, and drug treatment was discontinued.

In another report, a 46-year-old male worker was exposed to methyl chloroformate while repairing a methyl chloroformate pipeline (Penkovitch and Anikin 1988). The liquid soaked his clothing and penetrated to the skin; he reported itching and burning. He was wearing a gas mask during the accident; thus, no inhalation exposure occurred until he removed the gas mask in the shower room. He then reported a sharp, choking smell and developed burning of the eyes, tearing, sore throat, and a cough while showering for 3-5 min. Methyl chloroformate concentrations were not reported. He returned to his home and reported no abnormal symptoms for 4-5 h. He then developed a sore, burning throat, chills, asthma, and productive cough. The asthma and cough progressed, and he was admitted to a hospital 22 h after the accident. He presented with pulmonary edema which resolved within 24 h after treatment with Prednisolone and Lasix.

AIHA (2006a) described a report of individual injuries and a fatality in workers exposed to methyl chloroformates; the primary reports (Hey and Thiess 1968 and Thiess and Hey 1968) were in German and were not translated. AIHA (2006a) indicated that the nonfatal symptoms consisted of ocular irritation, laryngitis, and dry, racking cough, all of which resolved within 1-2 h. In the fatal case, severe pulmonary edema and death ensued after exposure to a concentration estimated by the study authors to be about 40,000 ppm (AIHA 2006a).

2.3.3. Developmental and Reproductive Toxicity

No developmental or reproductive studies of acute human exposure to methyl chloroformate were available.

2.3.4. Genotoxicity

No genotoxic studies of acute human exposure to methyl chloroformate were available.

2.3.5. Carcinogenicity

No carcinogenicity studies of human exposure to methyl chloroformate were available.

2.3.6. Summary

Case reports of methyl chloroformate toxicity are available; however, details of exposure concentration and duration were not available. Signs of exposure included ocular and upper respiratory irritation followed by a latent period which ultimately led to pulmonary edema. For the workers in these reports, the latency periods were 36 h (Schuckmann 1972) and 22 h (Penkovitch and Anikin 1988). No human data on lethality, developmental toxicity, reproductive toxicity, genotoxicity, or carcinogenicity on methyl chloroformate were found.

2.4. Animal Toxicity Data

2.4.1. Acute Lethality

2.4.1.1. Rats

Groups of five male and five female Charles River albino rats were exposed to methyl chloroformate vapor at 0, 145, 173, 233, or 274 ppm (nominal concentrations) for 1 h, followed by a 14-day observation period (IBT 1975). Vapor was generated by bubbling clean, dry air through undiluted methyl chloroformate in a gas washing bottle. The resulting air-vapor mixture was then introduced into the exposure chamber. The 1-h LC₅₀ was determined to be 163 ppm, and the calculated BMCL₀₅ is 74 ppm. Male rats appeared to be more sensitive than females. Hypoactivity, ptosis, ruffed fur, enophthalmus, and dyspnea were observed in all rats during exposure. Evidence of acute bronchiolitis followed by fibrosis of the pulmonary parenchyma was observed in animals killed on day 14 post-exposure and in rats that died during the experiment. Data from this study are summarized in Table 2-7.

TABLE 2-7 Mortality in Charles River Albino Rats Exposed to Methyl Chloroformate for 1 Hour

Abbreviations: BMCL₀₅, benchmark concentration, 95% lower confidence limit with 5% response; LC₅₀, lethal concentration, 50% lethality.

Source: Adapted from IBT 1975.

In another study, groups of 10 male Sprague Dawley rats were exposed to methyl chloroformate at 735, 2,947, 9610, or 66,235 ppm (nominal concentrations) for 1 h (WARF Institute, Inc. 1972). A “semi-portable” exposure chamber containing an exhaust fan for adjustable air flow was used. Methyl chloroformate was administered into the incoming air stream just before it entered the chamber port, and exposure concentrations were calculated by dividing the total amount sprayed into the chamber by the total cubic feet of air circulated through the chamber. All animals died within 18 h of exposure (see Table 2-8).

Groups of five male and five female Fischer 344 rats (main group) were exposed to methyl chloroformate vapor at 0, 26, 110, 133, 159, or 192 ppm for 1 h in a 3-ft wide Hinner-style chamber (Fisher et al. 1981a). Chamber concentrations were monitored by real time variable pathlength infrared photospectrometry. In addition 10, 10, and 20 rats/sex (satellite rats) were exposed concurrently to methyl chloroformate at 26, 110, or 133 ppm, respectively. One male and one female satellite rat in each exposure group and two male and two female rats in the three lower-exposure groups were killed 4 h, 24 h, 9 days, or 10 days after exposure. All other surviving animals were killed 14 days after exposure. The LC₅₀ values were 100 ppm for females and 92-123 ppm for males at 14-days post-exposure. Respiratory distress occurred in all main group rats exposed at 110, 133, 159, and 192 ppm during the first 24 h after exposure. Respiratory distress resolved within 24 h in the 110-ppm group; however, the effect persisted through day 14 in the other exposure groups and was accompanied by lethargy, weakness, and inactivity. Concentration-related red or clear ocular and nasal discharge and gross pulmonary lesions were observed in rats exposed at 110, 133, 159, and 192 ppm. Controls and rats in the 26-ppm group were clinically normal. Rats in the satellite group responded similarly to corresponding rats in the main group. In the main study group, decreased mean body weight and body weight gain were observed in the 110-, 133-, 159-, and 192-ppm rats and correlated with poor clinical status prior to death or study termination. No effect on body weight was observed in rats exposed at 26 ppm. Lesions found in satellite rats exposed at 110 and 133 ppm were comparable at all three sacrifice times and included severe degeneration, necrosis, erosion, and ulceration of the nasal turbinates and tracheal mucosal epithelia; alveolar hemorrhage; and erosion of bronchial and bronchiolar epithelia. Effects were similar. By day 9 or 10, the nasal turbinate effects had resolved, but regeneration was incomplete and purulent rhinitis persisted. Other respiratory tract and pulmonary lesions seen at 4 and 24 h resolved after 9 or 10 days. Pulmonary edema was observed in some rats in the 110-, 133-, 159-, and 192-ppm groups. No pulmonary edema was observed in controls or in the group exposed at 26 ppm.

Vernot et al. (1977) reported a 1-h LC₅₀ of 88 ppm (64-123 ppm) for male and 103 ppm (90-118 ppm) for female Sprague-Dawley rats. Experiments were performed in bell jars using groups of five rats per concentration; concentrations were determined analytically. No further experimental details were available.

TABLE 2-8 Mortality in Sprague-Dawley Rats Exposed to Methyl Chloroformate for 1 Hour

Source: Adapted from WARF Institute, Inc. 1972.

Groups of five male and five female SPF Wistar rats were exposed to methyl chloroformate at 35, 45, 57, or 73 ppm (analytic concentrations) for 4 h, followed by a 14-day observation period (Hollander et al. 1986). The whole body exposures were performed in a 2.25-m³ exposure chamber operated under dynamic flow conditions. Methyl chloroformate concentrations were measured every 15 min during exposure using a single beam photometer, and were measured analytically every 120 min using gas chromatography. Clinical signs observed in all treatment groups in a concentration-related manner included palpebral fissure narrowed or closed; increased grooming; squatting posture; accelerated, irregular, and jerky respiration; gasping; drowsiness; staggering movements; wimpering and crackling breathing sounds; sneezing; and piloerection. Body weight gain was reduced in both sexes after exposure, but animals surviving to study termination regained initial body weight. There were no gross treatment-related effects at necropsy in animals surviving to study termination. Gross examination of animals that died during the study showed dark red to black lungs, foamy liquid in the lungs, red aqueous liquid in the thoracic cavity, and distended gastrointestinal tracts. Histopathologic examination showed increased permeability in the alveolar septa and corresponding damage to bronchial epithelium; this effect was found in all treatment groups. Four-hour LC₅₀ values of 51 ppm and 53 ppm were calculated for males and females, respectively. A combined male and female BMCL₀₅ of 42.4 ppm and combined male and female BMC₀₁ of 47.8 ppm were calculated. Mortality data are summarized in Table 2-9.

Groups of 10 male and 10 female Sprague-Dawley rats were exposed to methyl chloroformate at nominal concentrations of 16, 65, 96, or 127 ppm (analytic concentrations were 1.5, 13.7, 33.6, and 31.0 ppm, respectively) for 4 h, followed by a 14-day observation period (BASF 1980a). Whole body exposures were conducted in a 200-L glass-steel inhalation chamber. Analytic concentrations were measured by gas chromatography. Clinical signs in the 65-, 96-, and 127-ppm groups included dyspnea, gasping, blistering in front of noses, red ocular and nasal discharge and encrustations, ruffled and sticky fur, staggering, distended abdomen, poor general state, attempts to escape, impaired coordination, salivation, and squatting posture. Animals in the 16-ppm group exhibited jerky respiration and

eyelid closure. Body weight gain was initially decreased in the three highest concentration groups; this effect resolved in surviving animals by day 14 post-exposure. Four hour LC₅₀ values of 13 ppm and 18 ppm were calculated for males and females, respectively. A combined male and female LC₅₀ value of 15 ppm was also calculated. Data from this study are summarized in Table 2-10. The LC₅₀ values calculated from this study are 3-4 times lower than those found in the Hoechst (Hollander et al. 1986) study and are inconsistent with other data (see Table 2-12).

Death occurred in 12/12 rats exposed to methyl chloroformate vapor (20°C) at 37,500 ppm for 3 min (BASF 1981a). Clinical signs included vigorous escape behavior, severe mucous membrane irritation, and gasping. Pulmonary emphysema with petechial hemorrhages and dilation on the right side of the heart were observed at necropsy.

TABLE 2-9 Mortality in SPF Wistar Rats Exposed to Methyl Chloroformate for 4 Hours

Abbreviations: BMC₀₅, benchmark concentration, 1% response; BMCL₀₁, benchmark concentration, 95% lower confidence limit with 5% response; LC₅₀, lethal concentration, 50% lethality.

Source: Hollander et al. 1986.

TABLE 2-10 Mortality in Sprague-Dawley Rats Exposed to Methyl Chloroformate for 4 Hours

Abbreviations: LC₅₀, lethal concentration, 50% lethality.

Source: Adapted from BASF 1980a.

Death occurred in 11/12, 5/6, and 6/6 rats exposed to an “atmosphere enriched or saturated” with methyl chloroformate vapor (20°C) for 3, 10, and 30 min, respectively (BASF 1978). Clinical signs included vigorous escape behavior, severe mucous membrane irritation, corneal opacity, dyspnea, and convulsions. Pulmonary edema and emphysema and bilateral dilation of the heart were found at necropsy.

Death occurred in 10/10 rats exposed to an “atmosphere enriched or saturated” with methyl chloroformate vapor (20°C) for 3 min (Hollander and Weigand 1985). Clinical signs included jerky respiration, extreme excitation, and severe corneal opacity. Pleural hemorrhages were found at necropsy.

The following oral LD₅₀ values for methyl chloroformate were reported: 190 mg/kg for male Sprague-Dawley rats (Vernot et al. 1977); 110 mg/kg for female Sprague-Dawley rats (Vernot et al. 1977); 313 mg/kg for male and female Sprague-Dawley rats (BASF 1981b); and 220 mg/kg (WARF Institute Inc. 1972). A dermal LD₅₀ value of 894 mg/kg was reported for male and female Sprague-Dawley rats (BASF 1981c). In another study, a dermal LD₅₀ of more than 2 mL/kg was reported for male rats (WARF Institute, Inc. 1972).

A 4-week repeated exposure study (BASF 1993) described both lethal and nonlethal effects in rats (see Section 2.3.2 [Repeated Exposure] for details of the study).

