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5
Phosphorus Oxychloride1
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 have
been defined as follows:
AEGL-1 is the airborne concentration (expressed as parts per million
[ppm] or milligrams per cubic meter] mg/m3]) of a substance at or above which
it is predicted that the general population, including susceptible individuals,
could experience notable discomfort, irritation, or certain asymptomatic, non-
1
This document was prepared by the AEGL Development Team composed of Robert
Young (Oak Ridge National Laboratory) and Tom Hornshaw (National Advisory Com-
mittee [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 has concluded that
the AEGLs developed in this document are scientifically valid conclusions based on the
data reviewed by the NRC and are consistent with the NRC guidelines reports (NRC
1993, 2001).
227
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228 Acute Exposure Guideline Levels
sensory effects. However, the effects are not disabling and are transient and re-
versible 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 levels that
could produce mild and progressively increasing but transient and nondisabling
odor, taste, and sensory irritation or certain asymptomatic, nonsensory effects.
With increasing airborne concentrations above each AEGL, there is a progres-
sive increase in the likelihood of occurrence and the severity of effects described
for each corresponding AEGL. Although the AEGLs 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 corresponding AEGL.
SUMMARY
Phosphorus oxychloride is a colorless fuming liquid with a pungent odor.
It is stable to over 300°C but is highly reactive with water yielding phosphoric
acid and hydrogen chloride. It is used in the manufacture of plasticizers, hydrau-
lic fluids, gasoline additives, fire-retarding agents, and in the manufacture of
alkyl and aryl orthophosphate trimesters.
Information regarding exposure of humans to phosphorus oxychloride are
qualitative reports that indicate notable dermal, ocular, pharyngeal, and pulmo-
nary irritation following acute and subchronic (intermittent) exposures. Most
reports lacked exposure concentrations, with the exception of one report of oc-
cupational exposure to phosphorus oxychloride of 1.6-11.2 ppm. Effects often
persisted after cessation of exposure, especially in individuals experiencing
more severe effects. Neither odor detection data nor lethality data are available
for humans.
Quantitative data in animals are limited to reports of lethality. These data
include a 4-h LC50 (concentration lethal to 50% of test animals) of 44.4 ppm for
rats and 52.5 ppm for guinea pigs, and an unverified 4-h LC50 of 32 ppm for rats.
A 5-15 min exposure of rats and guinea pigs to phosphorus oxychloride at 0.96
ppm was stated to be a “threshold response” in one report. A brief report from
industry indicated immediate adverse responses (at 2 min) and death (18 min)
after exposure to a very high concentration (25,462 ppm). The studies affirm the
extreme irritation properties of phosphorus oxychloride, although the exposures
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Phosphorus Oxychloride
described also resulted in lethality. No information was available on reproduc-
tive and developmental toxicity, genotoxicity, or carcinogenicity.
There are no definitive data regarding the metabolism or precise mecha-
nism of action of phosphorus oxychloride toxicity. On the basis of the available
human and animal toxicity data and the chemical properties of phosphorus oxy-
chloride, it was assumed that the primary effect is damage to mucosal surfaces
and, for respiratory effects, subsequent pulmonary edema. The lethal potency of
phosphorus oxychloride, however, does not appear to be explained simply by
the action of its degradation products (phosphoric acid and hydrogen chloride).
AEGL-1 values were not derived for phosphorus oxychloride. No human
or animal data relevant to the derivation of any AEGL-1 for phosphorus oxy-
chloride were located.
AEGL-2 values were not derived for phosphorus oxychloride. No expo-
sure-response data relevant to the derivation of any AEGL-2 were located. Esti-
mating AEGL-2 values by a reduction in AEGL-3 values was considered tenu-
ous and difficult to justify in the absence of such data.
AEGL-3 values were developed using an estimate of the lethality thresh-
old on the basis of a 4-h LC50 of 48.4 ppm in rats (Weeks et al. 1964). Although
exposure-response data were unavailable, the lethality threshold was estimated
as one-third of the 4-h LC50 (48.4 ppm ÷ 3 = 16.1 ppm). This is also justified
because many respiratory tract irritants have exposure-response relationships in
which the transition from progressive irritation and repairable epithelial tissue
damage to lethal pulmonary damage occurs abruptly. Because of uncertainties
regarding species variability in the lethal response to phosphorus oxychloride
and the lack of lethality data in humans, an order-of-magnitude uncertainty ad-
justment was applied for interspecies variability. Contact irritation resulting in
damage to mucosal surfaces appears to be involved in the toxic response to
phosphorus oxychloride. This response is probably a function of the extreme
reactivity of phosphorus oxychloride and its dissociation products with tissues
(especially pulmonary mucosal surfaces), and probably does not vary greatly
among individuals. Therefore, the uncertainty adjustment selected for intraspe-
cies variability was 3. A larger uncertainty factor would result in AEGL-3 val-
ues that are inconsistent with human data. The concentration exposure and time
relationship for many irritant and systemically acting vapors and gases may be
described by the equation Cn × t = k, where the exponent n ranges from 0.8 to
3.5. In the absence of an empirically-derived exponent (n), conservative and
protective AEGL values were calculated by temporal scaling; n = 3 when ex-
trapolating to shorter time points and n = 1 when extrapolating to longer time
points.
