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6 Phosphorus Trichloride1 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 Robert Young (Oak Ridge National Laboratory) and Tom Hornshaw (National Advisory Committee [NAC] on Acute Exposure Guideline Levels for Hazardous Substances). 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 concludes 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). 250

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251 Phosphorus Trichloride 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 levels for the general public, including susceptible subpopulations, such as infants, children, the elderly, persons with asthma, and those with other illnesses, it is recognized that individuals, subject to idiosyncratic responses, could experience the effects described at concentrations below the correspond- ing AEGL. SUMMARY Phosphorus trichloride (CAS no. 007719-12-2) is a colorless, clear fuming liquid with a pungent, irritating odor. In the presence of water, the chemical de- composes rapidly in a highly exothermic reaction to phosphonic acid, or hydro- gen chloride, and pyrophosphonic acids. The primary use of phosphorus trichlo- ride is for the production of phosphonic acid which, in turn, is used in the production of glyphosphate herbicides. Annual domestic production of 294,000 tons has been reported. No acute lethality data on humans are available. Qualitative data regarding human exposures indicate signs and symptoms of exposure consistent with a highly irritating chemical; ocular and dermal irritation, respiratory tract irrita- tion, shortness of breath, and nausea. Lethality data are available for rats, cats, and guinea pigs. Cursory studies conducted nearly 100 years ago in Germany provided preliminary data on lethal and nonlethal effects in cats and guinea pigs following various treatment regi- mens with inhaled phosphorus trichloride. Although results of the studies indi- cated the respiratory tract to be a critical target, the methods and results of these studies were not verifiable. Weeks et al. (1964) reported 4-h LC50 values of 104.5 ppm and 50.1 ppm for rats and guinea pigs, respectively. An unpublished study by Hazleton Laboratories (1983) identified a no-observed-adverse-effect level (NOAEL) of 3.4 ppm and a lowest-observed-adverse-effect level (LOAEL

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252 Acute Exposure Guideline Levels (histopathologic changes in the respiratory tract) of 11 ppm following repeated exposure (6 h/day, 5 days/week for 4 weeks) of rats. There are no data regarding reproductive and developmental toxicity, genotoxicity, or carcinogenicity of phosphorus trichloride. Definitive data regarding the mechanism of action of phosphorus trichloride are unavailable. Decomposition products (hydrogen chlo- ride, phosphonic acid, and pyrophosphonic acids) are responsible, at least in part, for the contact irritation reported by humans, and the irritation and tissue damage observed in animal species. The concentration-time relationship for many irritant and systemically act- ing vapors and gases may be described by Cn × t = k, where the exponent n ranges from 0.8 to 3.5. Due to the limited toxicity data for this chemical, an em- pirical derivation of n was not possible. In the absence of an empirically derived exponent (n), and to obtain conservative and protective AEGL values, temporal scaling was performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points using the Cn × t = k equation. Because phosphorus trichloride is a contact irritant, minor irritation effects are not expected to vary with exposure duration (NRC 2001). Therefore, all AEGL- 1 values were set at 0.34 ppm (the 3.4 ppm point-of departure adjusted by a total uncertainty factor of 10). The 10-min AEGL-3 values were set equivalent to the 30-min values due to uncertainties in extrapolating from the experimental expo- sure durations of 4 h and greater. Quantitative data consistent with AEGL-1 effects were unavailable. Occu- pational exposures of humans to 1.8-3.6 ppm for 2-6 h (Sassi 1952) and expo- sure of rats to 3.4 ppm for 6 h/day, 5 days/week for 4 weeks (Hazleton Labora- tories 1983) were without notable effect. The occupational exposure data lacked details regarding pairing of the exposure durations (weeks to months) to expo- sure concentrations. The 3.4 ppm exposure of rats data was considered a NOAEL for AEGL-1 effects. These data as well as the AEGL-1 values are sup- ported by the human experience. The interspecies uncertainty factor was limited to 3 because of the concordance of the animal data with the human experience and because the most sensitive species tested (guinea pig) was only about 2-fold more sensitive. The intraspecies uncertainty factor was limited to 3 because pri- mary effects of phosphorus trichloride (irritation and subsequent tissue damage) appear to be due, in part, to hydrogen chloride and phosphonic acid resulting from chemical dissociation. Additional reduction of the AEGL-1 values would be inconsistent with available human and animal data. Information consistent with AEGL-2 effects was limited to an occupa- tional exposure report and a multiple exposure study with rats. For occupational exposures, there was notable irritation following 2-6 h of exposure to approxi- mately 14-27 ppm phosphorus trichloride and more severe but reversible irrita- tion following exposures of 1-8 weeks. Reports providing qualitative informa- tion but no exposure terms affirmed the potential for respiratory tract irritation following acute exposures to phosphorus trichloride. Data for rats showed upper respiratory tract involvement following multiple exposures (over 4 weeks) to 11 ppm but not to 3.4 ppm (Hazleton Laboratories 1983). For development of