2.4.1.2. Mice

Following a 10-min fresh air control period, groups of four male Swiss-Webster mice were exposed head only to methyl chloroformate aerosol at nominal concentrations of 0, 16.5, 25, 35, 50, 75, or 125 ppm for 30 min (Carpenter 1982a). The mice were then removed and exposed to fresh air for a 10-min recovery period, and respiratory rates were monitored continuously during both the exposure and recovery periods. Undiluted methyl chloroformate was delivered to a Pitt No. 1 aerosol generator via a 2-cc syringe, driven by a pump at a known rate. Aerosol was directed into a 9-L stainless steel chamber which was continuously evacuated at a rate of 20 L/min. An RD₅₀ (concentration that reduced the respiratory rate by 50%) of 52.4 ppm was calculated. Results of this study are summarized in Table 2-11.

Gurova et al. (1977) reported a 2-h LC₅₀ of 47 ppm for mice. No other experimental details were available.

2.4.2. Repeated Exposure

In an inhalation range-finding study, groups of five male and five female Sprague-Dawley rats were exposed to methyl chloroformate at 0, 1.9, 6.2, or 19.5 ppm for 6 h/day for 5 days (Kenny et al. 1992). No treatment-related effects were observed in the 1.9-ppm group. Clinical signs in the 6.2- and 19.5-ppm groups included blinking, licking the inside of the mouth, ruffled fur,

and sneezing. In the 19.5-ppm group, males sneezed and had noisy nasal breathing in between exposures. Decreased body weight was accompanied by decreased food and water consumption in rats exposed at 19.5 ppm. Rats were necropsied 3 days post-exposure. Lungs failed to collapse in 1/5 males and 3/5 females in the 6.2-ppm group and 5/5 females in the 19.5-ppm group. Petechial bleeding was found in the lungs of 1/5 males in the 6.2-ppm group and 5/5 males and 1/5 females in the 19.5-ppm group. Pulmonary weight was increased in all high-concentration females; organ weights were not examined in males because of experimental error during necropsy. Inflammatory and erosive mucous membrane lesions were found in the nose, larynx, and trachea, and bronchiolitis and pneumonia were observed in high-concentration rats. Focal epithelial hyperplasia of the nasal mucosa was found in the 6.2- and 19.5-ppm groups. Comparison of histologic findings in a satellite group examined immediately after 3 days of exposure suggested that regeneration and repair of epithelial lesions had occurred in animals examined 3 days post-exposure.

In a repeated-exposure study, groups of five male and five female Sprague-Dawley rats were exposed to methyl chloroformate at 0, 0.13, 0.38, 1.01, 3.1, or 8.8 ppm for 6 h/day, 5 days/week for 4 weeks (BASF 1993). Mortality was occurred in 2/5 male and 1/5 female rats at 8.8 ppm during the final week of exposure. Clinical signs, observed only at 8.8 ppm, included blinking, hunched posture, rapid breathing pattern, and noisy breathing. Decreased body weight gain and food consumption were also observed in the 8.8-ppm animal. Increased packed cell volume, increased hemoglobin concentration, increased red cell count, increased neutrophil count, increased total protein, decreased albumin, increased globulin, decreased albumin-to-globulin ratio, and increased cholesterol were observed at 8.8 ppm as well. In addition, uncollapsed lungs, pulmonary congestion, enlarged tracheobronchial and medistinal lymph nodes, and increased pulmonary weight were observed at necropsy in rats exposed at 8.8 ppm. Histopathologic lesions of the nasal turbinates were observed at 3.1 and 8.8 ppm, whereas lesions were observed in the larynx of animals exposed at 1.01, 3.1, and 8.8 ppm.

TABLE 2-11 Effects in Male Swiss-Webster Mice Exposed to Methyl Chloroformate for 30 Minutes

Source: Carpenter 1982a.

Groups of 10 male and 10 female Wistar rats were exposed to methyl chloroformate at 0, 0.40, 2.15, 3.98, or 7.83 ppm for 6 h/day, 5 days/week for 3, 10, 20, or 65 exposures (90-day study with interim necropsies after 3, 14, and 28 study days; satellite groups also contained 10 rats/sex/concentration) (BASF 1999a). In addition clinical evaluations and complete necropsy, cell proliferation measurements were performed in four female rats per group. 5-Bromo-2′-deoxyuridine was administered to these females via subcutaneously implanted minipumps. Pumps remained in the animals for 8 h or 3 days for evaluation of cell proliferation in the nasal cavity and laryngeal epithelia. Four male rats in the 7.83-ppm group died; deaths occurred after 24, 32, 36, and 41 exposures. Clinical signs were observed only in high-concentration animals and included rubbing of snout, sneezing, nasal crusts and abnormal respiration in the animals that died, and general morbidity. Decreased body weight and body weight gain were noted in males in the 3.98- and 7.83-ppm groups killed after three exposures and at study termination. At necropsy, gross effects were observed only in the 7.83-ppm group and included red foci in the lungs. Animals in the high-concentration group, except for those killed after three exposures, had increased pulmonary weights. Concentration and duration-related histologic effects were restricted to the respiratory tract and occurred in 2.15-, 3.98-, and 7.83-ppm animals at all sacrifice times. Nasal and laryngeal squamous cell metaplasia was found at 2.15, 3.98, and 7.83 ppm. Focal epithelial hyperplasia and squamous cell metaplasia and hyperplasia of the trachea and lungs occurred at 3.98 and 7.83 ppm. No histopathologic effects were found in the 0.40-ppm group. Cell proliferation was increased at 2.15 ppm after 20 and 65 days, and at 3.98 and 7.83 ppm after 10, 20, and 65 days. The significant increases occurred in the respiratory and transitional cell epithelium of the nose and in the ciliated and squamous epithelium of the larynx. No cell proliferation was observed at 0.40 ppm.

Groups of four male and four female Alderly Park SPF rats were exposed to methyl chloroformate vapor in isopropanol at 1, 5, or 20 ppm for 6 h for 15 exposures (Gage 1970). The vapor concentrations were produced by injecting liquid at a known rate into a metered stream of air with a controlled fluid-feed atomizer. No effects were observed at 1 ppm. Nasal irritation and lethargy were observed at 5 ppm, and nasal irritation, respiratory difficulty, weight loss, lethargy, and poor condition were observed at 20 ppm. Distended lungs and pulmonary hemorrhage, and renal congestion were found at autopsy in the 20-ppm group. No further details were provided.

2.4.3. Developmental and Reproductive Toxicity

Developmental and reproductive studies regarding animal exposure to methyl chloroformate were not available.

2.4.4. Genotoxicity

Methyl chloroformate was negative in Ames bacterial reverse-mutation-assay tests with Salmonella typhimurium strains TA98, TA100, TA1535, and TA1537 in the presence or absence of S9 mix (Hoechst 1977; Miltenburger 1985; BASF 1988a). Methyl chloroformate induced chromosome aberrations in Chinese hamster V79 cells in the presence of S9 mix; no increase in aberrations occurred in the absence of S9 mix (Miltenburger 1986).

2.4.5. Carcinogenicity

No carcinogenicity data on methyl chloroformate were found.

2.4.6. Summary

Animal toxicity data on methyl chloroformate include acute and repeated-exposure inhalation studies. Rat 1-h LC₅₀ values were relatively consistent between studies as follows: 163 ppm for male and female Charles River rats (IBT1975); 92-123 ppm and 100 ppm for male and female Fischer 344 rats, respectively (Fisher et al. 1981a); and 88 ppm and 103 ppm for male and female Sprague Dawley rats, respectively (Vernot et al. 1977). Rat 4-h LC₅₀ values were reported to be 51-53 ppm (Hollander et al. 1986) and 15 ppm (BASF 1980a); however, the 15-ppm value is an outlier when compared to other available data. Signs of toxicity included body weight loss, weakness and lethargy, respiratory distress, hematologic effects consistent with decreased oxygen availability (assumed secondary to pulmonary congestion and edema), and bronchiolitis, fibrosis, and pulmonary edema. A 30-min RD₅₀ of 47.2 ppm (nominal concentration) was reported for male Swiss-Webster mice (Carpenter 1982a). Methyl chloroformate did not induce mutations in an Ames bacterial reverse mutation assay (Hoechst 1977; Miltenburger 1985; BASF 1988a) but did induce chromosomal aberrations in Chinese hamster V79 cells in the presence of S9 mix (Miltenburger 1986). No data concerning developmental or reproductive toxicity or carcinogenicity of methyl chloroformate were found in the literature. Animal data on methyl chloroformate are summarized in Table 2-12.

2.5. Data Analysis for AEGL-1

2.5.1. Human Data Relevant to AEGL-1

No human data on methyl chloroformate consistent with the definition of AEGL-1 were available.

TABLE 2-12 Summary of Inhalation Toxicity Studies of Methyl Chloroformate

Abbreviations: BMCL₀₁, benchmark concentration, 95% lower confidence limit with 5% response; LC₅₀, lethal concentration, 50% lethality; RD₅₀, concentration that reduces the respiratory rate by 50%.

2.5.2. Animal Data Relevant to AEGL-1

No animal data on methyl chloroformate consistent with the definition of AEGL-1 were available.

2.5.3. Derivation of AEGL-1 Values

Data were insufficient to derive AEGL-1 values for methyl chloroformate. Therefore, AEGL-1 values are not recommended.

2.6. Data Analysis for AEGL-2

2.6.1. Human Data Relevant to AEGL-2

Case reports of human poisonings with methyl chloroformate include descriptions of effects consistent with the definition of AEGL-2. However, because reliable concentration and exposure duration information were not available, the data are not appropriate for deriving AEGL-2 values.

2.6.2. Animal Data Relevant to AEGL-2

No acute animal data on methyl chloroformate consistent with the definition of AEGL-2 were available.

2.6.3. Derivation of AEGL-2 Values

No acute inhalation data appropriate for deriving AEGL-2 values for methyl chloroformate were available. Thus, the AEGL-2 values were calculated by taking one-third of the AEGL-3 values. That approached is used to estimate a threshold for irreversible effects if a chemical has a steep concentration-response curve (NRC 2001). Lethality data on methyl chloroformate provide evidence of such a curve. In studies of rats exposed to methyl chloroformate for 4 h, Hollander et al. (1986) reported an LC₅₀ of 51-53 ppm, no mortality at 45 ppm, and 80% mortality at 57 ppm. In another study using rats, the 1-h LC₅₀ was 100 ppm, and rats exposed at 26 ppm for 1 h were clinically normal and had no mortality (Fisher et al. 1981a). The AEGL-2 values for methyl chloroformate are presented in Table 2-13.

The AEGL-2 values are further 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).

TABLE 2-13 AEGL-2 Values for Methyl Chloroformate

2.7. Data Analysis for AEGL-3

2.7.1. Human Data Relevant to AEGL-3

Human lethality data on methyl chloroformate were anecdotal and lacked reliable concentration and exposure duration information. Thus, those reports were not appropriate for establishing AEGL-3 values.

2.7.2. Animal Data Relevant to AEGL-3

Rat 1-h LC₅₀ values for methyl chloroformate were: 163 ppm for male and female Charles River rats (IBT 1975); 92-123 ppm and 100 ppm for male and female Fischer 344 rats, respectively (Fisher et al. 1981a); and 88 ppm and 103 ppm for male and female Sprague Dawley rats, respectively (Vernot et al. 1977). Exposure of male and female Fischer-344 rats to methyl chloroformate at 26 ppm methyl chloroformate 1 h resulted in no deaths (Fisher et al. 1981a). Four-hour LC₅₀ values of 51 ppm and 53 ppm were calculated for male and female Wistar rats, respectively; a combined male and female BMCL₀₅ value of 42.4 ppm and combined male and female BMC₀₁ (benchmark concentration, 1% response) value of 47.8 ppm were also calculated (Hollander et al. 1986).