The AEGL values for phosphorus oxychloride are presented in Table 5-1.
The range of interspecies variability remains uncertain because of sparse animal
data and the lack of quantitative exposure-response data for humans. The lack of
exposure-response data for nonlethal effects in animals or humans is a signifi-
cant data deficiency.
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230 Acute Exposure Guideline Levels
1. INTRODUCTION
Phosphorus oxychloride is a colorless, clear, fuming liquid with a musty,
pungent odor. No odor threshold data are available. Phosphorus oxychloride is a
chlorinating agent used in the manufacture of plasticizers, hydraulic fluids, gaso-
line additives, and fire retarding agents (O’Neil et al. 2001). It is also used ex-
tensively in the manufacture of alkyl and aryl orthophosphate triesters. The
physicochemical data on phosphorus oxychloride are presented in Table 5-2.
The chemical is stable to >300ºC but is highly reactive with water yielding
phosphoric acid and hydrogen chloride. The decomposition reaction is:
POCl3 + 3H2O → H3PO4 + 3HCl
TABLE 5-1 Summary of AEGL Values for Phosphorus Oxychloridea
Classification 10 min 30 min 1h 4h 8h End Point (Reference)
AEGL-1 Not recommended
(Nondisabling)
AEGL-2 Not recommended
(Disabling)
AEGL-3 1.1 ppm 1.1 ppm 0.85 ppm 0.54 ppm 0.27 ppm Estimate of lethality
(Lethality (6.9 (6.9 (5.3 (3.4 (1.7 threshold in rats
mg/m3) mg/m3) mg/m3) mg/m3) mg/m3) (16.1 ppm); 3-fold
reduction in 4-h
LC50 of 48.4 ppm
(Weeks et al. 1964)
a
Absence of AEGL-1 and AEGL-2 values does not imply that exposure below the
AEGL-3 is without adverse effect.
TABLE 5-2 Chemical and Physical Data for Phosphorus Oxychloride
Parameter Value Reference
Synonyms Phosphoryl chloride, phosphorus Fee et al. 1996; O’Neil et
chloride, phosphorus oxytrichloride, al. 2001; RTECS 2009
trichlorophosphine oxide,
trichlorophosphorus oxide
CAS registry number 10025-87-3 O’Neil et al. 2001
Chemical formula POCl3 O’Neil et al. 2001
Molecular weight 153.33 O’Neil et al. 2001
Physical state Liquid O’Neil et al. 2001
Melting point 1.25°C O’Neil et al. 2001
Boiling point 105.8°C O’Neil et al. 2001
Density 1.645 at 25°C O’Neil et al. 2001
Solubility Decomposes in water and alcohol Fee et al. 1996
Vapor pressure 40 mmHg (27.3°C) HSDB 2009
1 ppm = 6.27 mg/m3
Conversion factors in air NIOSH 2005
1 mg/m3 = 0.16 ppm
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Phosphorus Oxychloride
2. HUMAN TOXICITY DATA
2.1. Acute Lethality
No data were available regarding the acute lethality of phosphorus oxy-
chloride in humans.
2.2. Nonlethal Toxicity
Most information on acute exposure of humans to phosphorus oxychloride
is from secondary sources (ACGIH 1991; O’Neil et al. 2001). The following
signs and symptoms were reported for acute exposures: headache, respiratory
tract and eye irritation, chest pain, dyspnea, and nephritis. Chronic asthma-like
conditions after acute exposure have also been reported (Sassi 1954; HSDB
2009). However, exposure-response data for these responses are lacking. Al-
though there are no reports that provide quantitative data appropriate for AEGL
development, they do affirm that the respiratory tract is a primary target for
toxic responses following acute inhalation exposure to phosphorus oxychloride.
