2

Ethyl Phosphorodichloridate1

Acute Exposure Guideline Levels

PREFACE

Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guideline Levels for Hazardous Substances (NAC/AEGL Committee) has been established to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals.

AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distinguished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows:

AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory

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1This document was prepared by the AEGL Development Team composed of Cheryl Bast (Oak Ridge National Laboratory), Lisa Ingerman (SRC, Inc.), Chemical Manager Dieter Heinz (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agency). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclusions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001).



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2 Ethyl Phosphorodichloridate1 Acute Exposure Guideline Levels PREFACE Under the authority of the Federal Advisory Committee Act (FACA) P.L. 92-463 of 1972, the National Advisory Committee for Acute Exposure Guide- line Levels for Hazardous Substances (NAC/AEGL Committee) has been estab- lished to identify, review, and interpret relevant toxicologic and other scientific data and develop AEGLs for high-priority, acutely toxic chemicals. AEGLs represent threshold exposure limits for the general public and are applicable to emergency exposure periods ranging from 10 minutes (min) to 8 hours (h). Three levels—AEGL-1, AEGL-2, and AEGL-3—are developed for each of five exposure periods (10 and 30 min and 1, 4, and 8 h) and are distin- guished by varying degrees of severity of toxic effects. The three AEGLs are defined as follows: AEGL-1 is the airborne concentration (expressed as parts per million or milligrams per cubic meter [ppm or mg/m3]) of a substance above which it is predicted that the general population, including susceptible individuals, could experience notable discomfort, irritation, or certain asymptomatic, nonsensory 1 This document was prepared by the AEGL Development Team composed of Cheryl Bast (Oak Ridge National Laboratory), Lisa Ingerman (SRC, Inc.), Chemical Manager Dieter Heinz (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances), and Ernest V. Falke (U.S. Environmental Protection Agen- cy). The NAC reviewed and revised the document and AEGLs as deemed necessary. Both the document and the AEGL values were then reviewed by the National Research Council (NRC) Committee on Acute Exposure Guideline Levels. The NRC committee has concluded that the AEGLs developed in this document are scientifically valid conclu- sions based on the data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC 1993, 2001). 42

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Ethyl Phosphorodichloridate 43 effects. However, the effects are not disabling and are transient and reversible upon cessation of exposure. AEGL-2 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience irreversible or other serious, long-lasting adverse health effects or an impaired ability to escape. AEGL-3 is the airborne concentration (expressed as ppm or mg/m3) of a substance above which it is predicted that the general population, including sus- ceptible individuals, could experience life-threatening health effects or death. Airborne concentrations below the AEGL-1 represent exposure concentra- tions that could produce mild and progressively increasing but transient and nondisabling odor, taste, and sensory irritation or certain asymptomatic, nonsen- sory effects. With increasing airborne concentrations above each AEGL, there is a progressive increase in the likelihood of occurrence and the severity of effects described for each corresponding AEGL. Although the AEGL values represent threshold concentrations for the general public, including susceptible subpopula- tions, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic respons- es, could experience the effects described at concentrations below the corre- sponding AEGL. SUMMARY Ethyl phosphorodichloridate is a colorless liquid used as an intermediate in the preparation of the pesticide ethoprop. The vapor irritates the eyes, nose, and throat; the liquid burns skin and eyes and causes severe burns of the mouth and stomach if ingested. Ethyl phosphorodichloridate reacts with water to produce hydrogen chloride fumes. Data were insufficient for derivation of AEGL-1 values. Therefore, AEGL-1 values are not recommended for ethyl phosphorodichloridate. In the absence of appropriate chemical-specific data, a fractional reduction of the AEGL-3 values was used to derive AEGL-2 values. For chemicals with a steep concentration-response curve, AEGL-3 values may be divided by 3 to estimate AEGL-2 values (NRC 2001). Therefore, the AEGL-2 values for ethyl phosphorodichloridate were obtained by dividing the AEGL-3 values for ethyl phosphorodichloridate by 3. A 4-h BMCL05 (benchmark concentration, 95% lower confidence limit with 5% response) of 38.0 ppm (Bayer 1983) for male and female rats exposed to ethyl phosphorodichloridate was used as the point of departure for calculating AEGL-3 values. The BMCL05 is considered a threshold for lethality, and is supported by the fact that no mortality was observed in rats exposed to ethyl phosphorodichloridate at 37 ppm for 4 h. Values were scaled across time using the equation Cn × t = k, where n = 3 when extrapolating to shorter durations and