2.7.3. Derivation of AEGL-3 Values

The calculated 4-h BMCL₀₅ value of 42.4 ppm for methyl chloroformate in rats (Hollander et al. 1986) was the point-of-departure for AEGL-3 values. 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 rat studies of methyl chloroformate (Gage 1970; Kenny et al. 1992; BASF 1993, 1999a). 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). Thus, interspecies and intraspecies uncertainty factors of 3 would represent the potential for any toxicodynamic variability, resulting in a total uncertainty factor of 10 applied to

the estimated threshold for lethality (42.4 ppm). Time scaling was performed using the equation Cⁿ × t = k, where the exponent, n, ranges from 0.8 to 3.1 (ten Berge et al. 1986). Data on methyl chloroformate were insufficient for calculating an empirical value for the exponent n, so default values of n = 3 when extrapolating from longer to shorter durations (10 min, 30 min, and 1 h) and n = 1 when extrapolating from shorter to longer durations (8 h) were used. Time scaling a 4-h point-of-departure to a 10-min AEGL-3 value is supported by a 1-h LC₅₀ study (IBT 1975); a 10-min AEGL-3 value calculated on the basis of a BMCL₀₅ from the study would be 13 ppm, which supports the time-scaled value of 12 ppm calculated from the study by Hoechst (Hollander et al. 1986). The AEGL-3 values for methyl chloroformate are presented in Table 2-14; the calculations are presented in Appendix B.

The AEGL-3 values are further 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 1999a), 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).

2.8. Summary of AEGLs

2.8.1. AEGL Values and Toxicity End Points

The AEGL values for methyl chloroformate are presented in Table 2-15. Data were insufficient for deriving AEGL-1 values. AEGL-2 values were derived by dividing AEGL-3 values by 3, and AEGL-3 values were based on an estimated 4-h lethality threshold in rats. A derivation summary and category plot of the AEGL values and toxicity data are presented in Appendixes C and D, respectively.

2.8.2. Other Standards and Guidelines

The American Industrial Hygiene Association (AIHA) has developed emergency response planning guidelines (ERPGs) for methyl chloroformate (see Table 2-16). The ERPGs are very similar to the corresponding 1-h AEGL values. No other exposure standards or guidelines exposure have been established for methyl chloroformate.

TABLE 2-14 AEGL-3 Values for Methyl Chloroformate

TABLE 2-15 AEGL Values for Methyl Chloroformate^a

^aTreatment of people exposed to chloroformates should consider that pulmonary edema frequently occurs, but its symptoms may not manifest for several hours after exposure and may be aggravated by physical exertion.

^bNR, not recommended. Absence of an AEGL-1 value does not imply that exposure below the AEGL-2 value is without adverse effects.

TABLE 2-16 Standards and Guidelines for Methyl Chloroformate

^aNR, not recommended. Absence of an AEGL-1 value does not imply that exposure below the AEGL-2 value is without adverse effects.

^bERPG-1 (emergency response planning guidelines, American Industrial Hygiene Association) (AIHA 2006a, 2013) is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing other than mild transient adverse health effects or perceiving a clearly defined objectionable odor.

EPRG-2 (emergency response planning guidelines, American Industrial Hygiene Association) (AIHA 2006a, 2013) is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing irreversible or other serious health effects or symptoms that could impair an individual’s ability to take protective action.

EPRG-3 (emergency response planning guidelines, American Industrial Hygiene Association) (AIHA 2013) is the maximum airborne concentration below which nearly all individuals could be exposed for up to 1 hour without experiencing or developing life-threatening health effects.

^cNA, not appropriate. Classified by AIHA as not appropriate because the odor threshold is above the EPRG-2 level.

2.8.3. Data Adequacy and Research Needs

The only human data on methyl chloroformate are from anecdotal reports. Animal data include acute and repeated-exposure rat inhalation studies and a mouse RD₅₀ study. Support provided by the repeated-exposure studies adds to confidence in the AEGL values.

3. ETHYL CHLOROFORMATE

3.1. Summary

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

No acute inhalation data appropriate for deriving AEGL-2 values for ethyl chloroformate were available. Thus, the AEGL-2 values were calculated by taking one-third of the AEGL-3 values. That approached 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.

For AEGL-3 values, an estimate of the threshold for lethality was used as the point-of-departure. The threshold was estimated by taking one-third of the most conservative 1-h LC₅₀ value (145 ppm ÷ 3 = 48 ppm) in rats (Vernot et al. 1977). That concentration is also supported by the study by Fisher et al. (1981b), which reported no deaths in rats exposed to ethyl chloroformate 47 ppm for 1 h. The effects of the chloroformates result from the direct-acting corrosive effects on the airways, in the absence of other systemic effects. Supporting information for this mode of action comes from observations in rats of respiratory effects (e.g., pulmonary congestion, pulmonary edema, and emphysema) in lethality studies of ethyl chloroformate (BASF 1970a,b; Gage 1970; WARF Institute, Inc. 1978; Fisher et al. 1981b). 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). Thus, interspecies and intraspecies uncertainty factors of 3 would represent the potential for any toxicodynamic variability, resulting in a total uncertainty factor of 10 applied to the estimated threshold for lethality (48 ppm). Use of these factors is consistent with the ones applied in calculating AEGL-3 values for the structural analogs, methyl chloroformate, isopropyl chloroformate, and n-butyl chloroformate. The AEGL values for those analogs were considered protective when compared with chemical-specific, repeated-exposure data. Time scaling was performed using the equation Cⁿ × t = k (ten Berge et al. 1986). Data on ethyl chloroformate were insufficient for calculating

an empirical value for the exponent n, so default values of n = 3 when extrapolating from longer to shorter durations (10 and 30 min) and n = 1 when extrapolating from shorter to longer durations (4 and 8 h) were used.

The AEGL values for ethyl chloroformate are presented in Table 2-17.

3.2. Chemical and Physical Properties

Ethyl chloroformate hydrolyzes in water to form ethanol, carbon dioxide, and hydrogen chloride. Selected chemical and physical properties of ethyl chloroformate are presented in Table 2-18.

3.3. Human Toxicity Data

3.3.1. Acute Lethality

Information concerning death in humans after inhalation exposure to ethyl chloroformate was not available.

3.3.2. Nonlethal Toxicity

3.3.2.1. Case Report

A chemical operator employed in the manufacture of polyvinyl chloride was splashed with an undetermined amount of ethyl chloroformate when a plastic hose blew off a pump that was dispensing ethyl chloroformate (Bowra 1981). The worker was wearing a polyvinyl chloride apron, safety shoes, long gloves, and a full-face fresh-air mask, which helped to restrict exposure to ethyl chloroformate to an area on his right thigh. He showered in a domestic shower, and developed ocular irritation and cough, presumably because the warmth and humidity of the shower room produced ethyl chloroformate fumes from his discarded clothing. Symptoms subsided until 3.5 h after the incident when he began to experience chest tightness and difficulty breathing. He was slightly cyanotic, had audible crepitations at the base of his right lung, and had a reddened area on the right thigh. He was hospitalized and subsequently developed pulmonary edema. He received medical treatment and his symptoms resolved over the next few days, with no long-term effects.

3.3.3. Developmental and Reproductive Toxicity

Developmental and reproductive studies of acute human exposure to ethyl chloroformate were not available.

TABLE 2-17 AEGL Values for Ethyl Chloroformate^a

^aTreatment of people exposed to chloroformates should consider that pulmonary edema frequently occurs, but its symptoms may not manifest for several hours after exposure and may be aggravated by physical exertion.

^bNR, not recommended. Absence of an AEGL-1 value does not imply that exposure below the AEGL-2 is without adverse effects.

TABLE 2-18 Chemical and Physical Properties of Ethyl Chloroformate

3.3.4. Genotoxicity

Genotoxicity studies of acute human exposure to ethyl chloroformate were not available.

3.3.5. Carcinogenicity

Carcinogenicity studies of human exposure to ethyl chloroformate were not available.

3.3.6. Summary

Information on human exposure to ethyl chloroformate is available from a single occupational case report. The report suggests that ethyl chloroformate is a respiratory-tract irritant and is capable of inducing delayed pulmonary edema, but no exposure concentration or duration information was available. No humans studies of the developmental toxicity, reproductive toxicity, genotoxicity, or carcinogenicity of ethyl chloroformate were available.

3.4. Animal Toxicity Data

3.4.1. Acute Lethality

3.4.1.1. Rats

Groups of 10 male Sprague Dawley rats were exposed to ethyl chloroformate at 365 or 730 ppm (nominal concentrations) for 1 h (WARF Institute, Inc. 1978). A “semi-portable” exposure chamber containing an exhaust fan for adjustable air flow was used. Ethyl chloroformate was administered into the incoming air stream just before it entered the chamber port, and exposure concentrations were calculated by dividing the total amount sprayed into the chamber by the total cubic feet of air circulated through the chamber. Within 1 min, and throughout the 1-h exposure period, animals in both groups had closed eyes and were gasping. Animals in the 730-ppm group fell into a semi-conscious state after 10 min of exposure, and all were dead 1-2 h after exposure. All animals in the 365-ppm group died within 24 h after exposure. Hemorrhage in all lung lobes and in the trachea were found at gross necropsy.

Groups of five male and five female Fischer-344 rats were exposed to ethyl chloroformate vapor at 0, 47, 153, 180, 245, or 270 ppm for 1 h in a 3-foot wide Hinner-style chamber, followed by a 14-day observation period (Fisher et al. 1981b). Chamber concentrations were monitored by real time variable pathlength infrared photospectrometry. The LC₅₀ values were 189 ppm (164-216 ppm) for male rats and 200 ppm (173-232 ppm) for female rats after 14-days post-exposure.

Controls and rats in the 47-ppm group were clinically normal and had no treatment-related effects at necropsy. Body weight gain was decreased in surviving males and females in the 153- and 180-ppm groups at day 7 and at termination. All rats in the 245- and 270-ppm groups died before the scheduled sacrifice. Average relative lung weight of animals in the 245- and 270-ppm groups was approximately 3-times greater than that of controls, and corroborating lesions indicative of acute alveolar hemorrhage were observed. Relative lung weight was also increased (magnitude not specified) in the 153- and 180-ppm groups. Red lung coloration was observed in one male and one female in the 153-ppm group, and two females and one male in the 180-ppm group.

Vernot et al. (1977) reported 1-h LC₅₀s of 145 ppm (140-150 ppm) for male and 170 ppm (150-180) ppm for female Sprague-Dawley rats. Experiments were performed in bell jars using groups of five rats per concentrations; concentrations were determined analytically. No further experimental details were available.

Death occurred in 9/10 rats exposed to ethyl chloroformate at 200 ppm for 1 h (BASF 1970a). Clinical signs included mucous membrane irritation and gasping. Pulmonary congestion and edema were found at necropsy.

Death occurred in 11/12 rats exposed to an “atmosphere enriched or saturated” with ethyl chloroformate vapor (20°C) for 3 min (BASF 1970b). Clinical signs included vigorous escape behavior, severe mucous membrane irritation, and gasping. Pulmonary congestion, pulmonary edema, and emphysema were found at necropsy.