An accident involving an explosive release of phosphorus oxychloride,
hydrogen chloride, oxalic acid, phosphorus pentachloride, and oxalyl chloride
was reported by Rosenthal et al. (1978). Eight men and three women, ages 22-56
years, were exposed for approximately 30 sec to 2 min (the time required to es-
cape from the contaminated area). The major signs and symptoms of exposure
were wheezing, shortness of breath, conjunctivitis, and coughing. Nine people
exhibited effects on ventilatory function; six recovered within a few days. In the
other three individuals, disturbances in respiratory function returned to normal
after 4 wk in one patient and 2.5 mo in the second, but persisted after 2 y in the
third patient. The applicability of this report to AEGL development is question-
able because of the lack of data on exposure concentrations and of concurrent
exposure to other chemicals that have similar toxic effects.
Sassi (1954) described 20 cases of acute and subchronic occupational ex-
posure in the manufacture of phosphorus oxychloride. Exposure concentrations
varied from 10-20 mg/m3 (1.6-3.2 ppm) for normal conditions to 70 mg/m3 (11.2
ppm) for accidents. The signs and symptoms of acute exposures included irrita-
tion of the eyes and throat, dyspnea, dry cough, and bronchial stenosis (occur-
ring several days after exposure). Long-term exposures resulted in more severe
effects, including conditions characterized as asthmatic bronchitis and emphy-
sema. Although concentrations for various exposure situations were provided in
the report, there were no information on exposure durations.
Velsicol Chemical Corporation (1978) reported eye irritation in a worker
exposed to phosphorus oxychloride. No information was provided on the con-
centrations to which the worker was exposed nor the severity of the irritation.
The worker did, however, return to work; a 3-d “probable length of disability”
was noted.
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232 Acute Exposure Guideline Levels
A health hazard evaluation conducted by the National Institute of Occupa-
tional Safety and Health (NIOSH) of the FMC Corporation plant in Nitro, West
Virginia, reported that workers with known repeated exposures to phosphorus
oxychloride or phosphorus trichloride experienced a significantly higher (p
< 0.001) prevalence (65%) of respiratory symptoms (chest tightness, wheezing,
difficulty breathing) compared with unexposed workers (5%) (Tharr and Singal
1980). However, no correlation was found between results of pulmonary func-
tion tests on the workers and exposure to these chemicals. The study involved 37
exposed workers and 22 unexposed workers. Most air samples were below de-
tection limits, although one employee (wearing a chlorine gas mask) was ex-
posed to phosphorus oxychloride at approximately 4 mg/m3 for about 25 min; no
effects reported for this individual.
A follow-up study by NIOSH on 26 of the exposed workers and 11 of the
unexposed workers at FMC Corporation reported that half of the exposed work-
ers 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 1981). Results of pulmonary
function tests did not reveal significant effects from exposure to phosphorus
oxychloride (or phosphorus trichloride). No significant difference in pulmonary
function (FEV1) was found in the exposed workers compared with the unex-
posed workers over a 2-y period. The small sample size reduces the power of the
study to detect such changes and, therefore, compromises the apparent negative
finding. Additionally, it appeared that the pulmonary function tests were per-
formed after the occurrence of the symptoms noted in the questionnaires com-
pleted by the workers.
On January 22, 1984, approximately 6,500 gallons of phosphorus oxychlo-
ride were released from a large storage tank at a chemical plant in Sauget, Illi-
nois, as a result of an icicle shearing a pipe nipple off the tank (T. Hornshaw,
Office of Chemical Safety, Illinois EPA, pers. communication, 2009). The
plume affected seven employees, and moved into neighboring Rush City, Illi-
nois. Thirty five citizens were treated at area hospitals, most from a neighbor-
hood approximately one-half mile from the plant. The most common signs and
symptoms were respiratory tract irritation and stomach pain. Five citizens were
admitted overnight but none were in serious condition, and were later released.
All of the affected employees were examined by a company physician and were
cleared to resume work the same day. No measurements of airborne concentra-
tions were taken.
2.3. Developmental and Reproductive Toxicity
No human developmental and reproductive toxicity data concerning phos-
phorus oxychloride were found.
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Phosphorus Oxychloride
2.4. Genotoxicity
No human genotoxicity data on phosphorus oxychloride were found.
2.5. Carcinogenicity
No human data were found regarding the carcinogenic potential of phos-
phorus oxychloride.
2.7. Summary
Most information on the toxic response of humans to phosphorus oxy-
chloride is from secondary reports that lack quantitative exposure-response data.
The chemical appears to be extremely irritating to the respiratory tract and other
mucous membranes. Both port-of-entry and systemic effects have been reported.