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44 Acute Exposure Guideline Levels n = 1 when extrapolating to longer durations in order to derive values protective of human health (NRC 2001). Extrapolating a 4-h value to a 10-min AEGL-3 value is justified because no deaths were noted in male rats exposed to ethyl phosphorodichloridate at 20,900 ppm or in female rats exposed at 16,700 ppm for 10 min (Bayer 1983). Uncertainty factors of 10 were applied to account for interspecies differences and intraspecies variability, because of the lack of information available to describe species differences in toxicity and inter- individual variability. Rat studies suggest that vapors are irritating to the eyes and nose, and that pulmonary edema increases with concentration (Bayer 1983; Rhone-Poulenc, Inc. 1990). The liquid was corrosive to the skin and eyes of rabbits (Rhone- Poulenc, Inc. 1990). It also reportedly reacts with water to produce hydrogen chloride, which supports a mechanism of primary irritation. AEGL values for ethyl phosphorodichloridate are presented in Table 2-1. 1. INTRODUCTION Ethyl phosphorodichloridate is a colorless liquid used as an intermediate in the preparation of the pesticide ethoprop. The vapor irritates the eyes, nose, and throat; the liquid burns the skin and eyes and causes severe burns of the mouth and stomach if ingested. Ethyl phosphorodichloridate reacts with water to produce hydrogen chloride fumes. When heated to decomposition, toxic fumes of hydrogen chloride and phosphoric acid or phosphorus oxides may be formed (HSDB 2002). Selected physicochemical properties of ethyl phosphorodichloridate are presented in Table 2-2. TABLE 2-1 AEGL Values for Ethyl Phosphorodichloridate End Point Classification 10 min 30 min 1h 4h 8h (Reference) AEGL-1 NR NR NR NR NR Insufficient data (nondisabling)a AEGL-2 0.37 ppm 0.25 ppm 0.20 ppm 0.13 ppm 0.063 ppm One-third the (disabling) (2.4 (1.7 (1.3 (0.86 (0.40 AEGL-3 values. mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) AEGL-3 1.1 ppm 0.76 ppm 0.60 ppm 0.38 ppm 0.19 ppm 4-h threshold for (lethal) (7.3 (5.0 (4.0 (2.5 (1.3 lethality (BMCL05) mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) of 38 ppm in rats (Bayer 1983). Abbreviations: BMCL05, benchmark concentration, 95% lower confidence limit with 5% response; NR, not recommended. a Absence of an AEGL-1 value does not imply that concentrations below the AEGL-2 are without effect.

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Ethyl Phosphorodichloridate 45 TABLE 2-2 Chemical and Physical Data for Ethyl Phosphorodichloridate Parameter Value Reference Synonyms Ethyl diphosphorodichloridate; Bayer 1983; ethylesterdichloride; HSDB 2002 dichloroethoxyphosphine oxide; dichlorophosphoric acid, ethyl ester CAS registry no. 1498-51-7 HSDB 2002 Chemical formula C2H5Cl2O2P HSDB 2002 Molecular weight 162.94 HSDB 2002 Physical state Colorless liquid HSDB 2002 Boiling point 167°C HSDB 2002 Specific gravity 1.35 at 19°C HSDB 2002 Solubility in water 1.4388 g/100 mL at 20°C; Lide 1999 Surface tension 32.8 dynes/cm at 20°C HSDB 2002 Heat of combustion -2,600 cal/g HSDB 2002 3 Conversion factors in air 1 ppm = 6.6 mg/m 1 mg/m3 = 0.15 ppm 2. HUMAN TOXICITY DATA 2.1. Acute Lethality Human lethality data were not found. 2.2. Nonlethal Toxicity Human nonlethal toxicity data were not found. 2.3. Case Reports Ocular irritation was reported in a worker exposed to ethyl phosphorodi- chloridate at a plant in Mount Pleasant, Tennessee (Rhone-Poulenc, Inc. 1990). No other information was available. 2.4. Developmental and Reproductive Effects Data on the developmental and reproductive toxicity of ethyl phosphorodi- chloridate in humans were not available.

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46 Acute Exposure Guideline Levels 2.5. Genotoxicity No information regarding the genotoxicity of ethyl phosphorodichloridate in humans was available. 2.6. Carcinogenicity No information regarding the carcinogenicity of ethyl phosphorodichlori- date in humans was available. 2.7. Summary Ocular irritation was reported in a worker exposed to ethyl phosphorodi- chloridate; however, no other information regarding this case was available. No other human data were located. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Rats One-Hour Exposure In a range-finding study, groups of five male and five female Sprague- Dawley rats were exposed to ethyl phosphorodichloridate (97.5% active ingredient) at 6.16, 66, or 134 ppm (analytic concentrations) for 1 h, followed by a 14-day observation period (Rhone-Poulenc, Inc. 1990). Because the test material is sensitive to oxygen and moisture, the test atmosphere was generated using a dry nitrogen-oxygen mixture. Ethyl phosphorodichloridate was delivered to the breathing zone of the animals, and exposure concentrations were determined by gas chromatographic analysis of impinger samples. Exposures were conducted in a 100-L plexiglass chamber with a glass front. Physical observations for clinical signs were recorded at 15-min intervals during exposure, and all animals received detailed physical examinations immediately prior to exposure, hourly for 2 h post-exposure, and daily thereafter. Animals were weighed just prior to exposure on day 1, on day 8, and just prior to sacrifice on day 15. All surviving animals were killed on day 15 and complete gross necropsies were performed on all rats. During exposures, labored breathing, gasping, and decreased activity were noted in all treatment groups; the time of onset was not reported. Clinical signs observed in all treatment groups during the 2 h immediately following exposure included labored breathing, gasping, decreased activity, anogenital staining, and moist rales