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253 Phosphorus Trichloride AEGL-2 values, the 11 ppm exposure in rats was considered a NOAEL for AEGL-2 effects. Uncertainty factor application was the same as for the AEGL-1 tier. AEGL-3 values were developed based upon a 3-fold reduction of the 4-h LC50 (Weeks et al. 1964) as an estimate of the lethality threshold (104.3 ppm/3 = 34.8 ppm). A total uncertainty factor adjustment of 10 was used to develop the AEGL-3 values. Animal data indicated some variability in the toxic response to phosphorus trichloride with guinea pigs being the more sensitive among the spe- cies tested but only about 2-fold compared to the rat. Additionally, further re- duction of the AEGL-3 values did not appear warranted based upon the human occupational exposure data. Therefore, uncertainty adjustment regarding inter- species variability was limited to 3. To account for intraspecies variability, a factor of 3 was applied. The uncertainty of intraspecies variability was limited to 3 because primary effects of phosphorus trichloride (irritation and subsequent tissue damage) appear to be due, in part, to hydrogen chloride and phosphonic acid resulting from chemical dissociation. Additionally, these products would likely affect all mucosal surfaces in a similar manner and would do so independ- ent of metabolism processes. The total uncertainty factor of 10 may be justified by human exposure data showing that repeated 2 to 6-h exposures of up to 27 ppm were without life-threatening consequences. Furthermore, the results of the Hazleton Laboratories (1983) study showed no fatalities in rats following multi- ple 6-h exposures to 11 ppm. The AEGL values for phosphorus trichloride are presented in Table 6-1. TABLE 6-1 Proposed AEGL Values for Phosphorus Trichloride Classification 10 min 30 min 1h 4h 8h End Point (Reference) AEGL-1 0.34 0.34 00.34 0.34 0.34 NOAEL of 3.4 ppm in rats (Nondisabling) ppm ppm ppm ppm ppm exposed 6 h/day, 5 days/week for 4 weeks; no time scaling for irritant (Hazleton Laboratories 1983) AEGL-2 2.5 2.5 2.0 1.3 0.83 NOAEL for AEGL-2 (Disabling) ppm ppm ppm ppm ppm tier effects; based upon respiratory tract histopathology in rats exposed 6 h/day, 5 days/week for 4 weeks (Hazleton Laboratories 1983) AEGL-3 7.0 7.0 5.6 3.5 1.8 Estimated lethality (Lethal) ppm ppm ppm ppm ppm threshold based upon 3-fold reduction of rat 4-h LC50 (104.3 ppm/3 = 34.8 ppm) (Weeks et al. 1964)a a Based upon animal data, lethality may be delayed.

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254 Acute Exposure Guideline Levels 1. INTRODUCTION Phosphorus trichloride (CAS No. 007719-12-2) is a colorless, clear, fum- ing liquid with a pungent, irritating odor (Fee et al. 1996). Odor threshold in- formation is unavailable for this chemical. Domestic production of approxi- mately 294,000 tons has been reported (SRI 1992). The primary use of phos- phorus trichloride is for the production of phosphonic acid which, in turn, is used in the production of the herbicide, glyophosphate. Phosphorus trichloride decomposes rapidly in water in highly exothermic reactions. It may also decom- pose in moist air to hydrochloric acid and hydrated phosphoric acid. The reac- tion products include phosphonic acid, hydrogen chloride, or pyrophosphonic acids, depending on the mole ratio of water and phosphorus trichloride (Fee et al. 1996). If the mole ratio of water and phosphorus trichloride is greater than 3, the following reaction will occur. The chemical and physical data on phosphorus trichloride are presented in Table 6-2. PCl3 + 3 H2O → H3PO3 + 3 HCl If the mole ratio is 2.5 to 3, reaction products will be a mixture of phosphonic acid and pyrophosphonic acids. OO O ║║ ║ 3 PCl3 + 8 H2O → 9 HCl + HPOPH + HPOH ││ │ HO OH OH TABLE 6-2 Chemical and Physical Data for Phosphorus Trichloride Phosphorus chloride, Fee et al. 1996; NIOSH Synonyms trichlorophosphine 2005 RTECS 2009 CAS Registry No. 007719-12-2 O’Neil et al. 2001 Chemical formula PCl3 O’Neil et al. 2001 Molecular weight 137.33 O’Neil et al. 2001 Physical state Liquid O’Neil et al. 2001 Boiling and melting point 76°C/-112°C O’Neil et al. 2001 Density 1.574 O’Neil et al. 2001 Solubility Decomposes in water and alcohol Fee et al. 1996 Vapor pressure 100 mm Hg at 21°C ACGIH 1991 1 ppm = 5.6 mg/m3 Conversion factors in air Beliles and Beliles 1993 1 mg/m3 = 0.18 ppm

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255 Phosphorus Trichloride 2. HUMAN TOXICITY DATA 2.1. Acute Lethality No acute lethality exposure-response data or case reports are currently available. 2.2. Nonlethal Toxicity Sassi (1952) summarized twenty cases of acute (2-6 h) or “subacute” (1-8 weeks of work) exposures of workers to phosphorus trichloride. The concentra- tion of phosphorus trichloride in the workrooms ranged from 10-20 mg/m3 (~1.8-3.6 ppm) under normal conditions to 80-150 mg/m3 (~14-27 ppm) during periods when the plant was “out of order.” The method by which the concentra- tions were determined was not stated in the translated abstract. For the acute exposures, workers experienced a burning sensation in the eyes and throat, pho- tophobia, chest tightness, dry cough, and slight bronchitis which occurred within 2-6 h of exposure. It is unclear, however, if the reported symptoms were associ- ated with the “out of order” condition or were also present to some extent during “normal” operation. For the “subacute” exposures, pharyngeal irritation, cough- ing, catarrh, dyspnea, and asthmatic bronchitis occurred at 1-8 weeks of expo- sure. Slight increases in body temperature and moderate leucocytosis with neu- trophilia were also reported for both exposures. Signs and symptoms reportedly resolved in 3 to 6 days for the acute exposures and 10-15 days for the subacute exposures. An abstract by Wason et al. (1982) provided information on an assessment of 27 individuals exposed to phosphorus trichloride released in a railroad acci- dent in 1980. The report indicated that the phosphorus trichloride reacted with water used to disperse the spillage and with air moisture that resulted in the re- lease of phosphoric and hydrochloric acids and phosphorus oxides. No informa- tion was provided regarding weather conditions (e.g., wind, temperature, humid- ity) at the time of the accident. Signs and symptoms were characteristic of exposure to irritants and included burning eyes (86%), shortness of breath (59%), throat irritation (59%), lacrimation (59%), headache (48%), nausea (48%), burning sensation on the skin (44%), and sputum production (41%). Ad- ditional effects occurring in 33% or less of the patients included chest pains, wheezing, skin rash, blurred vision, vomiting, and abdominal pain. Lactate de- hydrogenase was mildly elevated and serum bilirubin and/or serum transami- nases were elevated in three individuals. Results of pulmonary function tests showed greater severity of effect with decreasing distance from the release site. At 2 months, 86% of the individuals who were within 1/16 mile were hypoxe- mic while only 50% of those 1/16 to 1/8 mile distance were hypoxemic. There were no exposure durations provided (probably >1.5 h as described below) and no exposure concentrations were measured or estimated.

