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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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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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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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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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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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Phosphorus Trichloride
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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-
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htmlgen?HSDB [accessed Dec. 7, 2010].
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Centers for Disease Control, National Institute for Occupational Safety and Health,
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www.lasrook.net/lasrookNL/maclijst2004.htm [accessed Dec. 6, 2010].
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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
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Guide to Chemical Hazards: Phosphorus Trichloride. U.S. Department of Health and
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for Selected Airborne Contaminants, Vol. 2. Washington, DC: National Academy
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NRC (National Research Council). 1993. Guidelines for Developing Community Emer-
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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
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Dec. 7, 2010].
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272 Acute Exposure Guideline Levels
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Wason, S., I. Gomolin, P. Gross, S. Mariam, and F.H. Lovejoy. 1984. Phosphorus trichlo-
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Acute vapor toxicity of phosphorus oxychloride, phosphorus trichloride and
methyl phosphonic dichloride. Am. Ind. Hyg. J. 25:470-475.
OCR for page 273
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.