Primary reports describe occupational exposures to phosphorus oxychloride, but
they involve simultaneous exposures to other irritating chemicals (e.g., hydrogen
chloride, oxalic acid, phosphorus pentachloride, oxalyl chloride) and lack infor-
mation on exposure concentrations and durations. The reports affirm signs and
symptoms of nasopharyngeal, ocular, and dermal irritation, and ventilatory dys-
function following acute exposures. Concurrent exposures to other chemicals,
especially those having the same effects and targets as phosphorus oxychloride,
compromise the usefulness of human exposure data for quantitative determina-
tion of AEGL values.
3. ANIMAL TOXICITY DATA
3.1. Acute Lethality
Quantitative data on the acute lethality of phosphorus oxychloride are
from a single study in rats and guinea pigs, and an unverified 4-h LC50 value for
rats.
3.1.1. Rats
Weeks et al. (1964) reported on the acute lethality of phosphorus oxychlo-
ride in female rats. The experimental protocol consisted of a group of 20 young
adult female rats (strain not specified) exposed to phosphorus oxychloride (con-
centrations not provided) followed by a 14-d observation period. Another group
of 20 rats was similarly exposed to phosphorus oxychloride and ammonia (for
neutralization of hydrolysis products). The test vapors were generated by pass-
ing dried nitrogen through the liquid test article. The vapors were then mixed
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234 Acute Exposure Guideline Levels
with influent air before being pumped into the chamber. Test article concentra-
tions were determined by collection and weighing of material on a filter. These
samples were also analyzed for phosphorus, nitrogen, and chloride. The test
atmospheres were calculated as microgram of phosphorus per liter of air (μg/L)
and as micromoles of phosphorus oxychloride per mole of air (µmole/mole).
The latter expression assumed no hydrolysis of the test material (hydrolysis,
however, was calculated to be about 15%). During exposure, rats exhibited signs
of irritation (pawing and scratching of the nose and head) and had porphyrin
secretions around the eyes. Gasping and convulsions preceded death which oc-
curred within 48 h. No further details were provided regarding time of deaths.
The 4-h LC50 for rats was reported as 48.4 μmole/mole (48.4 ppm). Neutraliza-
tion with ammonia lowered the 4-h LC50 to 44.4 μmole/mole (44.4 ppm). Al-
though simultaneous exposure to ammonia reduced or eliminated signs of irrita-
tion, it resulted in gross and microscopic pathologic findings (dark red lungs,
desquamation of respiratory tract epithelium, and plugging of bronchial and
bronchiolar lumens). The LC50 values do not necessarily imply that the test ma-
terial was in a vapor from. In fact, it is probable that vapor and aerosol forms
were present in the exposure atmosphere. With the exception of the median le-
thal concentration values, no other exposure-response data were provided.
In a study by Molodkina (1974), acute inhalation exposure of rats to lethal
or near-lethal concentrations of phosphorus oxychloride resulted in immediate
signs of irritation (rubbing of faces and restlessness). The rats exhibited inactiv-
ity and decreased respiration after 5-15 min, followed by convulsions. Rats that
survived showed continued lacrimation and corneal opacities, and ulcers around
the mouth several days after exposure ended. The report identified a “threshold
concentration” of 0.006 mg/L (0.96 ppm) on the basis of “integrated characteris-
tics.” It is unclear as to what effect this threshold pertains or the precise nature
of the “integrated characteristics.” Information in this report affirms the irrita-
tion and lethal capacity of phosphorus oxychloride after acute inhalation expo-
sure.
Details regarding a 4-h LC50 of 32 ppm for rats in a 1972 study (Marhold
1972 as cited in RTECS 2009) were unavailable for analysis and could not be
verified.
The results of an inhalation study in rats were provided in a brief report by
Monsanto (1991). Male Sprague-Dawley rats (number not specified) were ex-
posed to phosphorus oxychloride at 159.7 mg/L (25,462 ppm) for 18 min. Con-
ditions in the 35-L chamber were: 25°C, 85% humidity, and 4.0 L/min airflow.
The concentration of the test material was such that there was a fog in the cham-
ber. Within 2 min the rats were having difficulty breathing and their eyes were
closed. After 10 min, weakness, convulsions, and collapse were observed, and
one rat died. All rats were dead after 18 min. Necropsy revealed lung conges-
tion. No further details were provided.