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256 Acute Exposure Guideline Levels Wason et al. (1984) reported in more detail on the railroad accident in- volving spillage of phosphorus trichloride. The report focused on 17 individuals (16 men and one woman, ages 21-59 years), seven of whom were requested to return for follow-up study after the initial medical examination. Signs and symp- toms of exposure included eye, skin and throat irritation, nausea, vomiting, blurred vision, headache, and various effects associated with respiration and ventilation (e.g., wheezing, cough, chest pain, dyspnea, sputum production). Chest x-rays of all subjects were normal and there was no evidence of hepatic toxicity. Spirometry tests revealed that the subjects (10 of 17) who were closest (within 110 yards) to the accident site had a significant decrease in vital capac- ity, maximal breathing capacity, FEV1, and maximal ventilatory flow rate at 25% of vital capacity. An improvement in the ventilatory changes was seen 1 month later. Subjects closer to the release site appeared to exhibit signs and symptoms of greater severity. It was also found that patients that were exposed for less than 1 h and 30 min had significantly (p = 0.02) greater maximal expira- tory flow rates at 25% of vital capacity than did those individuals exposed for longer periods. Water was used to disperse the spilled phosphorus trichloride and, as noted in the report, the actual exposure most likely involved phosphoric acid and hydrochloric acid more so than phosphorus trichloride. Eight subjects were exposed for less than 1 h and 30 min and nine were exposed longer (dura- tion not specified). Pulmonary function tests in the seven follow-up patients 1 month after the accident revealed significant improvements in vital capacity, FEV1, peak expiratory flow rate, and maximal expiratory flow rate at 50% vital capacity. Although this report provides information regarding the nonlethal ef- fects in humans following exposure to phosphorus trichloride, there were no data on the exposure concentrations and it is uncertain as to the precise chemi- cals (i.e., phosphorus trichloride and/or its degradation products) to which the people were exposed. A NIOSH health hazard evaluation of workers at the FMC plant in Nitro, West Virginia revealed that those with known repeated exposures to phosphorus oxychloride and/or phosphorus trichloride experienced a significantly higher (p < 0.001) prevalence (65%) of occasional respiratory symptoms (chest tight- ness, wheezing, difficulty breathing) compared to unexposed workers (5%) (Tharr and Singal 1980). However, no correlation was found between results of pulmonary function tests on the workers and exposure to these chemicals. The study utilized 37 exposed workers and 22 unexposed workers. Most air samples were below detection limits although one employee (with respiratory protection of a chlorine gas mask) was exposed to 6 mg phosphorus trichloride/m3 (1 ppm) for 1 h during a truck-loading operation (no effects were reported for this indi- vidual). A follow-up study conducted by NIOSH on 26 of the exposed workers and 11 of the unexposed workers from the aforementioned FMC Corp. group re- vealed that half of the exposed workers reported significantly (p < 0.002) more episodes of respiratory effects (wheezing, breathlessness, and chest tightness) compared to the unexposed workers who reported no such effects (Moody

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257 Phosphorus Trichloride 1981). Results of pulmonary function tests did not reveal significant findings regarding effects of phosphorus trichloride (or phosphorus oxychloride) expo- sure. No significant difference in pulmonary function (FEV1) was found in the exposed workers vs. the unexposed workers over a 2-year period. The small sample size, however, reduces the power of the study to detect such changes. Although lacking exposure terms, there is information regarding acciden- tal releases of phosphorus trichloride in Illinois (T. Hornshaw, Office of Chemi- cal Safety, Illinois EPA, personal communication, 2009). Two significant re- leases of phosphorus trichloride occurred in 1988 from a chemical plant in Sauget, Illinois. The first, on April 17, resulted from overfilling of a railroad tanker, with an estimated 6,000-12,000 pounds released in the railroad yard. The plume caused the evacuation of approximately 22 square blocks, and 417 citi- zens of neighboring Rush City and East St. Louis, Illinois reported to area hospi- tals for treatment. Two of these citizens were admitted overnight and subse- quently released. Eye and respiratory irritation were the main symptoms reported. The second incident resulted from failure of a rupture disk during start- up procedures at the plant on July 31. It was calculated that no more than 50 pounds of phosphorus trichloride were released from the plant, and the plant’s security and industrial hygiene personnel were able to visually track and bound the plume that moved into Rush City. Their reports indicated that the plume traveled approximately 2 miles before dissipating. This plume caused 244 citi- zens to report to area hospitals for treatment. Eight of these citizens were admit- ted; seven were kept overnight and released, while the eighth was kept for 3 days before release. This patient’s history of asthma contributed to the severity of effects, and the asthma was also aggravated by the exposure to the phospho- rus trichloride. The main complaints of the citizens were eye, nose, and throat irritation. No measurements of airborne concentrations were made during either incident. 2.3. Epidemiologic Studies No epidemiologic studies of phosphorus trichloride toxicity are currently available. 2.4. Developmental and Reproductive Toxicity Data regarding the reproductive and developmental toxicity of phosphorus trichloride in humans are not available. 2.5. Genotoxicity No human genotoxicity data for phosphorus trichloride are currently available.