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Ethyl Phosphorodichloridate 47 (anogenital staining and moist rales developed after exposure). During the 14- day observation period, surviving rats in the 66- and 134-ppm groups continued to exhibit labored breathing and rales throughout the observation period without full recovery. Rats in the 6.16-ppm group exhibited labored breathing, rales, fine tremors, and nasal discharge for a “few days” after exposure; however, the animals fully recovered during the second week post-exposure prior to sacrifice. “Significant” weight loss was noted one week following exposure in the 66- and 134-ppm groups; however, surviving rats showed some recovery prior to sacrifice. Animals in the 6.16 ppm-group gained weight during the 2 week observation period. Mortality was seen in the 66- and 134-ppm groups (see Table 2-3). All deaths occurred between days 2 and 9, with “most” being within 48-h post-exposure. There appeared to be a dose-related increase in lung weights in animals sacrificed 2-weeks post-exposure; the investigators suggest this increase may be the result of edema. No other treatment-related effects were noted at necropsy. The investigators calculated LC50 (lethal concentration, 50% lethality) values of 43.4 ppm for both sexes, 64.6 ppm for males, and 48.1 ppm for females. A group of 10 male rats was exposed to ethyl phosphorodichloridate at approximately 350 ppm (nominal concentration) for 1 h, followed by a 14-day observation period (Rhone-Poulenc, Inc. 1990). The test material was metered, using a syringe infusion pump, into a stainless steel pneumatic spraying system driven by houseline air. The resulting aerosol was passed into a 40-L exposure chamber. A nominal concentration was calculated on basis of the amount of test material used and total air volume. During exposure, mild hyperemia, decreased locomotor activity, salivation, and lacrimation were noted; severe respiratory difficulty was observed during the final 15 min of exposure. Post-exposure, weight gain was reportedly slow. Seven of 10 rats died; deaths occurred on post- exposure days 2, 5, 6, 8, 10, 12, and 14. Four-Hour Exposure Groups of 10 male and 10 female rats (strain not specified) were exposed to ethyl phosphorodichloridate (98-99% active ingredient) at 37, 61, 75, 90, 143, or 355 ppm (analytic concentrations) for 4 h, followed by a 14-day observation period (Bayer 1983). Exposures were conducted in a 10-L glass chamber, and “minimized dermal contact”. Test atmosphere concentrations were determined by absorption spectrometry. Animals were weighed before exposure and once weekly during the observation period. Gross necropsies were performed on all test animals. Clinical signs during and after exposure included disturbed behavioral patterns associated with severe respiratory problems. Ocular and nasal irritation was also noted. Clinical signs were assumed to be noted in all dose groups; however, specific signs associated with different exposure concentrations were not reported. No significant treatment-related effects on body weight were found. Necropsy findings in rats that died during the study

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48 Acute Exposure Guideline Levels included severely bloated edematous lungs, spots in the lungs, brownish colored liver, pale kidneys, red renal pelvis, stomach ulcers, red intestinal wall, and dark red gastrointestinal tract contents of slimy consistency. The investigators sug- gested that the gastrointestinal effects were the result of ingestion. Rats killed after the 14-day observation period exhibited slightly bloated lungs at the higher concentrations. Specific necropsy findings associated with the different concentrations were not reported. The investigators calculated LC50 values of 91.6 ppm for both sexes, 85 ppm for males, and 99.8 ppm for females. The time of deaths was not reported. Mortality data and BMCL05 (see Appendix B) and BMC01 (benchmark concentration with 1% response) values are presented in Table 2-4. TABLE 2-3 Mortality in Rats Exposed by Inhalation to Ethyl Phosphorodichloridate for 1 Hour Mortality Incidence Concentration (ppm) Male Female Total 6.16 0/5 0/5 0/10 66 5/5 3/5 8/10 134 3/5 4/5 7/10 Estimated LC50 (ppm) 64.6 48.1 43.4 Source: Rhone-Poulenc, Inc. 1990. TABLE 2-4 Mortality in Rats Exposed by Inhalation to Ethyl Phosphorodichloridate for 4 Hours Mortality Incidence Concentration (ppm) Male Female Total 37 0/10 0/10 0/20 61 2/10 NR 2/10 75 1/10 3/10 4/20 90 7/10 5/10 12/20 143 10/10 7/10 17/20 355 10/10 10/10 20/20 LC50 (ppm) 85 99.8 91.6 a BMCL05 (ppm) 43.7 25.8 38.0 a BMC01 (ppm) 48.1 32.1 38.2 Abbreviations: NR, not reported; no explanation provided. a Values calculated for this technical support document. Source: Bayer 1983.