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Phosphorus Oxychloride
3.1.2. Guinea pigs
Weeks et al. (1964) conducted experiments using groups of 10 male
guinea pigs. The experimental protocol was the same as that described for the
experiments with rats. The response of the guinea pigs was consistent with ex-
posure to an irritating chemical (restlessness, lacrimation, pawing at nose and
head). The 4-h LC50 was 52.5 μmole/mole (52.5 ppm). Deaths occurred within
48 h after exposure; no further details were provided. Neutralization of the
phosphorus oxychloride with ammonia resulted in a lowering of the LC50 to 41.3
μ mole/mole (41.3 ppm). As in the study with rats, simultaneous exposure of the
guinea pigs to ammonia appeared to decrease the irritation responses to the
phosphorus oxychloride but increase overall toxicity. The series of exposures
and the respective responses used to obtain the median lethal concentration were
not provided and, therefore, no other exposure-response data are available.
The previously discussed (Section 3.1.1) study by Molodkina (1974) also
examined the response of guinea pigs to acute inhalation of phosphorus oxy-
chloride. Lacrimation and corneal opacities were reported for animals after acute
exposure to lethal or near lethal concentrations. No other details were reported.
3.2. Nonlethal Toxicity
Definitive exposure-response data for nonlethal toxicity in animals were
not available. Weeks et al. (1964) and Molodkina (1974) reported that acute
inhalation of phosphorus oxychloride (for up to 4 h) by rats and guinea pigs re-
sulted in severe irritation (rubbing of face, lacrimation, porphyrin secretions,
desquamation of pulmonary epithelium), but the precise concentrations and ex-
posure durations were not provided. The only exposure-duration data provided
were median lethality values. Thus, it is difficult to determine concentrations of
phosphorus oxychloride that might cause nonlethal responses without potential
for lethality.
3.3. Developmental and Reproductive Toxicity
No animal developmental and reproductive toxicity data concerning phos-
phorus oxychloride were found.
3.4. Genotoxicity
No animal genotoxicity data on phosphorus oxychloride were found.
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236 Acute Exposure Guideline Levels
3.5. Carcinogenicity
No animal data were found regarding the carcinogenic potential of phos-
phorus oxychloride.
3.6. Summary
Quantitative exposure-response toxicity data in animals were from lethal-
ity studies rats and guinea pigs (Table 5-3). A report by Weeks et al. (1964) pro-
vided an adequate description of the experimental protocol and 4-h LC50 value
for rats (44.4 ppm) and guinea pigs (52.5 ppm). A study by Molodkina (1974)
also examined the toxic response of rats and guinea pigs to inhaled phosphorus
oxychloride; exposure to phosphorus oxychloride at 0.96 ppm for 5-15 min was
considered a threshold response. However, the characteristics of the responses or
what constituted the “threshold” were not provided. A brief report from Mon-
santo (1991) showed immediate adverse responses (after 2 min) and death (after
18 min) after exposure to phosphorus oxychloride of 25,462 ppm. Acute lethal-
ity values from a secondary source could not be verified. The available studies
affirm the extreme irritation properties of phosphorus oxychloride, although the
exposure concentrations described also resulted in lethality. No information was
available regarding reproductive and developmental toxicity, genotoxicity, or
carcinogenicity.
4. SPECIAL CONSIDERATIONS
4.1. Metabolism and Disposition
No data on the metabolism and disposition of phosphorus oxychloride
were found.
TABLE 5-3 Acute Lethality of Phosphorus Oxychloride in Laboratory Animals
Species Lethality Value Reference
Rat 4-h LC50 = 48.4 ppm Weeks et al. 1964
Rat 4-h LC50 = 32 ppm (not verified) Marhold 1972 as cited in
RTECS 2009
Rat 100% lethality = 25,462 ppm Monsanto 1991
after 18 min
Guinea pig 4-h LC50 = 52.5 ppm Weeks et al. 1964
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Phosphorus Oxychloride
4.2. Mechanism of Toxicity
The precise mechanism of toxicity of inhaled phosphorus oxychloride has
not been elucidated. The irritant properties of phosphorus oxychloride might be
from its decomposition products, phosphoric acid and hydrogen chloride. How-
ever, the acute lethality of phosphorus oxychloride appears to be greater than
from the decomposition products alone. For example, the 1-h LC50 values for
phosphoric acid and hydrochloric acid in rats are >212 ppm and 3,124 ppm, re-
spectively, whereas the 1-h LC50 for phosphorus oxychloride is 76 ppm (esti-
mated by temporal extrapolation from 4-h data). Although the acute lethality of
inhaled phosphorus oxychloride probably results from damage to the respiratory
epithelium and pulmonary edema, the role of delivery to this target tissue re-
mains uncertain. Exposure to phosphorus oxychloride might allow the formation
of larger concentrations of phosphoric acid and hydrochloric acid in the lungs
than would be possible from exposures to each of the chemicals alone. This
would cause greater damage and explain, in part, the greater toxicity of phos-
phorus oxychloride.