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258 Acute Exposure Guideline Levels 2.6. Carcinogenicity Information regarding the potential carcinogenicity of phosphorus trichlo- ride in humans is not available. 2.7. Summary There are no data regarding lethal exposures of humans to phosphorus tri- chloride but some information on nonlethal exposures is available. Workers ex- posed to phosphorus trichloride following a railroad car spill exhibited signs and symptoms consistent with exposure to a highly irritating chemical. Although the reports of this accident describe qualitatively the effects of exposure, there are no quantitative exposure-response terms. Pulmonary function deficits (e.g., vital capacity, FEV1, peak expiratory flow rate, maximal expiratory flow rate at 50% vital capacity) that correlated with distance from the release showed improve- ment at 1 month following the exposure. The effects reported could be attributed to phosphorus trichloride decomposition products (phosphonic acid and hydro- gen chloride) as well as the parent compound. In an occupational exposure set- ting, workers experienced a burning sensation in the eyes and throat, photopho- bia, chest tightness, dry cough, and slight bronchitis following 2-6 h of exposure to approximately 14-27 ppm phosphorus trichloride. Exposure of workers to these levels for 1-8 weeks resulted in pharyngeal irritation, coughing, catarrh, dyspnea, and asthmatic bronchitis. Increases in body temperature and moderate leucocytosis with neutrophilia were also reported for both exposure durations, but all signs and symptoms resolved upon removal from the exposure. The de- tection of elevated LDH activity in individuals following accidental exposures may imply other organ and tissue damage. 3. ANIMAL TOXICITY DATA 3.1. Acute Lethality 3.1.1. Rats Weeks et al. (1964) reported on the acute lethality of phosphorus trichlo- ride in female rats exposed for 4 h to an atmosphere of phosphorus trichloride generated by passing nitrogen gas through the liquid test material. Chemical analysis was used to determine the amount of the test material in the exposure chamber. The rats were observed for 14 days after removal from exposure. The rats were restless and exhibited labored breathing during the exposure. During the exposure, the eyes were closed and there was considerable porphyrin secre- tion around the eyes. Deaths occurred over a period of 10 days indicating, under the conditions of this experiment, a notable latency period in the lethal response. The nostrils and paws of the exposed rats exhibited swelling, edema, discolora-

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259 Phosphorus Trichloride tion and subsequent sloughing of tissues that was consistent with the activity of a corrosive agent. Microscopic examination revealed necrosis of epithelium and supporting structures in the nostrils but pulmonary damage was considered to be negligible. The investigators noted that the primary site of damage appeared to be the kidneys and was characterized by nephrosis of tubules in the cortico- medullary region. A 4-h LC50 of 104.3 ppm was calculated and reported by the investigators. The exposure concentrations tested to obtain this value were not reported and, therefore, there was no information regarding the exposure- response relationship. 3.1.2. Guinea Pigs Weeks et al. (1964) also examined the lethal effects of phosphorus trichlo- ride on guinea pigs exposed for 4 h. The experimental protocol was as described for the experiments with rats (Section 3.1.1). Based upon the published report, the response of guinea pigs was similar to that of rats; restlessness, signs of ocu- lar and nasopharyngeal irritation, and renal damage. With the exception of the 4- h LC50 of 50.1 ppm, no additional exposure-response data were provided. Results of early inhalation exposure experiments reported by Butjagin (1904) showed that guinea pigs exposed to 623 ppm phosphorus trichloride died shortly after 3 h of exposure. 3.1.3. Cats Butjagin (1904) reported that test animals (guinea pigs and cats) died shortly after a 3-h exposure to 623 ppm. In another experiment, one cat exposed to 694 ppm died after 306 min. 3.2. Nonlethal Toxicity 3.2.1. Rats In an unpublished study conducted for the Monsanto Company (Hazleton Laboratories 1983), groups of 15 Sprague-Dawley rats (15/sex/group) were ex- posed to phosphorus trichloride vapor/aerosol for 6 h/day, 5 days/week for 4 weeks. Over the 4-week period, nominal exposure concentrations were 0.5, 3.0, or 10.0 ppm and analytical concentrations were 0.49, 3.37, and 10.96 ppm. The test atmosphere was generated by passing air (200-990 cc/min depending upon the test concentration group) over the headspace above a non-specified volume of phosphorus trichloride in a flask. The vapor was then carried to the test chambers via Teflon7 tubing. Sample concentrations were determined three times per day by collecting chamber samples in impingers containing 20 mL of sodium hydroxide. The samples were subsequently analyzed in a chloride meter