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Ethyl Phosphorodichloridate 49 In another experiment, Bayer (1983) exposed groups of five male or five female rats to ‘saturated’ atmospheres of ethyl phosphorodichloridate for 10 min, 30 min, or 1 h, followed by a 14-day observation period. Exposure and analytic methods were similar to those described in the 4-h study (Bayer 1983). Clinical signs and gross necropsy results were similar to those described in the 4-h study (see Table 2-5). Oral Exposure An oral LD50 of 220 ± 41 mg/kg in rats was reported for ethyl phospho- rodichloridate (Rhone- Poulenc, Inc. 1990). 3.1.2. Rabbits A dermal LD50 of 2,350 ± 997 mg/kg in rabbits was reported for ethyl phosphorodichloridate (Rhone-Poulenc, Inc. 1990). 3.1.3. Summary of Animal Lethality Data Animal lethality data on ethyl phosphorodichloridate are limited to rats. One-hour LC50 values of 43.4 ppm for rats of both sexes, 64.6 ppm for males, and 48.1 ppm for females were calculated (Rhone-Poulenc, Inc. 1990). In another 1-h study, seven of 10 male rats died after exposure to ethyl phos- phorodichloridate at approximately 350 ppm (Rhone-Poulenc, Inc. 1990). Four- hour LC50 values of 85 ppm for male and 99.8 ppm for female rats were calculated (Bayer 1983). No lethality was reported in rats exposed to ethyl phos- phorodichloridate at 16,700-20,900 ppm for 10 min; whereas, 90% mortality was noted in rats exposed at 10,700-14,400 ppm for 30 min and 100% mortality was noted in rats exposed at 12,000-13,700 ppm for 1 h (Bayer 1983). In all studies, clinical signs were consistent with irritation, and deaths were likely due to pulmonary edema. 3.2. Nonlethal Toxicity 3.2.1. Rabbits A primary dermal irritation index for ethyl phosphorodichloridate of 7.16 was reported for rabbits. Ocular irritation scores of 92 at 1 h, and 100 at 1, 2, 3, 4, 7, 8, 9, 10, and 14 days were also reported (Rhone-Poulenc, Inc. 1990). These scores classify ethyl phosphorodichloridate as corrosive.

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50 Acute Exposure Guideline Levels TABLE 2-5 Mortality and Clinical Findings in Rats Exposed by Inhalation to Saturated Concentrations of Ethyl Phosphorodichloridate Concentration Mortality Time of (ppm) Duration Sex Incidence Death Clinical Signs, Comments 20,900 10 min Male 0/5 – No weight gain during week 1 post-exposure; significant weight 16,700 10 min Female 0/5 – gain during week 2 post-exposure. 14,400 30 min Male 5/5 Day 1 Significant weight loss throughout 14-day follow-up period in single 10,700 30 min Female 4/5 Days 3-4 surviving female. 13,700 1h Male 5/5 Day 1 During exposure: audible oral noises; cramped walking; ocular 12,000 1h Female 5/5 Days 1-3 and nasal irritation. Source: Bayer 1983. 3.2.2. Guinea Pigs Ethyl phosphorodichloridate was negative in a guinea pig sensitization (Buehler) test (Rhone- Poulenc, Inc. 1990). 3.2.3. Summary of Nonlethal Toxicity in Animals Ethyl phosphorodichloridate was corrosive to the skin and eyes of rabbits and was negative in a guinea pig sensitization test (Rhone-Poulenc, Inc. 1990). 3.3. Developmental and Reproductive Effects No developmental or reproductive data were found. 3.4. Genotoxicity No genotoxicity data were found. 3.5. Carcinogenicity No carcinogenicity data were found. 4. SPECIAL CONSIDERATIONS 4.1. Metabolism and Disposition Metabolism and disposition data for ethyl phosphorodichloridate in humans or animals were not available.