4.3. Structure-Activity Relationships
Barbee et al. (1995) conducted an acute toxicity study in which groups of
10 rats were exposed to oxalyl chloride (COCl)2 at 0, 462, 866, 1,232, 1,694, or
2,233 ppm for 1 hr. The 1-h LC50 was 1,840 ppm. The acute lethality of oxalyl
chloride was similar to that of hydrogen chloride, but oxalyl chloride was much
less toxic than phosphorus oxychloride. Because the toxicity of phosphorus oxy-
chloride appears to be greater than that of hydrogen chloride, it is unlikely that
the mechanisms of toxicity for the two chemicals are the same. Thus, the devel-
opment of AEGL values on the basis of analogy to hydrogen chloride produc-
tion alone might underestimate the toxic potential of phosphorus oxychloride.
Phosphorus trichloride produces many of the same signs and symptoms as
phosphorus oxychloride after acute inhalation exposures (Weeks et al. 1964;
ACGIH 1991) and also undergoes rapid hydrolysis to hydrogen chloride and
phosphonic acid. Data from rats and guinea pigs (Weeks et al. 1964) suggest
that the lethal potency of phosphorus oxychloride might be similar to that of
phosphorus trichloride. The rat 4-h LC50 values for both chemicals are approxi-
mately 50 ppm which supports the contention that they have similar toxicity.
Information on human exposures to phosphorus trichloride verify a potential for
irritation of the respiratory tract, nasopharyngeal region, eyes, and skin, and ef-
fects on ventilatory function (Wason et al. 1982, 1984). These human exposure
reports provide qualitative information on the toxic response to the chemical, but
lack measurements of exposure.
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Phosphorus Oxychloride
6. DATA ANALYSIS FOR AEGL-2
6.1. Summary of Human Data Relevant to AEGL-2
Quantitative exposure-response data in humans are not available for de-
velopment of AEGL-2 values for phosphorus oxychloride. Information regard-
ing the human experience is based on qualitative and semi-quantitative informa-
tion regarding signs and symptoms (respiratory tract irritation that might persist
for extended periods and ocular and dermal irritation) of exposed individuals.
The information in these reports suggest very brief exposure to phosphorus oxy-
chloride at low concentrations (1.6-3.2 ppm) might cause irritation severe
enough to impair egress from a contaminated area. Additionally, data from ani-
mal studies suggest that acute exposure to phosphorus oxychloride might cause
contact irritation damage (e.g., corneal opacities) that could be irreversible.
However, definitive exposure concentration and duration measurements were
lacking for these animal studies, thereby preventing exposure-response assess-
ments for AEGL-2 development.
6.2. Summary of Animal Data Relevant to AEGL-2
Animal data on effect severity consistent with AEGL-2 were based on
qualitative descriptions of responses in animals exposed to lethal or near-lethal
concentrations. Signs of exposure in these studies were consistent with extreme
irritation of the eyes, nasopharyngeal region, and the respiratory tract. However,
exposure concentration data and exposure duration data were not available.
6.3. Derivation of AEGL-2
Exposure-response data were not available for developing AEGL-2 values
for phosphorus oxychloride (Table 5-5). The lack of information regarding the
exposure-response relationship makes estimating AEGL-2 values by reducing
AEGL-3 values difficult to justify.
7. DATA ANALYSIS FOR AEGL-3
7.1. Summary of Human Data Relevant to AEGL-3
Information is not available regarding lethality in humans exposed to
phosphorus oxychloride.
TABLE 5-5 AEGL-2 Values for Phosphorus Oxychloride
10 min 30 min 1h 4h 8h
Not recommended
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240 Acute Exposure Guideline Levels
7.2. Summary of Animal Data Relevant to AEGL-3
Lethality data are based on 4-h LC50 values for rats and guinea pigs. Two
4-h LC50 values are available for rats: 48.4 ppm (Weeks et al. 1964) and 32 ppm
(Marhold 1972 as cited in RTECS 2009, unverifiable). A single 4-h LC50 for
guinea pigs is 52.5 ppm (Weeks et al. 1964). The range of exposure used to de-
termine these median lethal concentrations, however, were not reported. There-
fore, it is not possible to assess the exposure-response relationship. The avail-
able data suggest that species variability in the lethal response to phosphorus
oxychloride is not great. However, there is still uncertainty regarding the range
of susceptibility among species because data are available from only one well
described study on two species.