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260 Acute Exposure Guideline Levels and expressed as ppm phosphorus trichloride. Over the 4-week exposure period, concentration excursions deviated from target values by -2.0, + 12.3, and + 9.6% for the low, medium, and high-dose groups, respectively. A control group was exposed to filtered air under the same conditions. No rat died during the expo- sure period and no treatment-related adverse effects were observed. All rats were sacrificed and necropsied on day 29. Histological alterations in the max- illo- and nasoturbinates and in the lateral wall of the nasal cavity were observed in seven male and four females of the high-dose group; the remaining high-dose rats exhibited no remarkable findings in the nasal cavities and turbinates. Squamous metaplasia of the respiratory epithelium was also present in six males and four females of the high-dose group. There were no treatment-related effects on hematologic or biochemical parameters, and no ophthalmologic effects or body weight/organ weight changes were observed. Under the conditions of this study, 3.4 ppm was considered a NOAEL in rats. 3.2.2. Guinea Pigs In experiments reported by Butjagin (1904), guinea pigs were exposed to phosphorus trichloride at various concentrations for different durations (1-6 h). Only minor effects (restlessness, salivary and nasal secretions, coughing, and irregular respiration) were observed following 6-h exposure to 0.71 ppm or 1-h exposure to 1.78 to 5.36 ppm. In the report summary, it was also noted that ex- posures of 50-90 ppm for 1 h produced severe signs of toxicity. The phosphorus trichloride concentrations were determined by measurement of chlorine. It ap- pears that only one to three animals were used for any given exposure and, for some experiments, the same animals were used in multiple tests. 3.2.3. Cats Butjagin (1904) also conducted experiments with adult cats (2.1- 4.0 kg) exposed to phosphorus trichloride as previously described for guinea pigs. The results were similar to those reported for the guinea pigs; 6-h exposure to 0.71 ppm or 1-h exposure to 1.78 to 5.36 ppm produced signs of restlessness and nasopharyngeal irritation. Six-hour exposures to concentrations of 135 to 303 ppm rapidly produced signs of severe irritation (salivary, nasal, and ocular se- cretions, breathing through the mouth, irregular and severely labored respira- tion). Histological examination at 6 to 7 days after exposure revealed severely damaged nasal septum and bronchioles, and pulmonary edema. Inasmuch as these animals were terminated for necropsy, it is likely (based upon the findings) that they might not have survived. In summary, the study author reported that 1- h exposure to 50-90 ppm resulted in severe signs of toxicity. It appears that for at least some of the experiments, the same cats were used.

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271 Phosphorus Trichloride DFG (Deutsche Forschungsgemeinschaft). 1999. List of MAK and BAT Values 1999. Maximum Concentrations and Biological Tolerance Values at the Workplace Re- port No. 35. Weinheim, Federal Republic of Germany: Wiley VCH. Hazleton Laboratories. 1983. Subacute Inhalation Toxicity Study in Rats - Phosphorus Trichloride. Final Report. Project No. 241-141. Hazleton Laboratories America, Inc. HSDB (Hazardous Substances Data Bank). 2007. Phosphorus Trichloride (CASRN 7719- 12-2). 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 Dec. 7, 2010]. Moody, P.L. 1981. Health Hazard Evaluation Report: FMC Corporation, Nitro, West Virginia. HETA 81-089-965. U.S. Department of Health and Human Services, Centers for Disease Control, National Institute for Occupational Safety and Health, Cincinnati, OH. MSZW (Ministerie van Sociale Zaken en Werkgelegenheid). 2004. Nationale MAC-lijst 2004: Fosfor trichloride. Den Haag: SDU Uitgevers [online]. Available: http:// www.lasrook.net/lasrookNL/maclijst2004.htm [accessed Dec. 6, 2010]. NIOSH (National Institute for Occupational Safety and Health). 1996. Documentation for Immediately Dangerous to Life or Health Concentrations (IDLH): NIOSH Chemical Listing and Documentation of Revised IDLH Values (as of 3/1/95)- Phosphorus Trichloride. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health. August 1996 [online]. Available: http://www.cdc.gov/niosh/idlh/ 7719122.html [accessed Nov. 16, 2010]. NIOSH (National Institute for Occupational Safety and Health). 2005. NIOSH Pocket Guide to Chemical Hazards: Phosphorus Trichloride. U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, National Institute for Occupational Safety and Health, Cincinnati, OH. September 2005 [online]. Avail- able: http://www.cdc.gov/niosh/npg/npgd0511.html [accessed Nov. 23, 2010]. NRC (National Research Council). 1984. Emergency and Continuous Exposure Limits for Selected Airborne Contaminants, Vol. 2. Washington, DC: National Academy Press. NRC (National Research Council). 1993. Guidelines for Developing Community Emer- gency 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. O'Neil, M.J., A. Smith, and P.E. Heckelman, eds. 2001. Phosphorus trichloride. P. 1319 in The Merck Index: An Encyclopedia of Chemicals and Drugs, 13th Ed. White- house Station, NJ: Merck. RTECS (Registry of Toxic Effects of Chemical Substances), 2009. Phosphorus Chloride. RTECS No. TH3675000. National Institute for Occupational Safety and Health [online]. Available: http://www.cdc.gov/niosh-rtecs/TH381378.html [accessed Dec. 7, 2010]. Sassi, C. 1952. Occupational poisoning with phosphorus trichloride. Med. Lav. 43(8- 9):298-306. SRI International. 1992. 1992 Directory of Chemical Producers: United States of Amer- ica. Menlo Park, CA: SRI International, 85:1.