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Ethyl Phosphorodichloridate 51 4.2. Mechanism of Toxicity On the basis of clinical signs of toxicity and the physico-chemical properties of ethyl phosphorodichloridate, its mechanism of toxicity appears to be that of primary irritation. Rat lethality studies reported that vapors of ethyl phosphorodichloridate are irritating to the eyes and nose, and that the incidence of pulmonary edema increases with concentration (Bayer 1983; Rhone-Poulenc, Inc. 1990). Liquid ethyl phosphorodichloridate was corrosive to the skin and eyes of rabbits (Rhone-Poulenc, Inc. 1990). Little information on the reactivity of ethyl phosphorodichloridate was found in the literature. It reportedly reacts with water to produce hydrogen chloride fumes, and may also produce fumes of phosphoric acid when heated (HSDB 2002). Because those products are irritating and corrosive, they may contribute to or be responsible for the irritation observed after exposure to ethyl phosphorodichloridate; however, the rate of decomposition and relative contribution of these decomposition products to the toxicity of the parent compound is unknown. Under conditions that promote aerosolization of ethyl phosphorodichloridate, transport to the deeper airways may occur, leading to greater lung injury and possibly delayed clinically manifested effects. 4.3. Structure-Activity Relationships No structure-activity information on ethyl phosphorodichloridate was available. 4.4. Species Variability Data are insufficient to determine species variability for ethyl phos- phorodichloridate; however, because the clinical signs and physico-chemical properties suggest that its mechanism of toxicity may be primary irritation, little species variability is expected (NRC 2001). 4.5. Temporal Extrapolation The concentration-time relationship for many irritant and systemically acting vapors and gases may be described by the equation Cn × t = k, where the exponent ranges from 0.8 to 3.5 (ten Berge et al. 1986). In the absence of data to allow empirical derivation of the exponent n, temporal scaling was performed using n = 3 when extrapolating to shorter durations and n = 1 when extrapolating to longer durations (NRC 2001).

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52 Acute Exposure Guideline Levels 5. DATA ANALYSIS FOR AEGL-1 5.1. Human Data Relevant to AEGL-1 No human data relevant to derivation of AEGL-1 values for ethyl phos- phorodichloridate were available. 5.2. Animal Data Relevant to AEGL-1 No animal data relevant to derivation of AEGL-1 values for ethyl phos- phorodichloridate were available. 5.3. Derivation of AEGL-1 Values No human or animal data were available for derivation of AEGL-1 values for ethyl phosphorodichloridate. Therefore, AEGL-1 values are not recommended. 6. DATA ANALYSIS FOR AEGL-2 6.1. Human Data Relevant to AEGL-2 No human data relevant to derivation of AEGL-2 values for ethyl phos- phorodichloridate were available. 6.2. Animal Data Relevant to AEGL-2 No animal data relevant to derivation of AEGL-2 values for ethyl phos- phorodichloridate were available. 6.3. Derivation of AEGL-2 Values In the absence of appropriate chemical-specific data, a fractional reduction of the AEGL-3 values may be used to derive AEGL-2 values (NRC 2001). For chemicals with a steep concentration-response curve, AEGL-3 values may be divided by 3 to estimate AEGL-2 values (NRC 2001). Therefore, AEGL-2 values will be estimated by dividing AEGL-3 values by 3. AEGL-2 values are presented in Table 2-6, and calculations are presented in Appendix A. 7. DATA ANALYSIS FOR AEGL-3 7.1. Human Data Relevant to AEGL-3 No human data relevant to derivation of AEGL-3 values for ethyl phos- phorodichloridate were located.

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Ethyl Phosphorodichloridate 55 8.3. Data Adequacy and Research Needs No human or animal data on ethyl phosphorodichloridate relevant to AEGL-1 or AEGL-2 end points were available. Toxicity data on this compound were limited to unpublished studies, including 1-h and 4-h lethality studies in rats exposed by inhalation (Bayer 1983; Rhone-Poulenc, Inc. 1990), LD50 esti- mates in rats (oral) and rabbits (dermal), dermal and ocular irritation data in rab- bits, and a guinea pig sensitization study (Rhone-Poulenc, Inc. 1990). No data were available on the metabolism and disposition of ethyl phosphorodichloridate in humans or animals. Anecdotal information provided by HSDB (2002) sug- gests that hydrogen chloride and phosphoric acid may represent decomposition products of ethyl phosphorodichloridate, but the rate of decomposition and rela- tive contribution of these decomposition products to the toxicity of the parent compound is unknown. Additional research on the acute inhalation toxicity of ethyl phosphorodichloridate in other species, the metabolism and disposition of ethyl phosphorodichloridate in the respiratory tract, and identification of the ultimate chemical compound(s) responsible for toxicity of this compound would enhance confidence in the AEGL values. 9. REFERENCES Bayer AG. 1983. Ethylesterdichloride [in German]. Report No. 11439 and 11715. Bayer AG, Wuppertal-Elberfeld. Attachment in letter from Mobay Corporation, Pitts- burg, PA, to U.S. EPA Submitting Toxicology Study on Ethylesterdichloride, Dat- ed 12/31/90. EPA Document No. 86910000570, Microfiche No. OTS0530306; and EPA Document No. 86910000571, Microfiche No. OTS0530307. HSDB (Hazardous Substances Data Bank). 2002. Ethyl Phosphorodichloridate (CAS Reg. No. 1498-51-7). TOXNET Specialized Information Services, U.S. National Library of Medicine, Bethesda, MD [online]. Available: http://toxnet.nlm.nih.gov/ cgi-bin/sis/htmlgen?HSDB [accessed Jan. 10, 2013]. Lide, D.R. 1999. P. 3-262 in CRC Handbook of Chemistry and Physics, 80th Ed. Boca Raton, FL: CRC Press. NRC (National Research Council). 1993. Guidelines for Developing Community Emergen- cy Exposure Levels for Hazardous Substances. Washington, DC: National Academy Press. NRC (National Research Council). 2001. Standing Operating Procedures for Developing Acute Exposure Guideline Levels for Hazardous Chemicals. Washington, DC: Na- tional Academy Press. Rhone-Poulenc, Inc. 1990. Letter from Rhone-Poulenc, Inc. to U.S. EPA Submitting Enclosed Toxicological Test on MOCAP Chloridate and an Acute Inhalation Tox- icity Study of EDCP in Rats with Attachments. EPA Document No. 86910000587. Microfiche No. OTS0528775. ten Berge, W.F., A. Zwart, and L.M. Appelman. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Haz- ard. Mater. 13(3):301-309.