Groups of four male and four female Alderly Park SPF rats were exposed to ethyl chloroformate vapor in isopropanol for 6 h at 1 ppm (20 exposures), 5 ppm (20 exposures), or 20 ppm (10 exposures) (Gage 1970). The vapor concen-trations were produced by injecting liquid at a known rate into a metered stream of air with a controlled fluid-feed atomizer. No effects were observed at 1 ppm, decreased weight gain was observed at 5 ppm, and nasal irritation, respiratory difficulty, weight loss, and poor condition were observed at 20 ppm. Distended lungs and pulmonary hemorrhage were found at necropsy in the 20-ppm group. No further details were provided.

Several oral LD₅₀ values have been reported, including 470 mg/kg (Vernot et al. 1977) and 411 mg/kg (WARF Institute, Inc. 1978) for male rats; 614 mg/kg for female Wistar rats (Hoechst 1975); and 244 mg/kg for an unspecified sex and strain of rat (BASF 1970c). Dermal LD₅₀ values have been reported to be greater than 2 mL/kg for male rats (WARF Institute, Inc. 1978) and 7,120 mg/kg for New Zealand white rabbits (Vernot et al. 1977).

3.4.1.2. Mice

Following a 10-min fresh air control period, groups of four male Swiss-Webster mice were exposed head only to ethyl chloroformate aerosol at concentrations of 0, 25, 50, 100, or 200 ppm for 30 min (Carpenter 1982b). The mice were then removed and exposed to fresh air for a 10-min recovery period,

and respiratory rates were monitored continuously during both the exposure and recovery periods. Undiluted ethyl chloroformate was delivered to a Pitt No. 1 aerosol generator via a 2-cc syringe, driven by a pump at a known rate. Aerosol was directed into a 9-L stainless steel chamber that was continuously evacuated at a rate of 20 L/min. An RD₅₀ (concentration that reduced the respiratory rate by 50%) of 77.5 ± 5.4 ppm was calculated. Results of this study are summarized in Table 2-19.

3.4.2. Developmental and Reproductive Toxicity

Studies concerning the developmental and reproductive toxicity of ethyl chloroformate were not found.

3.4.3. Genotoxicity

Ethyl chloroformate was negative in a preincubation test both with and without metabolic activation in S. typhimurium strains TA98, TA100, TA1535, and TA1537 (BASF 1988b).

3.4.4. Carcinogenicity

Groups of 50 male Sprague-Dawley rats were exposed to ethyl chloroformate by inhalation at concentrations of 1.5, 3.0, or 6.0 ppm for 6 h/day, 5 days/week for a total of 30 exposures (Sellakumar et al. 1987). No treatment-related effect on life span was observed. One animal in the 6.0-ppm group developed a squamous cell carcinoma of the nasal mucosa; the time to tumor appearance was 700 days. No nasal tumors were noted at 1.5 or 3.0 ppm. Ethyl chloroformate has not been assessed for carcinogenicity by the International Agency for Research on Cancer (IARC) or the National Toxicology Program (NTP).

TABLE 2-19 Effects in Male Mice Exposed to Ethyl Chloroformate for 30 Minutes

Source: Adapted from Carpenter 1982b.

Van Duuren et al. (1987) investigated the carcinogenicity of ethyl chloroformate in female ICR/Ha Swiss mice by dermal and subcutaneous administration. Groups of 30-50 mice were treated dermally with 3.0, 4.3, or 5.5 mg of ethyl chloroformate in acetone three times per week for 18-22 months. Tumor incidence was 0/50, 1/30, and 0/50, for the 3.0-, 4.3-, and 5.5-mg groups, respectively. In a dermal initiation-promotion assay, mice were administered a single 5.5 mg dose of ethyl chloroformate, followed 2 weeks later by thrice weekly applications of phorbol mysterate acetate (as a promoter) for 18-22 months. Tumors were found in 6/50 animals (four papillomas, two squamous cell carcinomas), suggesting that ethyl chloroformate may be a tumor promoter. In another study, mice were injected in the left flank once weekly with 0.3 or 1.1 mg of ethyl chloroformate in 0.1 mL of tricaprylin for 18-22 months. Tumor incidence was 1/50 in the 0.3-mg group (squamous cell carcinoma) and 0/50 in the 1.1-mg group.

3.4.5. Summary

Animal toxicity data for ethyl chloroformate are sparse. One-hour LC₅₀ values were relatively consistent between studies as follows: 189 ppm and 200 ppm for male and female Fischer-344 rats, respectively (Fisher et al. 1981b) and 145 ppm and 170 ppm for male and female Sprague Dawley rats, respectively (Vernot et al. 1977). Signs of toxicity included decreased body weight gain, respiratory distress, increased lung weight, and pulmonary edema. A 30-min RD₅₀ of 77.5 ppm (nominal concentration) was reported for male Swiss-Webster mice (Carpenter 1982b). No data on the developmental or reproductive toxicity of ethyl chloroformate were available. Ethyl chloroformate was negative in the Ames assay. Carcinogenicity data suggest that ethyl chloroformate may be a tumor promoter by the dermal route (Van Duuren et al. 1987). Animal data on ethyl chloroformate are summarized in Table 2-20.

3.5. Data Analysis for AEGL-1

3.5.1. Human Data Relevant to AEGL-1

No human data on ethyl chloroformate consistent with the definition of AEGL-1 were available.

3.5.2. Animal Data Relevant to AEGL-1

No animal data on ethyl chloroformate consistent with the definition of AEGL-1 were available.

TABLE 2-20 Summary of Acute Inhalation Toxicity Studies of Ethyl Chloroformate

Abbreviations: LC₅₀, lethal concentration, 50% lethality; RD₅₀, concentration that reduces respiratory rate by 50%.

3.5.3. Derivation of AEGL-1 Values

Data were insufficient to derive AEGL-1 values for ethyl chloroformate, so no values are recommended.

3.6. Data Analysis for AEGL-2

3.6.1. Human Data Relevant to AEGL-2

No appropriate human data on ethyl chloroformate consistent with the definition of AEGL-2 were available.

3.6.2. Animal Data Relevant to AEGL-2

No animal data on ethyl chloroformate consistent with the definition of AEGL-2 were available.

3.6.3. Derivation of AEGL-2 Values

No acute inhalation data appropriate for deriving AEGL-2 values for ethyl chloroformate were available. Thus, the AEGL-2 values were calculated by taking one-third of the AEGL-3 values. That approached 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. The AEGL-2 values for ethyl chloroformate are presented in Table 2-21.

3.7. Data Analysis for AEGL-3

3.7.1. Human Data Relevant to AEGL-3

No human data on ethyl chloroformate consistent with the definition of AEGL-3 were available.

3.7.2. Animal Data Relevant to AEGL-3

Rat 1-hour LC₅₀ values for ethyl chloroformate were: 189 ppm and 200 ppm for male and female Fischer-344 rats, respectively (Fisher et al. 1981b), and 145 ppm and 170 ppm for male and female Sprague Dawley rats, respectively (Vernot et al. 1977). Exposure of male and female Fischer-344 rats to ethyl chloroformate at 47 ppm for 1 h resulted in no deaths (Fisher et al. 1981b).

3.7.3. Derivation of AEGL-3 Values

One-third of the most conservative 1-h LC₅₀ value in rats (145 ppm ÷ 3 = 48 ppm) (Vernot et al., 1977) will be used as the point-of-departure for ethyl chloroformate AEGL-3 values. That concentration is considered a threshold for lethality and is supported by the study by Fisher et al. (1981b) that reported no deaths in rats exposed to ethyl chloroformate at 47 ppm for 1 h.

The effects of the chloroformates result from the direct-acting corrosive effects on the airways, in the absence of other systemic effects. Supporting information for this mode of action comes from observations in rats of respiratory effects (e.g., pulmonary congestion, pulmonary edema, and emphysema) in lethality studies of ethyl chloroformate (BASF 1970a,b; Gage 1970; WARF Institute, Inc. 1978; Fisher et al. 1981b). 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). Thus, interspecies and intraspecies uncertainty factors of 3 would represent the potential for any toxicodynamic

TABLE 2-21 AEGL-2 Values for Ethyl Chloroformate

variability, resulting in a total uncertainty factor of 10 applied to the estimated threshold for lethality (48 ppm). Use of these factors is consistent with the ones applied in calculating AEGL-3 values for the structural analogs, methyl chloroformate (see Section 2.7.3), isopropyl chloroformate (see Section 5.7.3), and n-butyl chloroformate (see Section 6.7.3). The AEGL values for those analogs were considered protective when compared with chemical-specific, repeated-exposure data. Time scaling was performed using the equation Cⁿ × t = k (ten Berge et al. 1986). Data on ethyl chloroformate were insufficient for calculating an empirical value for the exponent n, so default values of n = 3 when extrapolating from longer to shorter durations (10 and 30 min) and n = 1 when extrapolating from shorter to longer durations (4 and 8 h) were used. The AEGL-3 values for ethyl chloroformate are presented in Table 2-22; the calculations are presented in Appendix B.

3.8. Summary of AEGLs

3.8.1. AEGL Values and Toxicity End Points

The AEGL values for ethyl chloroformate are presented in Table 2-23. Data were insufficient for deriving AEGL-1 values. AEGL-2 values were derived by dividing AEGL-3 values by 3, and AEGL-3 values were based on an estimated 1-h lethality threshold in rats. A derivation summary and category plot of the AEGL values and toxicity data are presented in Appendixes C and D, respectively.

3.8.2. Other Standards and Guidelines

The American Industrial Hygiene Association (AIHA) has developed emergency response planning guidelines (ERGPs) for ethyl chloroformate (see Table 2-24). The ERPG-2 and ERPG-3 values are slightly higher than the 1-h AEGL-2 and AEGL-3 values. In support of the ERPG-3 value, AIHA (2006b) cites the nonlethal concentrations of 47 ppm for 1 h and of 20 ppm for repeated 6-h exposures identified in the study by Gage (1970). The rationale for the ERPG-2 value cites data from a 20-day repeated-exposure study in rats that found only weight loss at 5 ppm (Gage 1970). AIHA notes that concentrations greater than 5 ppm could result in respiratory and ocular irritation sufficient to impair escape. No other exposure standards were found for ethyl chloroformate.

TABLE 2-22 AEGL-3 Values for Ethyl Chloroformate

TABLE 2-23 AEGL Values for Ethyl Chloroformate^a

^aTreatment of people exposed to chloroformates should consider that pulmonary edema frequently occurs, but its symptoms may not manifest for several hours after exposure and may be aggravated by physical exertion.

^bNR, not recommended. Absence of an AEGL-1 value does not imply that exposure below the AEGL-2 value is without adverse effects.

TABLE 2-24 Standards and Guidelines for Ethyl Chloroformate

^aNR, not recommended. Absence of an AEGL-1 value does not imply that exposure below the AEGL-2 value is without adverse effects.

^bERPG-1 (emergency response planning guidelines, American Industrial Hygiene Association) (AIHA 2006b, 2013) is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing other than mild transient adverse health effects or perceiving a clearly defined objectionable odor.

EPRG-2 (emergency response planning guidelines, American Industrial Hygiene Association) (AIHA 2006b, 2013) is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing irreversible or other serious health effects or symptoms that could impair an individual’s ability to take protective action.

EPRG-3 (emergency response planning guidelines) (AIHA 2006b, 2013) is the maximum airborne concentration below which nearly all individuals could be exposed for up to 1 hour without experiencing or developing life-threatening health effects.

^cID: AIHA did not derive an EPRG-1 value because of insufficient data (lack of data on odor threshold and minor irritation).

3.8.3. Data Adequacy and Research Needs

Animal data on ethyl chloroformate include acute rat inhalation studies and a mouse RD₅₀ study. The consistency results observed in the rat LC₅₀ studies adds to confidence in the AEGL values.

4. ISOPROPYL CHLOROFORMATE

4.1. Summary

Data on isopropyl chloroformate were insufficient to derive of AEGL-1 values, so no values are recommended.