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272 Acute Exposure Guideline Levels 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. Tharr, D.G., and M. Singal. 1980. Health Hazard Evaluation Determination Report: FMC Corporation Specialty Chemicals Division: Nitro, WV. HHE-78-90-739. NTIS PB81-170920. National Institute for Occupational Safety and Health, Cincinnati, OH. Wason, S., I. Gomolin, P. Gross, and F.H. Lovejoy, Jr. 1982. Phosphorus trichloride ex- posure: A follow-up study of 27 exposed patients. Vet. Human Toxicol. 24(4):275- 276[Abstract B-5]. Wason, S., I. Gomolin, P. Gross, S. Mariam, and F.H. Lovejoy. 1984. Phosphorus trichlo- ride toxicity: Preliminary report. Am. J. Med. 77(6):1039-1042. Weeks, M.H., N.P. Musselman, P.P. Yevich, K.H. Jacobson, and F.W. Oberst. 1964. Acute vapor toxicity of phosphorus oxychloride, phosphorus trichloride and methyl phosphonic dichloride. Am. Ind. Hyg. J. 25:470-475.

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273 Phosphorus Trichloride APPENDIX A DERIVATION OF AEGL VALUES Derivation of AEGL-1 Values Key study: Hazleton Laboratories 1983 Toxicity end point: NOAEL of 3.4 ppm for rats following multiple exposure at 6 h/day, 5 days/week for 4 weeks. Scaling: No time scaling was applied for AEGL-1 because the contact irritation expected from exposure to phosphorus trichloride vapors is not expected to vary over time. This approach is consistent with the AEGL Standing Operating Procedures (NRC 2001). Uncertainty factors: Interspecies UF = 3; the attenuation of this uncertainty factor is justified by the fact that the guinea pig appears to be the most sensitive species tested. Intraspecies UF = 3; contact irritation and subsequent tissue damage appear to be due, in part, to hydrogen chloride and phosphonic acid resulting from chemical dissociaton and direct corrosive action of these components on mucosal surfaces. Additional application of uncertainty factor adjustment would provide AEGL-1 values that are inconsistent with limited data on human exposures. All AEGL-1 values were equivalent to the point-of- departure (3.4 ppm for 6 h) adjusted by a total uncertainty factor of 10 (3.4 ppm/10 = 0.34 ppm) because the contact irritation expected from exposure to phosphorus trichloride vapors is not expected to vary over time. This approach is consistent with the AEGL Standing Operating Procedures (NRC 2001). Derivation of AEGL-2 Key study: Hazleton Laboratories 1983

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274 Acute Exposure Guideline Levels Toxicity end point: LOAEL of 11 ppm for respiratory tract histopathologic changes in rats following multiple exposures at 6 h/day, 5 days/week for 4 weeks. Scaling: The concentration-time relationship for many irritant and systemically acting vapors and gases may be described by Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). Due to the limited toxicity data for this chemical, an empirical derivation of n was not possible. In the absence of an empirically derived exponent (n), and to obtain conservative and protective AEGL values, temporal scaling was performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points using the Cn × t = k equation. (11 ppm)1 × 6 h = 66 ppm-h (n = 1) (11 ppm)3 × 6 h = 7,986 ppm3-h (n = 3) Uncertainty factors: Interspecies UF = 3; the attenuation of this uncertainty factor is justified by the fact that the guinea pig appears to be the most sensitive species tested and because limited human exposure data (Sassi 1952) indicate that humans have experienced routine occupational exposures of up to 3.6 ppm without effect. Intraspecies UF = 3; contact irritation and subsequent tissue damage appear to be due, in part, to hydrogen chloride and phosphoric acid resulting from chemical dissociaton and direct corrosive action of these components on mucosal surfaces. Adjustments using a greater level of uncertainty would provide AEGL-2 values that are inconsistent with limited data on human exposures. 10-min AEGL-2 The 10-min AEGL-2, was set equivalent to the 30-min value (2.5 ppm) due to uncertainties in extrapolating from the 6-h experimental exposure duration to a 10-min duration. C3 × 0.5 h = 7,986 ppm3-h 30-min AEGL-2 C = 25.2 ppm 30-min AEGL-2 = 25.2 ppm/10 = 2.5 ppm (14 mg/m3)

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275 Phosphorus Trichloride C3 × 1 h = 7,986 ppm3-h 1-h AEGL-2 C = 20.0 ppm 1-h AEGL-2 = 20.0 ppm/10 = 2.0 ppm (11 mg/m3) C3 × 4 h = 7,986 ppm3-h 4-h AEGL-2 C = 12.6 ppm 4-h AEGL-2 = 12.6 ppm/10 = 1.3 ppm (7.3 mg/m3) C1 × 8 h = 66 ppm-h 8-h AEGL-2 C = 8.25 ppm 8-h AEGL-2 = 8.25 ppm/10 = 0.83 ppm (4.6 mg/m3) Derivation of AEGL-3 Key study: Weeks et al. 1964 Toxicity end point: Lethality threshold estimated as 3-fold reduction in the 4-h LC50 for rats (104.3 ppm/3 = 34.8 ppm); delayed response possible. Scaling: The concentration-time relationship for many irritant and systemically acting vapors and gases may be described by Cn × t = k, where the exponent n ranges from 0.8 to 3.5 (ten Berge et al. 1986). Due to the limited toxicity data for this chemical, an empirical derivation of n was not possible. In the absence of an empirically derived exponent (n) and to obtain conservative and protective AEGL values, temporal scaling was performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points using the Cn × t = k equation. (34.8 ppm)1 × 4 h = 139.2 ppm-h (n = 1) (34.8 ppm)3 × 4 h = 168,576.8 ppm3-h (n = 3) Uncertainty factors: Interspecies UF = 3; the attenuation of this uncertainty factor is justified by the fact that the guinea pig appears to be the most sensitive species tested and because limited human exposure data (Sassi 1952) indicate that humans have experienced exposures of up to 27 ppm without life-threatening consequences.