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56 Acute Exposure Guideline Levels APPENDIX A DERIVATION OF AEGL VALUES FOR ETHYL PHOSPHORODICHLORIDATE Derivation of AEGL-1 Values The available data were insufficient to derive AEGL-1 values for ethyl phosphorodichloridate. Therefore, AEGL-1 values were not recommended. Derivation of AEGL-2 Values In the absence of appropriate chemical-specific data, a fractional reduction of the AEGL-3 values may be used to derive AEGL-2 values. For chemicals with a steep concentration-response curve, AEGL-3 values may be divided by 3 to estimate AEGL-2 values (NRC 2001). 10-min AEGL-2: 1.1 ppm ÷ 3 = 0.37 ppm 30-min AEGL-2: 0.76 ppm ÷ 3 = 0.25 ppm 1-h AEGL-2: 0.60 ppm ÷ 3 = 0.20 ppm 4-h AEGL-2: 0.38 ppm ÷ 3 = 0.13 ppm 8-h AEGL-2: 0.19 ppm ÷ 3 = 0.06 ppm Derivation of AEGL-3 Values Key study: Bayer AG. 1983. Ethylesterdichloride [in German]. Report No. 11439 and 11715. Bayer AG, Wuppertal-Elberfeld. Attachment in Letter from Mobay Corporation, Pittsburg, PA, to U.S. EPA Submitting Toxicology Study on Ethylesterdichloride, Dated 12/31/90. EPA Document No. 86910000570, Microfiche No. OTS0530306; and EPA Document No. 86910000571, Microfiche No. OTS0530307. Toxicity end point: 4-h threshold for lethality in rats (BMCL05 = 38 ppm).

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Ethyl Phosphorodichloridate 57 Time scaling: Values scaled across time using the equation Cn × t = k, where n = 3 when extrapolating to shorter durations and n = 1 when extrapolating to longer durations to derive values protective of human health (NRC 2001). Extrapolating from the 4-h point of departure to the 10-min AEGL-3 value is justified because no deaths were noted in male rats exposed to ethyl phosphorodichloridate at 20,900 ppm or in female rats exposed at 16,700 ppm for 10 min (Bayer 1983). (38 ppm)3 × 4 h = 219,488 ppm-h (38 ppm)1 × 4 h = 152 ppm-h Uncertainty factors: 10 for interspecies differences 10 for intraspecies variability Modifying factor: None 10-min AEGL-3: C3 × 0.167 h = 219,488 ppm-h C3 = 1,314,299 ppm C = 109 ppm 109 ppm ÷ 100 = 1.1 ppm 30-min AEGL-3: C3 × 0.5 h = 219,488 ppm-h C3 = 438,976 ppm C = 76 ppm 76 ppm ÷ 100 = 0.76 ppm 1-h AEGL-3: C3 × 1 hr = 219,488 ppm-h C3 = 219,488 ppm C = 60 ppm 60 ppm ÷ 100 = 0.60 ppm 4-h AEGL-3: C = 38 ppm 38 ppm ÷ 100 = 0.38 ppm 8-h AEGL-3: C1 × 8 h = 152 ppm-h C = 19 ppm 19 ppm ÷ 100 = 0.19 ppm