No acute inhalation data appropriate for deriving AEGL-2 values for isopropyl chloroformate were available. Thus, the AEGL-2 values were calculated by taking one-third of the AEGL-3 values. That approached is used to estimate a threshold for irreversible effects if a chemical has a steep concentration-response curve (NRC 2001).

The point-of-departure was based on the 5-day repeated exposure study by Collins and Proctor (1984). In that study, there were no deaths in Sprague-Dawley rats from exposure to isopropyl chloroformate at 50 ppm for 6 h/day for 5 days, whereas exposure at 100 ppm for 6 h/day for 5 days resulted in deaths of 3/4 males (after 2, 4, and 5 days of treatment) and 3/4 females (after 3, 3, and 5 days of treatment). A concentration of 50 ppm was selected as the point-of-departure because there were no observed deaths in rats at 50 ppm (i.e., lethality threshold). The effects of the chloroformates result from the direct-acting corrosive effects on the airways, in the absence of other systemic effects. Supporting information for this point-of-departure is provided by the acute isopropyl chloroformate study conducted by Industrial Bio-Test Laboratories, Inc. (IBT 1970b). This study could not be used as the basis of the point of departure, due to the afformentioned issues with IBT studies. Supporting information for this mode of action comes from observations in rats of nasal irritation and respiratory effects (e.g., pulmonary inflammation, pulmonary edema, and emphysema) in short-term repeated-exposure studies of isopropyl chloroformate (Gage 1970; Collins and Proctor 1984). The 10- and 30-minute AEGL-3 of 11 ppm extrapolated from the 6-h point of departure of 50 ppm in rats are consistent with values that can potentially be derived from the estimated 15-min LC₅₀ of 283-345 ppm based on the results in mice by Anderson (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). Thus, interspecies and intraspecies uncertainty factors of 3 would represent the potential for any toxicodynamic variability, resulting in a total uncertainty factor of 10 applied to

the estimated threshold for lethality (50 ppm). Time scaling was performed using the equation Cⁿ × t = k (ten Berge et al. 1986). Data on isopropyl chloroformate were insufficient for calculating an empirical value for the exponent n, so default values of n = 3 when extrapolating from longer to shorter durations and n = 1 when extrapolating from shorter to longer durations were used. 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 exposure value. The AEGL values for isopropyl chloroformate are presented in Table 2-25.

4.2. Chemical and Physical Properties

Isopropyl chloroformate hydrolyzes in water to form isopropanol, carbon dioxide, and hydrogen chloride. Selected chemical and physical properties of isopropyl chloroformate are present in Table 2-26.

4.3. Human Toxicity Data

4.3.1. Acute Lethality

Information on human deaths after exposure to isopropyl chloroformate was not available.

4.3.2. Nonlethal Toxicity

Short-term, task-specific industrial hygiene monitoring for isopropyl chloroformate was conducted at a resins plant (Martin 1994). The monitoring was conducted to evaluate potential employee exposure during tank-truck unloading operations. Although employees wore full-face supplied-air respirators, neoprene gloves, rubber boots, and neoprene clothing, exposures were considered possible. The study was conducted to determine if PPE should be used during these operations. Thus the employees involved in the evaluation did wear PPE as potential exposure levels were unknown and since it was determined that the levels could exceed allowable levels, PPE was mandated for this operation Concentrations of isopropyl chloroformate measured from four personal monitors were 0.2-4.6 ppm for the sampled activity (20-40 min); measurements from two area samples were 0.06 and 1.7 ppm.

4.3.3. Developmental and Reproductive Toxicity

Developmental and reproductive studies on acute human exposure to isopropyl chloroformate were not available.

TABLE 2-25 AEGL Values for Isopropyl Chloroformate^a

^aTreatment of people exposed to chloroformates should consider that pulmonary edema frequently occurs, but its symptoms may not manifest for several hours after exposure and may be aggravated by physical exertion.

^bNR, not recommended. Absence of an AEGL-1 value does not imply that exposure below the AEGL-2 value is without adverse effects.

TABLE 2-26 Chemical and Physical Properties of Isopropyl Chloroformate

4.3.4. Genotoxicity

Genotoxicity studies regarding acute human exposure to isopropyl chloroformate were not available.

4.3.5. Carcinogenicity

Carcinogenicity studies of human exposure to isopropyl chloroformate were not available.

4.3.6. Summary

No human data on the lethal toxicity, developmental toxicity, reproductive toxicity, genotoxicity, or carcinogenicity of isopropyl chloroformate were available. One industrial hygiene report was available, but was not informative about potential health effects.

4.4. Animal Toxicity Data

4.4.1. Acute Lethality

4.4.1.1. Rats

Groups of five male and five female young adult Charles River albino rats were exposed to nominal concentrations of isopropyl chloroformate vapor at 300, 1,640, or 15,600 ppm for up to 1 h (IBT 1970b). Vapor was generated by bubbling clean, dry air through undiluted isopropyl chloroformate (8-10°C) in a water bath. The resulting vapor was mixed with additional dry air to obtain the desired vapor concentration. The test atmosphere was then introduced into the top of a 70-L Plexiglass inhalation chamber, dispersed by a baffle plate, and removed at the bottom of the chamber. Average nominal concentrations were calculated by dividing the total weight of the isopropyl chloroformate vaporized by the total volume of air used during each inhalation exposure. Animals in the mid- and high-exposure groups started gasping for breath within 15 min of exposure and exhibited convulsions and salivation. Low-concentration animals exhibited gasping and slight salivation. Necropsy of animals that died revealed moderate to severe pulmonary hyperemia. Rats that survived the 14-day observation period exhibited no gross abnormalities at necropsy. The 1-h LC₅₀ was 300 ppm. Data from this study are summarized in Table 2-27. As noted in Section 1.8, studies conducted by Industrial Bio-Test Laboratories are of questionable validity. Although the study of isopropyl chloroformate has not been externally audited, and the raw data from the study are not available, the study report was reviewed, but it was not used as a primary study for derivation of AEGLs.

TABLE 2-27 Effects in Rats Exposed to Isopropyl Chloroformate for Up to 1 Hour

Source: IBT 1970b.

In a limited study, no deaths occurred among 12 rats exposed to isopropyl chloroformate vapor at 200 ppm for 1 h (BASF 1968a). Clinical signs included slight mucosal irritation. No abnormalities were found at necropsy. BASF (1968a) did not have sufficient details about its design or the findings, so the study was considered inadequate to serve as the basis for AEGL-3 values.

Death occurred in 12/12 and 6/6 rats exposed to an “atmosphere saturated” with isopropyl chloroformate vapor for 3 or 10 min, respectively (BASF 1968b). Clinical signs included vigorous escape behavior, dyspnea, and convulsions. No abnormalities were found at necropsy.

In a repeated-exposure study (Collins and Proctor 1984), groups of four male and four female Sprague-Dawley rats were exposed to isopropyl chloroformate (analytic concentrations) at 0, 25, 50, or 100 ppm for 6 h/day for 5 days. Three high-concentration males died after 2, 4, and 5 days of treatment, respectively, and three high-concentration females died after 3, 3, and 4 days of treatment, respectively. Clinical observations on the day before death included lethargy, labored breathing, staining around the muzzle, muscular weakness, and low body temperature. At necropsy, uncollapsed lungs, fluid-filled tracheas, and red discoloration of various tissues (associated with lack of exsanguination) were observed. This study is described in more detail in Section 4.4.2.

Groups of four male and four female Alderly Park SPF rats were exposed to isopropyl chloroformate vapor in isopropanol at 5 ppm (unspecified exposure duration, 20 ppm (20 6-h exposures), 50 ppm (11 6-h exposures), or 200 ppm (1 5-h exposure) (Gage 1970). The vapor concentrations were produced by injecting liquid isopropyl chloroformate at a known rate into a metered stream of air with a controlled fluid-feed atomizer. No effects were observed at 5 ppm, and nasal irritation was observed at 20 ppm. At 50 ppm, respiratory difficulty, weight loss, and one death with pulmonary hemorrhage were observed. Two male rats died at 200 ppm. No further details of the study were available.

In an acute oral toxicity study (IBT 1971), groups of two male and two female Charles River albino rats were administered isopropyl chloroformate by gavage at 118.5, 177.8, 266.7, or 400 mg/kg and observed up to 14 days. No deaths occurred at the low dose, two animals died at 177.8 mg/kg, and all

animals died in the two highest dose groups. Deaths occurred between 1 h and 5 days post-exposure. Hypoactivity, muscular weakness, ptosis, hyperpnea, and ruffled fur were observed. Hemorrhages were found in the stomachs of animals that died during the study. An LD₅₀ (lethal dose, 50% lethality) of 177.8 mg/kg was calculated. An approximate oral LD₅₀ of 800 mg/kg was reported in rats (BASF 1968c).

4.4.1.2. Mice

Following a 10-min fresh air control period, groups of four male Swiss-Webster mice were exposed head only to isopropyl chloroformate at nominal concentrations of 0, 50, 75, 100, 200, or 500 ppm for 30 min (Carpenter 1982c). Although these exposures were generated as aerosols, the exposure was to the vapor based on the chemical vapor pressure. The mice were then removed to fresh air for a 10-min recovery period, and respiratory rates were monitored continuously during both the exposure and recovery periods. Undiluted isopropyl chloroformate was delivered to a Pitt No. 1 aerosol generator via a 2-cc syringe, driven by a pump at a known rate. Aerosol was directed into a 9-L stainless steel chamber, which was continuously evacuated at a rate of 20 L/min. An RD₅₀ of 104 ppm was calculated. Data from this study are summarized in Table 2-28.

In another study (Anderson 1984), groups of four male Swiss-Webster mice were exposed head only to isopropyl chloroformate vapor at nominal concentrations of 0, 177, 306, 443, or 883 ppm for 15 min. The vapor was introduced through a Harvard apparatus syringe drive into a Pitt No. 1 generator. The glass exposure chamber had a capacity of 2.2 L, and air flow was 8.8 L/mine. Baseline respiratory rates of each mouse were recorded for 10 min before exposure. Respiratory rates were recorded after 5 and 10 min of exposure, and the percentage in respiratory depression was calculated from these values. Animals were killed 24 h after exposure. Lung and body weights were obtained at time of death or at necropsy. The 15-min RD₅₀ was calculated to be 375 ppm, and the 15-min LC₅₀ was estimated to be about 283-345 ppm. Concentration-related increases in lung weight, indicative of pulmonary edema, were observed in treated animals compared to controls. The data from this study are summarized in Table 2-29.

4.4.2. Nonlethal Toxicity

Collins and Proctor (1984) exposed groups of four male and four female Sprague-Dawley rats to isopropyl chloroformate vapor at 0, 25, 50, or 100 ppm (analytical) for 6 h/day for 5 days. Isopropyl chloroformate vapor was generated using a sintered glass bubbler supplied with pre-dried compressed air. Chamber concentrations were achieved by adjusting the rate of air flow through the generator. The whole-body exposures were conducted in 600-L stainless-steel

and glass chambers. Actual test concentrations were determined hourly during treatment with an infrared gas analyzer, and nominal chamber concentrations were determined daily by calculating the amount of isopropyl chloroformate consumed per liter of air passing through the chamber. Mean daily measured chamber concentrations were 25, 50, and 100 ppm and corresponding nominal concentrations were 22, 42, and 86 ppm, respectively. The investigators attribute these differences to the low accuracy of the orifice plate system used to measure flow rate through the chamber. Three high-concentration males (after 2, 4, and 5 days of treatment) and three high-concentration females (after 3, 3, and 5 days of treatment) died during the exposure period. Clinical observations on the day before death included lethargy, labored breathing, staining around the muzzle, muscular weakness, and low body temperature. Treatment-related body weight loss was observed post-exposure in the mid- and high-concentration males and females and decreased body weight gain was observed in low-concentration males. Concentration-related increases (p < 0.02) in lung weight were observed in all treatment groups compared with controls. In animals surviving to the end of the study, enlarged bronchial lymph nodes were observed at necropsy in several animals in all concentration groups. Focal alveolar edema and bronchiolitis were observed in several mid-concentration and all high-concentration animals. Peribronchiolar mononuclear cell infiltrate was observed in low- and mid-concentration animals and is assumed to have preceded the bronchiolitis observed in the high-concentration animals. Animals from all three treatment groups exhibited focal pulmonary emphysema.