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276 Acute Exposure Guideline Levels Intraspecies UF = 3; contact irritation and subsequent tissue damage appear to be due, in part, to hydrogen chloride and phosphonic acid resulting from chemical dissociaton and direct corrosive action of these components on mucosal surfaces. Additional application of uncertainty factor adjustment would provide AEGL-3 values that are not consistent with limited data on human exposures or with the results of repeated exposures in rats wherein exposure to 11 ppm 6 h/day, 5 days/week for 4 weeks showed only histologic changes in the upper respiratory tract and no overt signs of toxicity 10-min AEGL-3 Due to uncertainties in extrapolating from a 4-h to 10-min exposure, the 10-min AEGL-3 is set equivalent to the 30-min value (7.0 ppm). C3 × 0.5 h = 168,576.8 ppm3-h 30-min AEGL-3 C = 69.6 ppm 30-min AEGL-3 = 69.6 ppm/10 = 7.0 ppm (39 mg/m3) C3 × 1 h = 168,576.8 ppm3-h 1-h AEGL-3 C = 55.2 ppm 1-h AEGL-3 = 55.2 ppm/10 = 5.6 ppm (31 mg/m3) C3 × 4 h = 168,576.8 ppm3-h 4-h AEGL-3 C = 34.8 ppm 4-h AEGL-3 = 34.8 ppm/10 = 3.5 ppm (20 mg/m3) C1 × 8 h = 139.2 ppm-h 8-h AEGL-3 C = 17.4 ppm 8-h AEGL-3 = 17.4 ppm/10 = 1.8 ppm (10 mg/m3)

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277 Phosphorus Trichloride APPENDIX B ACUTE EXPOSURE GUIDELINES FOR FOR PHOSPHORUS TRICHLORIDE Derivation Summary for Phosphorus Trichloride AEGL-1 VALUES 10 min 30 min 1h 4h 8h 0.34 ppm 0.34 ppm 0.34 ppm 0.34 ppm 0.34 ppm Reference: Hazleton Laboratories 1983 Test Species/Strain/Number: Sprague-Dawley rats; 15/sex/group Exposure Route/Concentrations/Durations: Inhalation exposure (whole-body) to 0, 0.5, 3.0, or 10.0 ppm (nominal) for 6 h/day, 5 days/week for 4 weeks Toxicity End Point: No effects noted at 3.4 ppm (analytical) following multiple exposure of rats over 4 weeks Time Scaling: No time scaling was applied for AEGL-1. All AEGL-1 values were equivalent to the point-of-departure (3.4 ppm for 6 h) adjusted by a total uncertainty factor of 10 (3.4 ppm/10 = 0.34 ppm) because the contact irritation expected from exposure to phosphorus trichloride vapors is not expected to vary over time. This approach is consistent with the AEGL Standing Operating Procedures (NRC 2001). Concentration/Time Selection/Rationale: In the absence of exposure-response data specific for AEGL-1 effects, the exposure to 3.4 ppm at 6 h/day, 5 days/week for 4 weeks was selected as a conservative basis for AEGL development. Uncertainty Factors/Rationale: Total uncertainty application of 10 Interspecies UF = 3: The interspecies uncertainty factor was limited to 3 because of the concordance of the animal data with the human experience and because the most sensitive species tested (guinea pig) was only about 2-fold more sensitive. Intraspecies UF= 3: The intraspecies uncertainty factor was limited to 3 because primary effects of phosphorus trichloride (irritation and subsequent tissue damage) appear to be due, in part, to hydrogen chloride and phosphonic acid resulting from chemical dissociation. Furthermore, the AEGL-1 is based upon a conservative assumption and additional reduction of the AEGL-1 values would be inconsistent with available human and animal data. Modifying Factor: Not applicable Animal-to-Human Dosimetric Adjustments: Not applicable Data adequacy: Neither human nor animal quantitative exposure-response data were available regarding effects consistent with AEGL-1 definition.. The 3.4-ppm exposure of rats over 4 weeks was selected as a NOAEL for AEGL-1. Although likely to be a conservative basis for developing AEGL-1 values, it may be justified due to the relative paucity of data on the toxic response to this chemical.