7.3. Derivation of AEGL-3
In lieu of additional data, the available 4-h LC50 values may be considered
for developing AEGL-3 values for phosphorus oxychloride. Because the rat ap-
pears to be a slightly more sensitive species than the guinea pig, the 4-h LC50 of
48.4 ppm identified by Weeks et al. (1964) was used as the basis for the AEGL-
3 values. The 32-ppm value reported in RTECS (2009) was not verified and,
therefore, was not used.
In the absence of complete data regarding the exposure-response curve
and assuming that the difference between nonlethal and lethal exposures is
small, the lethality threshold was estimated to be one-third of the 4-h rat LC50
(48.4 ppm/3 = 16.1 ppm). This extrapolation is also justified because many res-
piratory tract irritants have exposure-response relationships in which the transi-
tion from progressive irritation and repairable epithelial tissue damage to lethal
pulmonary damage occurs abruptly. A total uncertainty factor of 30 (10 for in-
terspecies variability and 3 for intraspecies variability) was used. The interspe-
cies uncertainty factor of 10 was maintained because there are data on only two
species (a single 4-h LC50 each for rats and guinea pigs) and no lethality data in
humans. Additionally, the study by Weeks et al. (1964) showed rats to be nota-
bly more sensitive to phosphorus oxychloride (4-h LC50 of 48.4 ppm) than to
phosphorus trichloride (4-h LC50 of 104. 3 ppm). Although signs of exposure in
humans are qualitatively similar to those observed in laboratory animals, there
are no quantitative exposure-response data in humans. An intraspecies uncer-
tainty factor of 3 was selected because a critical mechanism of phosphorus oxy-
chloride toxicity appears to involve irritation and destruction of pulmonary mu-
cosal surfaces; lethality resulting, at least in part, from damage to respiratory
tract epithelium. It is assumed that a basic contact irritation mechanism would
not vary greatly among individuals and that a 3-fold reduction would be suffi-
cient to protect individuals with moderately compromised respiratory function.
Further reduction of the AEGL-3 values by a greater uncertainty factor would
result in values inconsistent with occupational exposures reported by Sassi
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241
Phosphorus Oxychloride
(1954), where repeated exposures to concentrations up to 3.2 ppm resulted in
irritation and minor respiratory difficulties but not death. There are no data
available to determine a time-scaling factor. The concentration-exposure-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). In the absence of an empirically derived exponent (n), and to obtain
conservative and protective AEGL values, temporal scaling was performed us-
ing n = 3 when extrapolating to shorter time points and n = 1 when extrapolating
to longer time points. Because of uncertainties in extrapolating a 4-h exposure to
a 10-min exposure, the 10-min AEGL-3 is set equivalent to the 30-min AEGL-3
rather than using exponential scaling. The derivation of AEGL-3 values is
shown in Appendix A and the resulting values are summarized in Table 5-6.
8. SUMMARY OF PROPOSED AEGLS
8.1. AEGL Values and Toxicity Endpoints
The available toxicity data for phosphorus oxychloride indicate that irrita-
tion of the skin, eyes, nose, and respiratory tract are the most notable and often
reported signs of toxicity. Although these end points relevant to AEGL-1 and
AEGL-2 values, quantitative exposure-response data are lacking for develop-
ment of these values. Quantitative data on lethality in animals were available
and were considered appropriate for the basis of AEGL-3 development. The data
were, however, limited to a single study and two species.
8.2. Comparison with Other Standards and Guidelines
The World Health Organization (WHO 1989) reported that exposure
guidelines for phosphorus oxychloride range from 0.05-3 mg/m3 (0.008-0.48
ppm) in different countries. Standards and criteria for phosphorus oxychloride
are presented in Table 5-7.
8.3. Data Quality and Research Needs
Although qualitative data are available regarding the acute inhalation tox-
icity of phosphorus oxychloride in humans, quantitative exposure-response data
are lacking. Animal data include one study reporting LC50 values in rats and
guinea pigs. The animal data were sufficient for developing AEGL-3 values.
However, there are no data pertaining to the nonlethal responses in animals fol-
lowing inhalation exposure to phosphorus oxychloride. There are also insuffi-
cient data for determining the range of susceptibility among different species or
between the test animal species and humans.