4.4.3. Developmental and Reproductive Toxicity

No developmental or reproductive toxicity studies of isopropyl chloroformate were available.

TABLE 2-28 Effects in Mice Exposed to Isopropyl Chloroformate for 30 Minutes

Source: Carpenter 1982c.

TABLE 2-29 Effects in Mice Exposed to Isopropyl Chloroformate for 15 Minutes

^aDeaths 2 h or more after exposure.

^bAll deaths within 3 h of exposure.

^cAll deaths within 3 h of exposure.

Source: Anderson 1984.

4.4.4. Genotoxicity

Isopropyl chloroformate was negative in the standard plate test and preincubation test both with and without metabolic activation in S. typhimurium strains TA98, TA100, TA1535, and TA1537 and in Eschericha coli WP2 uvrA (BASF 1999b).

4.4.5. Carcinogenicity

Animal carcinogenicity data on isopropyl chloroformate were not available.

4.4.6. Summary

Animal toxicity data on isopropyl chloroformate are sparse. The chemical affected the respiratory rate of male Swiss-Webster mice; a 30-min RD₅₀ of 104 ppm (nominal concentration) was reported by Carpenter (1982c) and a 15-min RD₅₀ of 375 ppm (analytic concentration) was reported by Anderson (1984). For lethality, a 15-min LC₅₀ of 283-345 ppm was estimated for male Swiss-Webster mice (Anderson 1984) and a 1-h LC₅₀ of 300 ppm was calculated for Charles River albino rats (IBT 1970b). Repeated exposure to isopropyl chloroformate at 100 ppm resulted in death in Sprague-Dawley rats. At 25 and 50 ppm concentrations, body weight loss, increased pulmonary weight, and bronchiolitis were observed. Increased pulmonary weight and edema were consistently observed at necropsy in most studies. Isopropyl chloroformate was negative in the Ames assay. No developmental toxicity, reproductive toxicity, or carcinogenicity study of isopropyl chloroformate were available. Animal inhalation data on isopropyl chloroformate are summarized in Table 2-30.

TABLE 2-30 Summary of Inhalation Toxicity Studies of Isopropyl Chloroformate

^aThe calculated equilibrium vapor concentration of isopropyl chloroformate is 45,800 ppm; this concentration is well above the highest reported nominal concentration (15,600 ppm) tested.

4.5. Data Analysis for AEGL-1

4.5.1. Human Data Relevant to AEGL-1

No human data on isopropyl chloroformate consistent with the definition of AEGL-1 were available.

4.5.2. Animal Data Relevant to AEGL-1

No animal data on isopropyl chloroformate consistent with the definition of AEGL-1 were available.

4.5.3. Derivation of AEGL-1 Values

AEGL-1 values for isopropyl chloroformate are not recommended because of insufficient data.

4.6. Data Analysis of AEGL-2

4.6.1. Human Data Relevant to AEGL-2

No human data on isopropyl chloroformate consistent with the definition of AEGL-2 were available.

4.6.2. Animal Data Relevant to AEGL-2

No acute animal data on isopropyl chloroformate consistent with the definition of AEGL-2 were available.

4.6.3. Derivation of AEGL-2 Values

No appropriate acute inhalation data on isopropyl chloroformate consistent with the definition of AEGL-2 were available. Thus, the AEGL-2 values were calculated by taking one-third of the AEGL-3 values. That approached is used to estimate a threshold for irreversible effects if a chemical has a steep concentration-response curve (NRC 2001). The AEGL-2 values for isopropyl chloroformate are presented in Table 2-31. 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.

TABLE 2-31 AEGL-2 Values for Isopropyl Chloroformate

4.7. Data Analysis for AEGL-3

4.7.1. Human Data Relevant to AEGL-3

No human data on isopropyl chloroformate consistent with the definition of AEGL-3 were available.

4.7.2. Animal Data Relevant to AEGL-3

A 1-h LC₅₀ value of 300 ppm was calculated from a study in rats by Industrial Bio-Test Laboratories, Inc. (IBT 1970b). A 15-min mouse LC₅₀ of 283-345 ppm was estimated (Anderson 1984).

4.7.3. Derivation of AEGL-3 Values

The only study that provided enough information to obtain a concentration-response relationship for lethality associated with isopropyl chloroformate was one conducted by Industrial Bio-Test Laboratories, Inc. (IBT 1970b). However, as noted in Section 1.8, some studies performed by this laboratory have been discredited because of deficiencies in study conduct and discrepancies between raw data and study reports (OECD 2007). Therefore, this study was not used as a primary study for derivation of AEGL values. In the absence of suitable acute exposure studies, the point-of-departure was based on the 5-day repeated exposure study by Collins and Proctor (1984). In that study, there were no deaths from exposure to isopropyl chloroformate at 50 ppm for 6 h/day for 5 days, whereas exposure at 100 ppm resulted in deaths of 3/4 males (after 2, 4, and 5 days of treatment) and 3/4 females (after 3, 3, and 5 days of treatment). A 6-h concentration of 50 ppm was selected as the point-of-departure, which also is supported by the BASF (1968a) study that reported no deaths among 12 rats exposed to isopropyl chloroformate at approximately 200 ppm for 1 h. The effects of the chloroformates result from the direct-acting corrosive effects on the airways, in the absence of other systemic effects. Supporting information for this mode of action comes from observations in rats of nasal irritation and respiratory effects (e.g., pulmonary inflammation, pulmonary edema, and emphysema) in short-term repeated-exposure studies of 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). Thus, interspecies and intraspecies uncertainty factors of 3 would represent the potential for any toxicodynamic variability, resulting in a total uncertainty factor of 10 applied to the estimated threshold for lethality (50 ppm). Time scaling was performed using the equation Cⁿ × t = k (ten Berge et al. 1986). Data on isopropyl chloroformate were insufficient for calculating an empirical value for the exponent n, so default values of n = 3 when extrapolating from longer to shorter durations (10 and 30 min) and n = 1 when extrapolating from shorter to longer durations (4 and 8 h) were used. 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 exposure value. The AEGL-3 values for isopropyl chloroformate are presented in Table 2-32; the calculations are presented in Appendix B. The 10- and 30-min AEGL-3 of 11 ppm extrapolated from the 6-h point of departure of 50 ppm in rats are consistent with values that can potentially be derived from the estimated 15-min LC₅₀ of 283-345 ppm based on the results in mice by Anderson (1984) (see Table 2-30).

4.8. Summary of AEGLs

4.8.1. AEGL Values and Toxicity End Points

The AEGL values for isopropyl chloroformate are presented in Table 2-33. AEGL-1 values are not recommended because of insufficient data. AEGL-2 values were estimated by dividing the AEGL-3 values by 3, and AEGL-3 values were based a nonlethal concentration identified in a repeated-exposure study. A derivation summary and category plot of the AEGL values and toxicity data are presented in Appendixes C and D, respectively.

4.8.2. Other Standards and Guidelines

The following standards are available for isopropyl chloroformate and are presented in Table 2-34. The American Industrial Hygiene Association (AIHA 2004, 2013) derived emergency response planning guidelines (ERPG-2 and ERPG-3) for isopropyl chloroformate that are slightly higher than the 1-h AEGL-2 and AEGL-3 values. The ERPG-2 of 5 ppm is based in part on the RD₅₀ of 104 ppm in mice (Carpenter 1982c) and in part on the repeated exposure study in rats in which 20 ppm resulted in nasal irritation and 5 ppm was a no-observed-effect level (Gage 1970). The ERPG-3 of 20 ppm is based on the following lethality data: 5-h LC₅₀ of 200 ppm in rats and 1-h LC₅₀ of 299 ppm, both values attributed to personal communication; and deaths in 6/8 rats exposed to isopropyl chloroformate at 100 ppm for 6 h/day in a repeated-exposure study, cited as Bio-Research Laboratories Ltd. (1984). These data correspond to studies cited herein as Gage (1970) and Collins and Proctor (1984). AIHA (2004) indi-

cated that the ERPG-3 would protect against the effects of the hydrogen chloride decomposition product. No further information on the derivation of the ERPGs was provided.

TABLE 2-32 AEGL-3 Values for Isopropyl Chloroformate

TABLE 2-33 AEGL Values for Isopropyl Chloroformate^a

^aTreatment of people exposed to chloroformates should consider that pulmonary edema frequently occurs, but its symptoms may not manifest for several hours after exposure and may be aggravated by physical exertion.

^bNR, not recommended. Absence of an AEGL-1 value does not imply that exposure below the AEGL-2 value is without adverse effects.

TABLE 2-34 Standards and Guidelines for Isopropyl Chloroformate

^aNR, not recommended. Absence of an AEGL-1 value does not imply that exposure below the AEGL-2 value is without adverse effects.

^bERPG-1 (emergency response planning guidelines, American Industrial Hygiene Association) (AIHA 2004, 2013) is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing other than mild transient adverse health effects or perceiving a clearly defined objectionable odor.

^cAIHA did not derive an EPRG-1 value for isopropyl chloroformate because of insufficient data (lack of data on odor threshold and minor irritation).

EPRG-2 (emergency response planning guidelines, American Industrial Hygiene Association) (AIHA 2004, 2013) is the maximum airborne concentration below which it is believed nearly all individuals could be exposed for up to 1 h without experiencing or developing irreversible or other serious health effects or symptoms that could impair an individual’s ability to take protective action.

EPRG-3 (emergency response planning guidelines, American Industrial Hygiene Association) (AIHA 2004, 2013) is the maximum airborne concentration below which nearly all individuals could be exposed for up to 1 hour without experiencing or developing life-threatening health effects.

^cAIHA did not derive an EPRG-1 value for isopropyl chloroformate because of insufficient data (lack of data on odor threshold and minor irritation).

4.8.3. Data Adequacy and Research Needs

The database on isopropyl chloroformate is sparse. The most reliable data for estimating AEGL-3 values are from a repeated-exposure study in rats. The results of that study are supported by acute inhalation studies in rats and mice, although, as noted above, limitations precluded use of any of these as a primary study for derivation of AEGLs.

Acute inhalation lethality studies of isopropyl chloroformate conducted in accordance with current testing standards would help provide confirmation of the available animal toxicity data and provide chemical-specific acute 1-hour inhalation toxicity data to support the AEGL values.

5. n-PROPYL CHLOROFORMATE

5.1. Summary

Data on n-propyl chloroformate were insufficient to derive AEGL-1 values, so no values are recommended.

No appropriate acute inhalation data consistent with the definition of AEGL-2 or AEGL-3 were available on n-propyl chloroformate. However, this chemical is a structural analog of isopropyl chloroformate and has similar physical/chemical parameters. The two compounds produce similar adverse effects and appear to be of similar toxicity as demonstrated by Industrial Bio-Test Laboratories, Inc. (IBT 1970a) studies. Studies by IBT, while of uncertain quality, suggested 1-h LC₅₀ values of 410 ppm for n-propyl chloroformate and 300 ppm for isopropyl chloroformate. As noted in Section 1.8, no IBT studies were used as the principal or key study in deriving AEGLs for any of the chloroformates. In cases where IBT study reports were available, they were reviewed (but not formally audited), and if the findings were consistent with other studies of reputable validity, the results of the IBT studies are included and referred to as providing supporting evidence. The IBT LC₅₀ studies support the use of isopropyl chloroformate AEGL values for n-propyl chloroformate.