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278 Acute Exposure Guideline Levels AEGL-2 VALUES 10 min 30-min 1h 4h 8h 2.5 ppm 2.5 ppm 2.0 ppm 1.3 ppm 0.83 ppm Reference: Hazleton Laboratories 1983 Test Species/Strain/Number: Sprague-Dawley rats; 15/sex/group Exposure Route/Concentrations/Durations: Inhalation exposure (whole-body) to 0, 0.5, 3.0, or 10.0 ppm (nominal) for 6 h/day, 5 days/week for 4 weeks Toxicity End Point: Histopathologic alterations in respiratory tract in rats exposed to 11 ppm (analytical), 6 h/day, 5 days/week for 4 weeks. There were no concurrent hematologic or biochemical alterations indicative of a toxic response, and there were no ophthalmologic effects. The 11 ppm exposure concentration is considered a NOAEL for AEGL-2 tier effects. Time Scaling: The concentration-time relationship for many irritant and systemically acting vapors and gases may be described by Cn × t = k, where the exponent n ranges from 0.8 to 3.5. Due to the limited toxicity data for this chemical, an empirical derivation of n was not possible. In the absence of an empirically derived exponent (n), and to obtain conservative and protective AEGL values, temporal scaling was performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points using the Cn × t = k equation. For 10-min AEGL-2, values were set at equivalence to the 30-min values due to uncertainties in extrapolating from the experimental exposure durations of 4 h or greater. Concentration/Time Selection/Rationale: The multiple exposure of rats to 11 ppm over 4 weeks was considered a conservative estimate and NOAEL for AEGL-2 effects (i.e., the effects were neither disabling nor irreversible). Uncertainty Factors/Rationale: Total uncertainty application of 10. Interspecies UF = 3: The interspecies uncertainty factor was limited to 3 because of the concordance of the animal data with the human experience and because the most sensitive species tested (guinea pig) was only about 2-fold more sensitive. Intraspecies UF = 3: The intraspecies uncertainty factor was limited to 3 because primary effects of phosphorus trichloride (irritation and subsequent tissue damage) appear to be due, in part, to hydrogen chloride and phosphonic acid resulting from chemical dissociation. Furthermore, the AEGL-2 is based upon histopathologic changes in the respiratory tract that were not necessarily irreversible or disabling. Additional reduction of the AEGL-2 values would be inconsistent with available human and animal data. Modifying Factor: Not applicable Animal-to-Human Dosimetric Adjustments: Not applicable Data adequacy: Limited information regarding the human experience indicated that 2- to 6-h exposures to 1.8-3.6 ppm were without effect and that exposure to 14-27 ppm irritation of the eyes and upper respiratory tract, photophobia, chest tightness, and bronchitis. Because the effects were neither disabling nor irreversible, the end point used for AEGL-2 development is considered a NOAEL for AEGL-2 effects.

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279 Phosphorus Trichloride AEGL-3 VALUES 10 min 30 min 1h 4h 8h 7.0 ppm 7.0 ppm 5.6 ppm 3.5 ppm 1.8 ppm Reference: Weeks, M.H., N.P. Mussleman, P.P. Yevich, K.H. Jacobson, and F.W. Oberst. 1964. Acute vapor toxicity of phosphorus oxychloride, phosphorus trichloride and methyl phosphonic dichloride. Am. Ind. Hyg. J. 25: 470-475. Test Species/Strain/Number: female rats /strain not specified/20 per group Exposure Route/Concentrations/Durations: inhalation/median lethal concentrations derived but exposure concentrations not specified/4 h Toxicity End Point: estimated lethality threshold by 3-fold reduction of rat 4-h LC50 of 104.3 ppm Time Scaling: The concentration-time relationship for many irritant and systemically acting vapors and gases may be described by Cn × t = k, where the exponent n ranges from 0.8 to 3.5. Due to the limited toxicity data for this chemical, an empirical derivation of n was not possible. In the absence of an empirically derived exponent (n), and to obtain conservative and protective AEGL values, temporal scaling was performed using n = 3 when extrapolating to shorter time points and n = 1 when extrapolating to longer time points using the Cn × t = k equation. (34.8 ppm)1 × 4 h = 139.2 ppm-h (n = 1) (34.8 ppm)3 × 4 h = 168,576.8 ppm3-h (n = 3) Concentration/Time Selection/Rationale: a 3-fold reduction of the rat 4-h LC50 (104.3 ppm/3 = 34.8 ppm) was used as an estimate of the lethality threshold. Uncertainty Factors/Rationale: Total Uncertainty: 10 Interspecies UF = 3 Data for humans and animals indicate some variability in the toxic response to phosphorus trichloride but LC50 values for rodents exhibited approximately a 2-fold difference. Intraspecies UF = 3 The uncertainty for intraspecies variability was limited to 3 because primary effects of phosphorus trichloride (irritation and subsequent tissue damage) appear to be due, in part, to hydrogen chloride and phosphonic acid resulting from chemical dissociation and the direct corrosive action of these on mucosal surfaces. The overall uncertainty factor adjustment of 10 may be justified by limited human exposure data suggesting that humans could experience exposures of up to 27 ppm without life-threatening consequences. Furthermore, the results of a multiple exposure studies in rats (11 ppm 6 h/day, 5 days/week for 4 weeks) showed only histologic changes in the upper respiratory tract and no overt signs of toxicity. Modifying Factor: None applied Animal-to-Human Dosimetric Adjustments: Insufficient data (Continued)

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280 Acute Exposure Guideline Levels AEGL-3 VALUES Continued 10 min 30 min 1h 4h 8h 7.0 ppm 7.0 ppm 5.6 ppm 3.5 ppm 1.8 ppm Data adequacy: Lethality data are limited to two species and quantitative data for humans are limited. However, comparison of the AEGL-3 values with available data does not support application of uncertainty adjustment greater than that currently applied. Data suitable for determining exposure-time relationships are also lacking and impact on temporal extrapolation efforts. A delayed response is possible as demonstrated in the Weeks et al. (1964) study in which deaths of guinea pigs occurred up to 10 days post exposure.

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281 Phosphorus Trichloride APPENDIX C CATEGORY PLOT FOR PHOSPHORUS TRICHLORIDE Chemical Toxicity - TSD All Data Phosphorus trichloride 1000 Human - No Effect Human - Discomfort 100 Human - Disabling Animal - No Effect ppm 10 Animal - Discomfort AEGL-3 Animal - Disabling 1 AEGL-2 Animal - Some Lethality Animal - Lethal AEGL-1 AEGL 0 0 60 120 180 240 300 360 420 480 Minutes FIGURE 6-1 Category plot for phosphorus trichloride.