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58 Acute Exposure Guideline Levels APPENDIX B BENCHMARK CALCULATION FOR ETHYL PHOSPHORODICHLORIDATE Probit Model $Revision: 2.1 $ $Date: 2000/02/26 03:38:53 $ Input Data File: C:\BMDS\ Mon Jan 28 09:33:17 2008 BMDS MODEL RUN The form of the probability function is: P[response] = Background + (1-Background) * CumNorm(Intercept+Slope*Log(Dose)), where CumNorm(.) is the cumulative normal distribution function Dependent variable = COLUMN3 Independent variable = COLUMN1 Slope parameter is not restricted Total number of observations = 7 Total number of records with missing values = 0 Maximum number of iterations = 250 Relative Function Convergence has been set to: 1e-008 Parameter Convergence has been set to: 1e-008 User has chosen the log transformed model Default Initial (and Specified) Parameter Values Background = 0 Intercept = -8.25812 Slope = 1.795 Asymptotic Correlation Matrix of Parameter Estimates Intercept Slope Intercept 1 -1 Slope -1 1 (***The model parameter(s) background have been estimated at a boundary point, or have been specified by the user, and do not appear in the correlation matrix.) Parameter Estimates Variable Estimate Standard error Intercept -12.0173 2.35981 Slope 2.6604 0.526262 NA: indicates that this parameter has hit a bound implied by some inequality constraint and thus has no standard error.

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Ethyl Phosphorodichloridate 59 Analysis of Deviance Table Model Log (likelihood) Deviance Test DF P-value Full model -36.9265 Fitted model -38.3731 2.89329 5 0.7164 Reduced model -88.5645 103.276 6 <0.0001 AIC: 80.7463. Goodness of Fit Scaled Estimated Dose probability Expected Observed Size Residual 0.0000 0.0000 0.000 0 20 0 37.0000 0.0080 0.159 0 20 -0.4006 61.0000 0.1399 1.399 2 10 0.5477 75.0000 0.2977 5.954 4 20 -0.9556 90.0000 0.4817 9.633 12 20 1.059 143.0000 0.8822 17.643 17 20 -0.4462 355.0000 0.9998 19.997 20 20 0.05588 Chi-square = 2.70; DF = 5; P-value = 0.7465. Benchmark Dose Computation Specified effect = 0.05 Risk Type = Extra risk Confidence level = 0.95 BMD = 49.3439 BMDL = 37.9523 Probit 1 0.8 Fraction Affected 0.6 0.4 0.2 0 BMDL BMD 0 50 100 150 200 250 300 350 dose FIGURE B-1 Probit model with 0.95 confidence level.

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60 Acute Exposure Guideline Levels APPENDIX C ACUTE EXPOSURE GUIDELINE LEVELS FOR ETHYL PHOSPHORODICHLORIDATE Derivation Summary AEGL-1 VALUES The available data were insufficient to derive AEGL-1 values for ethyl phosphorodichloridate. Therefore, AEGL-1 values were not recommended. AEGL-2 VALUES 10 min 30 min 1h 4h 8h 0.37 ppm 0.25 ppm 0.20 ppm 0.13 ppm 0.063 ppm (2.4 mg/m3) (1.7 mg/m3) (1.3 mg/m3) (0.86 mg/m3) (0.40 mg/m3) Data adequacy: The available data were insufficient to derive AEGL-2 values for ethyl phosphorodichloridate. A fractional reduction of the AEGL-3 values may be used to derive AEGL-2 values. For chemicals with a steep concentration-response curve, AEGL-3 values may be divided by 3 to estimate AEGL-2 values (NRC 2001). AEGL -3 VALUES 10 min 30 min 1h 4h 8h 1.1 ppm 0.76 ppm 0.60 ppm 0.38 ppm 0.19 ppm (7.3 mg/m3) (5.0 mg/m3) (4.0 mg/m3) (2.5 mg/m3) (1.3 mg/m3) Reference: Bayer AG. 1983. Ethylesterdichloride [in German]. Report No. 11439 and 11715. Bayer AG, Wuppertal-Elberfeld. Attachment in Letter from Mobay Corporation to U.S. EPA Submitting Toxicology Study on Ethylesterdichloride, Dated 12/31/90.EPA Document No. 86910000570, Microfiche No.OTS05030306; and EPA Document No. 86910000571, Microfiche No. OTS05030307. Test Species/Strain/Sex/Number: Rat, strain not specified , 10 males and 10 females per group Exposure route/Concentrations/Durations: Inhalation; 37, 61, 75, 90, 143, or 355 ppm for 4 h Effects: Lethality Concentration Mortality (ppm) Male Female Total 37 0/10 0/10 0/20 61 0/10 Not reported 0/10 75 1/10 3/10 4/20