The database for isopropyl chloroformate is more robust, including studies conducted by other laboratories as well as repeated exposure studies. Because of the sparseness of the database on n-propyl chloroformate and the uncertainties associated with the quality of the available data, the AEGL-2 values for isopropyl chloroformate were adopted as surrogates for n-propyl chloroformate.

For AEGL-3 values, the only data on n-propyl chloroformate that provided an indication of a dose-response relationship for lethality was from a study conducted by Industrial Bio-Test Laboratories, Inc. (IBT 1970a). As noted in Section 1.8, the validity of the studies conducted by that laboratory is of questionable validity. The study of n-propyl chloroformate has not been externally audited, and the raw data from the study are not available. Because of this, the study was considered inadequate for use in deriving AEGL-3 values. A study by BASF (1970a) did not have sufficient details about its design or the findings, so the study also was considered inadequate to serve as the basis for AEGL-3 values. Because of the sparseness of the database and uncertainties in the quality of the available data for n-propyl chloroformate, AEGL-3 values for the isopropyl chloroformate were adopted as surrogates for n-propyl chloroformate (see Section 5 for details on how the values for isopropyl chloroformate were determined). The AEGL values for n-propyl chloroformate are presented in Table 2-35.

5.2. Chemical and Physical Properties

Propyl chloroformate hydrolyzes in water to form n-propanol, carbon dioxide, and hydrogen chloride. Selected chemical and physical properties of n-propyl chloroformate presented in Table 2-36.

TABLE 2-35 AEGL Values for n-Propyl Chloroformate^a

^aTreatment of people exposed to chloroformates should consider that pulmonary edema frequently occurs, but its symptoms may not manifest for several hours after exposure and may be aggravated by physical exertion.

^bNR, not recommended. Absence of an AEGL-1 value does not imply that exposure below the AEGL-2 value is without adverse effects.

TABLE 2-36 Chemical and Physical Properties of Propyl Chloroformate

5.3. Human Toxicity Data

5.3.1. Acute Lethality

No information on human lethality from exposure to n-propyl chloroformate was found.

5.3.2. Nonlethal Toxicity

No information about the nonlethal human toxicity from exposure to n-propyl chloroformate was found.

5.3.3. Developmental and Reproductive Toxicity

Developmental and reproductive studies on acute human exposure to n-propyl chloroformate were not available.

5.3.4. Genotoxicity

Genotoxicity studies on acute human exposure to n-propyl chloroformate were not available.

5.3.5. Carcinogenicity

Carcinogenicity studies on human exposure to n-propyl chloroformate were not available.

5.3.6. Summary

Data concerning human exposure to n-propyl chloroformate are not available.

5.4. Animal Toxicity Data

5.4.1. Acute Lethality

5.4.1.1. Rats

Groups of five male and five female young adult Charles River albino rats (320 g, average weight) were exposed to nominal concentrations of n-propyl chloroformate vapor at 249, 333, 1,000, 3,077, or 21,538 ppm for 1 h (IBT 1970a). Vapor was generated by bubbling clean, dry air through undiluted n-propyl chloroformate. The resulting vapor was mixed with additional dry air to obtain the desired vapor concentration. The test atmosphere was then introduced into the top of a 70-L Plexiglass inhalation chamber, dispersed by a baffle plate, and removed at the bottom of the chamber. Average nominal concentrations were calculated by dividing the total weight of the n-propyl chloroformate vaporized by the total volume of air used during each inhalation exposure. No adverse effects were observed in the 249-ppm group during exposure. Bloody nasal discharge and dyspnea were observed in the 333-ppm group near the end of the exposure period, while hyperactivity, clear nasal discharge, dyspnea, and salivation were observed in the 1,000-, 3,077-, and 21,538-ppm groups. No adverse effects on body weight were observed in any animals that survived the 14-day observation period; however, necropsy revealed slight to moderate hyperemia in these animals. Necropsy of animals that died during the study revealed moderate to severe pulmonary hyperemia. A 1-h LC₅₀ of 410 ppm, BMCL₀₅ of 216 ppm, and BMC₀₁ of 229 ppm were calculated. Results from this study are summarized in Table 2-37.

As noted in Section 1.8, the validity of the studies conducted by Industrial Bio-Test Laboratories is of questionable validity. The study of n-propyl chloroformate has not been externally audited, and the raw data from the study are not available.

In a limited study, death occurred in 3/10 rats exposed to n-propyl chloroformate at 200 ppm for 1 h (BASF 1970d). Clinical signs included restlessness, mucous membrane irritation, and dyspnea. Acute pulmonary emphysema was observed at necropsy. However, the report did not have sufficient details about its study design or the findings, so the study was considered inadequate to serve as the basis for AEGL-3 values. In another report, Death occurred in 12/12 rats exposed to an “atmosphere enriched or saturated” with n-propyl chloroformate vapor (20°C) for 3 min (BASF 1970e). Clinical signs included vigorous escape behavior, severe mucous membrane irritation, and gasping. Pulmonary congestion and edema were found at necropsy.

An oral LD₅₀ value for n-propyl chloroformate of 650 mg/kg was reported for Charles River albino rats (IBT 1970a). Oral LD₅₀ values of 1,212 mg/kg (BASF 1980b) and 872 mg/kg (BASF 1970f) were reported for Sprague-Dawley rats.

TABLE 2-37 Effect in Rats Exposed to n-Propyl Chloroformate for 1 Hour

Source: Data from IBT 1970a.

5.4.1.2. Mice

Following a 10-min fresh air control period, groups of four male Swiss-Webster mice were exposed head only to n-propyl chloroformate aerosol at concentrations of 0, 25, 50, 75, or 100 ppm for 30 min (Carpenter 1982b). The mice were then removed to fresh air for a 10-min recovery period, and respiratory rates were monitored continuously. Undiluted n-propyl chloro-formate was delivered to a Pitt No. 1 aerosol generator via a 2-cc syringe, driven by a pump at a known rate. Aerosol was directed into a 6-L stainless steel chamber which was continuously evacuated at a rate of 18.3 L/min. An RD₅₀ of 83.5 ± 2.17 ppm was calculated. Although RD₅₀ values are not used in the development of AEGL values, an RD₅₀ was reported, the data was reported and no dose response relationship was observed, limiting its usefulness in development of an AEGL3. Results of the study are summarized in Table 2-38.

5.4.2. Nonlethal Toxicity

5.4.2.1. Rabbits

Corneal opacity and iridal and conjunctival irritation were observed within 1 min after the eyes of albino rabbits were instilled with 0.1 mL of undiluted n-propyl chloroformate (IBT 1970a). The irritation became progressively worse, and maximum damage was present in all ocular tissues within 3-7 days. No improvement was observed after 14 days, so the chemical is considered extremely irritating to the eyes of albino rabbits.

Propyl chloroformate is also considered extremely irritating to the skin of albino rabbits (IBT 1970a). Severe erythema, edema, and burns were observed after dermal exposure of rabbits to 0.5 mL of undiluted n-propyl chloroformate for 24 h. Effects persisted through the 72-h observation period.

5.4.3. Developmental and Reproductive Toxicity

No information concerning the developmental or reproductive toxicity of n-propyl chloroformate was found.

TABLE 2-38 Effects in Male Swiss-Webster Mice Exposed to Propyl Chloroformate for 30 Minutes

Source: Carpenter 1982b.

5.4.4. Genotoxicity

Propyl chloroformate was negative in a preincubation test both with and without metabolic activation in S. typhimurium strains TA98, TA100, TA1535, and TA1537 (BASF 1988c).

5.4.5. Carcinogenicity

No information on the carcinogenicity of n-propyl chloroformate was found.

5.4.6. Summary

Animal toxicity data on n-propyl chloroformate is sparse. A 1-h LC₅₀ of 410 ppm, BMCL₀₅ of 216 ppm, and BMC₀₁ of 229 ppm were calculated for Charles River albino rats (IBT 1970a). n-Propyl chloroformate is severely irritating to the skin and eyes of albino rabbits (IBT 1970a).

5.5. Data Analysis for AEGL-1

5.5.1. Human Data Relevant to AEGL-1

No human data on n-propyl chloroformate consistent with the definition of AEGL-1 were available.

5.5.2. Animal Data Relevant to AEGL-1

No animal data on n-propyl chloroformate consistent with the definition of AEGL-1 were available.

5.5.3. Derivation of AEGL-1 Values

AEGL-1 values for n-propyl chloroformate are not recommended because of insufficient data.

5.6. Data Analysis for AEGL-2

5.6.1. Human Data Relevant to AEGL-2

No human data on n-propyl chloroformate consistent with the definition of AEGL-2 were available.

5.6.2. Animal Data Relevant to AEGL-2

No animal data on n-propyl chloroformate consistent with the definition of AEGL-2 were available.

5.6.3. Derivation of AEGL-2 Values

Chemical-specific data were insufficient to derive AEGL-2 values for n-propyl chloroformate. However, n-propyl chloroformate is a structural analog of isopropyl chloroformate, and the two compounds appear to be of similar toxicity (see Section 5.7.3). The database for isopropyl chloroformate is more robust, and includes studies conducted by laboratories other than IBT, as well as repeated exposure studies. Given the sparseness of the database and the uncertainties in the quality of the available data for n-propyl chloroformate, AEGL-2 values for isopropyl chloroformate were adopted as surrogates for n-propyl chloroformate (see Section 4 for how the isopropyl chloroformate values were determined). The AEGL-2 values for n-propyl chloroformate are presented in Table 2-39.

5.7. Data Analysis for AEGL-3

5.7.1. Human Data Relevant to AEGL-3

No human data on n-propyl chloroformate consistent with the definition of AEGL-3 were available.

5.7.2. Animal Data Relevant to AEGL-3

A 1-h rat LC₅₀ of 410 ppm and BMCL₀₅ of 216 ppm were calculated; no deaths were noted at 249 ppm (IBT 1970a). The limited BASF (1970d) reported mortalities in 3/10 rats exposed to n-propyl chloroformate at 200 ppm for 1 h. This study was inadequate to serve as the basis for AEGL-3 values because it did not provide sufficient details about its study design or the findings, and other concentrations were not tested.

TABLE 2-39 AEGL-2 Values for n-Propyl Chloroformate

5.7.3. Derivation of AEGL-3 Values

Propyl chloroformate is a structural analog of isopropyl chloroformate, and the two compounds appear to be of similar toxicity. Given the sparseness of the database and uncertainties in the quality of the available data for n-propyl chloroformate, AEGL-3 values for isopropyl chloroformate were adopted as surrogates for n-propyl chloroformate (see Section 5 for how the isopropyl chloroformate values were determined). The AEGL-3 values for n-propyl chloroformate are presented in Table 2-40.

5.8. Summary of AEGLs

5.8.1. AEGL Values and Toxicity End Points

The AEGL values for n-propyl chloroformate are presented in Table 2-41. AEGL-1 values are not recommended because of insufficient data. Data were also insufficient for deriving AEGL-2 and AEGL-3 values, so the AEGL values for isopropyl chloroformate were adopted for n-propyl chloroformate, as available data indicate that the two chemicals have similar toxicity.

5.8.2. Other Standards and Guidelines

No other exposure standards or guidelines for n-propyl chloroformate were found.