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Ethyl Phosphorodichloridate 61 75 1/10 3/10 4/20 90 7/10 5/10 12/20 143 10/10 7/10 17/20 355 10/10 10/10 20/20 LC50 85 ppm 99.8 ppm 91.6 ppm BMCL05 43.7 ppm 25.8 ppm 38.0 ppm BMC01 48.1 ppm 32.1 ppm 38.2 ppm End point/Concentration/Rationale: 4-h BMCL05 in rats of 38 ppm; threshold for lethality Uncertainty factors/Rationale: Interspecies: 10, no interspecies or mechanistic data. Intraspecies: 10, no data on interindividual variability. Modifying factor: None Animal-to-human dosimetric adjustment: Not applicable Time scaling: Cn × t = k, where n = 3 when extrapolating to shorter durations and n = 1 when extrapolating to longer durations to derive values protective of human health (NRC 2001). Extrapolating from a 4-h point of departure to a 10-min AEGL-3 value is justified because no deaths were noted in male rats exposed to ethyl phosphorodichloridate at 20,900 ppm or in female rats exposed at 16,700 ppm for 10 min (Bayer 1983). Data adequacy: Sparse data set.

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62 Acute Exposure Guideline Levels APPENDIX D CATEGORY PLOT FOR ETHYL PHOSPHORODICHLORIDATE TABLE D-1 Category plot of animal toxicity data on ethyl phosphorodichloridate com- pared with AEGL values.

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TABLE D-1 Data Used in Category Plot of AEGL Values for Ethyl Phosphorodichloridate Source Species Sex No. Exposures ppm Minutes Category Reference NAC/AEGL-1 NR 10 AEGL NAC/AEGL-1 NR 30 AEGL NAC/AEGL-1 NR 60 AEGL NAC/AEGL-1 NR 240 AEGL NAC/AEGL-1 NR 480 AEGL NAC/AEGL-2 0.37 10 AEGL NAC/AEGL-2 0.25 30 AEGL NAC/AEGL-2 0.20 60 AEGL NAC/AEGL-2 0.13 240 AEGL NAC/AEGL-2 0.063 480 AEGL NAC/AEGL-3 1.1 10 AEGL NAC/AEGL-3 0.76 30 AEGL NAC/AEGL-3 0.60 60 AEGL NAC/AEGL-3 0.38 240 AEGL NAC/AEGL-3 0.19 480 AEGL Rat 1 6.16 60 2 Labored breathing, gasping, decreased activity, rales, tremors (Rhone-Poulenc, Inc. 1990). Rat 1 66 60 SL Labored breathing, gasping, decreased activity, rales, tremors, weight loss, mortality 8/10 (Rhone-Poulenc, Inc. 1990). (Continued) 63

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64 TABLE D-1 Continued Source Species Sex No. Exposures ppm Minutes Category Reference Rat 1 134 60 SL Labored breathing, gasping, decreased activity, rales, tremors, weight loss, mortality 7/10 (Rhone-Poulenc, Inc. 1990). Rat 1 37 240 2 Severe ocular and nasal irritation, disturbed behavior, severe respiratory signs (Bayer 1983). Rat 1 61 240 SL Severe ocular and nasal irritation, disturbed behavior, severe respiratory signs, mortality 2/10 (Bayer 1983). Rat 1 75 240 SL Severe ocular and nasal irritation, disturbed behavior, severe respiratory signs, mortality 4/20 (Bayer 1983). Rat 1 90 240 SL Severe ocular and nasal irritation, disturbed behavior, severe respiratory signs, mortality 12/20 (Bayer 1983). Rat 1 143 240 SL Severe ocular and nasal irritation, disturbed behavior, severe respiratory signs, mortality 17/20 (Bayer 1983). Rat 1 355 240 3 Severe ocular and nasal irritation, disturbed behavior, severe respiratory signs, mortality 2/10 (Bayer 1983). Rat 1 350 60 SL Hyperemia, decreased activity, salivation, lacrimation, mortality 20/20 (Rhone-Poulenc, Inc. 1990).

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Rat 1 20,900 10 2 Severe ocular and nasal irritation, disturbed behavior, severe respiratory signs, no weight gain (Bayer 1983). Rat 1 16,700 10 2 Severe ocular and nasal irritation, disturbed behavior, severe respiratory signs, no weight gain (Bayer 1983). Rat 1 14,400 30 3 Severe ocular and nasal irritation, disturbed behavior, severe respiratory signs, weight loss, mortality 5/5 (Bayer 1983). Rat 1 10,700 30 SL Severe ocular and nasal irritation, disturbed behavior, severe respiratory signs, weight loss, mortality 4/5 (Bayer 1983). Rat 1 13,700 60 3 Severe ocular and nasal irritation, oral noises, cramped walking, mortality 5/5 (Bayer 1983). Rat 1 12,000 60 3 Severe ocular and nasal irritation, oral noises, cramped walking, mortality 5/5 (Bayer 1983). For category: 0 = no effect, 1 = discomfort, 2 = disabling, 3 = lethal; SL = some lethality. 65