TABLE 2-40 AEGL-3 Values for n-Propyl Chloroformate

TABLE 2-41 AEGL Values for n-Propyl Chloroformate^a

^aTreatment of people exposed to chloroformates should consider that pulmonary edema frequently occurs, but its symptoms may not manifest for several hours after exposure and may be aggravated by physical exertion.

^bNR, not recommended. Absence of an AEGL-1 value does not imply that exposure below the AEGL-2 value is without adverse effects.

5.8.3. Data Adequacy and Research Needs

Data on n-propyl chloroformate are sparse. Human data are not available. Animal data include two rat acute inhalation lethality studies (one of uncertain quality [IBT 1970a] and one with inadequate reporting [BASF 1970d]) and one mouse RD50 study. AEGLs for n-propyl chloroformate were therefore based on analogy to its structural analog, isopropyl chloroformate, which has a more robust database. Although, as noted in Section 1.8 and above, the IBT 1970a study was of limited usefulness and could not be relied upon as a primary study for derivation of AEGLs, the toxic effects and the LC₅₀ value reported in this 1-hour acute inhalation study provide supporting evidence for the n-propyl chloroformate AEGL values.

Acute inhalation lethality studies of n-propyl chloroformate conducted in accordance with current testing standards would help provide confirmation of the available animal toxicity lethality data and provide chemical-specific data to support the AEGL values.

6. ALLYL CHLOROFORMATE

6.1. Summary

Data on allyl chloroformate were insufficient to derive AEGL-1 values, so no values are recommended.

No appropriate acute inhalation data consistent with the definition of AEGL-2 were available. Thus, the AEGL-2 values were calculated by taking one-third of the AEGL-3 values. That approached 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 allyl 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).

Lethality data from a study by Stillmeadow Inc. (1987) was used to calculate a 1-h rat BMCL₀₅ of 21 ppm to be used as the lethality threshold point-of-departure for calculating AEGL-3 values. The effects of the chloroformates result from the direct-acting corrosive effects 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). Thus, interspecies and intraspecies uncertainty factors of 3 would represent the potential for any toxicodynamic variability, resulting in a total uncertainty factor of 10 applied to the estimated threshold for lethality (21 ppm). Use of these factors is consistent with the ones applied in calculating AEGL-3 values for the structural analogs, methyl chloroformate, isopropyl chloroformate, and n-butyl chloroformate. The AEGL values for those analogs were considered protective when compared with chemical-specific, repeated-exposure data. Time scaling was performed using the equation Cⁿ × t = k (ten Berge et al. 1986). Data on allyl chloroformate were insufficient for calculating an empirical value for the exponent n, so default values of n = 3 when extrapolating from longer to shorter durations (10 and 30 min) and n = 1 when extrapolating from shorter to longer durations (4 and 8 h) were used. The AEGL values for allyl chloroformate are presented in Table 2-41.

6.2. Chemical and Physical Properties

Allyl chloroformate hydrolyzes in water to form allyl alcohol, carbon dioxide, and hydrogen chloride. Selected chemical and physical properties of this chemical are presented in Table 2-42.

6.3. Human Toxicity Data

6.3.1. Acute Lethality

Information on human deaths after exposure to allyl chloroformate was not available.

TABLE 2-41 AEGL Values for Allyl Chloroformate^a

^aTreatment of people exposed to chloroformates should consider that pulmonary edema frequently occurs, but its symptoms may not manifest for several hours after exposure and may be aggravated by physical exertion.

^bNR, not recommended. Absence of a derived AEGL-1 value does not imply that exposure below the AEGL-2 value is without adverse effects.

TABLE 2-42 Chemical and Physical Properties of Allyl Chloroformate

Source: HSDB 2013.

6.3.2. Nonlethal Toxicity

Information concerning nonlethal toxicity in humans after exposure to allyl chloroformate was not available.

6.3.3. Developmental and Reproductive Toxicity

No human data on the developmental or reproductive toxicity of allyl chloroformate were available.

6.3.4. Genotoxicity

Genotoxicity studies on acute human exposure to allyl chloroformate were not available.

6.3.5. Carcinogenicity

Carcinogenicity studies on human exposure to allyl chloroformate were not available.

6.3.6. Summary

No human studies of the lethal toxicity, nonlethal toxicity, developmental toxicity, reproductive toxicity, genotoxicity, or carcinogenicity of allyl chloroformate were available.

6.4. Animal Toxicity Data

6.4.1. Acute Lethality

6.4.1.1. Rats

Groups of five male and five female Sprague Dawley rats were exposed to allyl chloroformate at 33.7, 65.0, 77.7, 134.5, 175.7, or 233.3 ppm for 1 h, followed by a 14-day observation period (Stillmeadow Inc. 1987). Animals were exposed in a 200-L stainless steel dynamic flow inhalation chamber. Aerosol was generated by aspirating the allyl chloroformate through a pressure operated spray nozzle. The concentrated aerosol was then diluted with dried, filtered air and drawn into the exposure chamber. Air flow was maintained through the use of a calibrated critical orifice, and air flow was recorded at 30-min intervals during the exposure period. The concentration of allyl chloroformate in the exposure atmosphere was determined analytically at 30 and 60 min via gas chromatography. Clinical signs were observed in all exposure groups and included decreased activity, body tremors, constricted pupils, diarrhea, emaciation, epistaxis, gasping, lacrimation, nasal discharge, piloerection, polyuria, ptosis, respiratory gurgle, and salivation. Nine of the 10 rats exposed at 33.7 ppm gained weight over the 14-day observation period, and the tenth animal retained a constant weight. All eight of the rats exposed at higher concentrations and survived the 14-day observation period lost weight. Gross necropsy findings included discoloration of the lungs, pulmonary edema, clear fluid in the thoracic cavity, gastrointestinal tract distended with gas, and discoloration of gastrointestinal tract contents. An LC₅₀ of 65.1 ppm, a BMCL₀₅ of 21 ppm, and a BMC₀₁ of 25.7 ppm were calculated. Data from this study are summarized in Table 2-43.

6.4.2. Developmental and Reproductive Toxicity

No information on the developmental or reproductive toxicity of allyl chloroformate was available.

6.4.3. Genotoxicity

No information on the genotoxicity of allyl chloroformate was available.

TABLE 2-43 Mortality in Sprague-Dawley Rats Exposed to Allyl Chloroformate for 1 Hour

Abbreviations: BMC₀₁, benchmark concentration with 1% response; BMCL₀₅, benchmark concentration, 95% lower confidence limit with 5% response; LC₅₀, lethal concentration, 50% lethality.

Source: Adapted from Stillmeadow Inc. 1987.

6.4.4. Carcinogenicity

No information on the carcinogenicity of allyl chloroformate was available.

6.4.5. Summary

Animal toxicity data on allyl chloroformate include one well-conducted rat lethality study, which described clinical signs consistent with severe irritation. Data from the study were used to estimate an LC₅₀ of 65.1 ppm, a BMCL₀₅ of 21 ppm, and a BMC₀₁ of 25.7 ppm. No studies of the reproductive toxicity, developmental toxicity, genotoxicity data, or carcinogenicity of allyl chloroformate were available.

6.5. Data Analysis for AEGL-1

6.5.1. Human Data Relevant to AEGL-1

No human data on allyl chloroformate consistent with the definition of AEGL-1 were available.

6.5.2. Animal Data Relevant to AEGL-1

No animal data on allyl chloroformate consistent with the definition of AEGL-1 were available.

6.5.3. Derivation of AEGL-1 Values

Data are insufficient to derive AEGL-1 values for allyl chloroformate, so no values are recommended.

6.6. Data Analysis for AEGL-2

6.6.1. Human Data Relevant to AEGL-2

No human data on allyl chloroformate consistent with the definition of AEGL-2 were available.

6.6.2. Animal Data Relevant to AEGL-2

No animal data on allyl chloroformate consistent with the definition of AEGL-2 were available.

6.6.3. Derivation of AEGL-2 Values

No appropriate acute inhalation data on allyl chloroformate consistent with the definition of AEGL-2 were available. Thus, the AEGL-2 values were calculated by taking one-third of the AEGL-3 values. That approached 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). The AEGL-2 values for allyl chloroformate are presented in Table 2-44.

6.7. Data Analysis for AEGL-3

6.7.1. Human Data Relevant to AEGL-3

No human data on allyl chloroformate consistent with the definition of AEGL-3 were available.

6.7.2. Animal Data Relevant to AEGL-3

A 1-h rat LC₅₀ of 65.1 ppm and a BMCL₀₅ of 21 ppm were calculated for allyl chloroformate (Stillmeadow Inc. 1987).

6.7.3. Derivation of AEGL-3 Values

The calculated 1-h rat BMCL₀₅ of 21 ppm (Stillmeadow Inc. 1987) was the point-of-departure for deriving AEGL-3 values for allyl chloroformate. The effects of the chloroformates result from the direct-acting corrosive effects 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). Thus, interspecies and intraspecies uncertainty factors of 3 would represent the potential for any toxicodynamic variability, resulting in a total uncertainty factor of 10 applied to the estimated threshold for lethality (21 ppm). Use of these factors is consistent with the ones applied in calculating AEGL-3 values for the structural analogs, methyl chloroformate (see Section 2.7.3), isopropyl chloroformate (see Section 5.7.3), and n-butyl chloroformate (see Section 6.7.3). The AEGL values for those analogs were considered protective when compared with chemical-specific, repeated-exposure data. Time scaling was performed using the equation Cⁿ × t = k (ten Berge et al. 1986). Data on allyl chloroformate were insufficient for calculating an empirical value for the exponent n, so default values of n = 3 when extrapolating from longer to shorter durations (10 and 30 min) and n = 1 when extrapolating from shorter to longer durations (4 and 8 h) were used. The AEGL-3 values for allyl chloroformate are presented in Table 2-45; the calculations are presented in Appendix B.

TABLE 2-44 AEGL-2 Values for Allyl Chloroformate

TABLE 2-45 AEGL-3 Values for Allyl Chloroformate

6.8. Summary of AEGLs

6.8.1. AEGL Values and Toxicity End Points

The AEGL values for allyl chloroformate are presented in Table 2-46. Data were insufficient for deriving AEGL-1 values. AEGL-2 values were derived by dividing AEGL-3 values by 3, and AEGL-3 values were based on a 1-h BMCL₀₅ for lethality in rats. A derivation summary and category plot of the AEGL values are presented in Appendixes C and D, respectively.

6.8.2. Other Standards and Guidelines

No other standards or guidelines for allyl chloroformate were found.

6.8.3. Data Adequacy and Research Needs

Only one study of allyl chloroformate was available.

7. n-BUTYL CHLOROFORMATE, ISOBUTYL CHLOROFORMATE, AND sec-BUTYL CHLOROFLORMATE

7.1. Summary

Data on n-butyl, isobutyl, or sec-butyl chloroformate were insufficient to derive AEGL-1 values, so no values were recommended.

The AEGL-2 and AEGL-3 values for n-butyl, isobutyl, and sec-butyl chloroformate are the same. Only n-butyl chloroformate had sufficient data from which to derive values. Because isobutyl chloroformate and sec-butyl are structural analogs of n-butyl chloroformate and appear to have similar toxicity (Carpenter 1982b), the values derived for n-butyl chloroformate were applied to these two chemicals.

TABLE 2-46 AEGL Values for Allyl Chloroformate^a

^aTreatment of people exposed to chloroformates should consider that pulmonary edema frequently occurs, but its symptoms may not manifest for several hours after exposure and may be aggravated by physical exertion.

^bNR, not recommended. Absence of an AEGL-1 value does not imply that exposure below the AEGL-2 value is without adverse effects.