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242 Acute Exposure Guideline Levels
TABLE 5-6 AEGL-3 Values for Phosphorus Oxychloride
10 min 30 min 1h 4h 8h
1.1 ppm 1.1 ppm 0.85 ppm 0.54 ppm 0.27 ppm
TABLE 5-7 Standards and Guidelines for Phosphorus Oxychloride
Exposure Duration
Guideline 10 min 30 min 1h 4h 8h
AEGL-1 Not recommended
AEGL-2 Not recommended
AEGL-3 1.1 ppm 1.1 ppm 0.85 ppm 0.54 ppm 0.27 ppm
a
TLV-TWA (ACGIH) 0.1 ppm
REL-TWA (NIOSH)b 0.1 ppm
c
REL-STEL (NIOSH) 0. 5 ppm
(15 min)
1.33 mg/m3
MAK Spitzenbegrenzung
(Germany)d (0.2 ppm)
0.6 mg/m3
MAC
(The Netherlands)e (0.1 ppm)
a
TLV-TWA (Threshold Limit Value-time-weighted average of the American Conference
of Governmental Industrial Hygienists) (ACGIH 2003) is the time-weighted average
concentration for a normal 8-h workday and a 40-h work week to which nearly all work-
ers may be repeatedly exposed, day after day, without adverse effect.
b
REL-TWA (recommended exposure limits-time-weighted average, National Institute for
Occupational Safety and Health) (NIOSH 2005) is analogous to the ACGIH-TLV-TWA.
c
REL-STEL (recommended exposure limits-short-term exposure limit, National Institute
for Occupational Safety and Health) (NIOSH 2005) is analogous to the ACGIH-TLV-
STEL.
d
MAK Spitzenbegrenzung (Kategorie II,2) [maximum workplace concentration (peak
limit category II,2)] (DFG 2002) constitutes the maximum average concentration to
which workers can be exposed for a period up to 30 min, with no more than two exposure
periods per work shift; total exposure may not exceed 8-h MAK.
e
MAC (maximaal aanvaarde concentratie [maximum accepted concentration]), Dutch
Expert Committee for Occupational Standards, The Netherlands (MSZW 2004) is analo-
gous to the ACGIH-TLV-TWA.
9. REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 1991. Phospho-
rus oxychloride. Pp. 1255-1256 in Documentation of the Threshold Limit Values
and Biological Exposure Indices, Vol. II, 6th Ed. American Conference of Gov-
ernmental Industrial Hygienists, Cincinnati, OH.
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Phosphorus Oxychloride
ACGIH (American Conference of Governmental Hygienists). 2003. TLVs and BEIs
Based on the Documentation of the Threshold Limit Values for Chemical Sub-
stances and Physical Agents and Biological Exposure Indices: Phosphorus Oxy-
chloride. American Conference of Governmental Hygienists, Cincinnati, OH.
AIHA (American Industrial Hygiene Association). 2009. Current AIHA ERPG Values
(2009). American Industrial Hygiene Association, Fairfax, VA [online]. Available:
http://www.aiha.org/foundations/GuidelineDevelopment/ERPG/Documents/ERP-
erpglevels.pdf [accessed Nov. 23, 2010].
Barbee, S.J., J.J. Stone, and R.J. Hilaski. 1995. Acute inhalation toxicology of oxalyl
chloride. Am. Ind. Hyg. Assoc. J. 56(1):74-76.
DFG (Deutsche Forschungsgemeinschaft). 2002. List of MAK and BAT Values 2002.
Maximum Concentrations and Biological Tolerance Values at the Workplace Re-
port No. 38. Weinheim, Federal Republic of Germany: Wiley VCH.
Fee, D.C., D.R. Gard, and C.H. Yang. 1996. Phosphorus compounds. Pp. 761-765 in
Kirk-Othmer Encyclopedia of Chemical Technology, Vol. 18. Paper to Pigment
Dispersions, 4th Ed., J. Kroschwitz, and M. Howe-Grant, eds. New York: Wiley.
HSDB (Hazardous Substances Data Bank). 2009. Phosphorus Oxychloride (CASRN
10025-87-3). 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 Nov. 23, 2010].
Marhold, J.V. 1972. Sbornik Výsledkù Toxikologického Vysetrení Látek a Pripravkù.
Institut pro Výchovu Vedoucich Pracovniku Chemického Prumyslu, Praha,
Czechoslovakia (as cited in RTECS 2009).
Molodkina, N.N. 1974. Comparative toxicity of the chloride compounds of phosphorus
(POCl3, PCl3, PCl5) in single and repeated exposures [in Russian]. Toksikol. Nov.
Prom. Khim. Veshchestv. 13: 107-114.
Monsanto Co. 1991. Initial Submission: Toxicity Studies on Phosphorus Oxychloride
(Final Report) with Cover Letter Dated 11/26/91. EPA Document No. 88-920
000388. U.S. Environmental Protection Agency, Washington, DC.
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: Fosforyltrichloride. Den Haag: SDU Uitgevers [online]. Available: http://
www.lasrook.net/lasrookNL/maclijst2004.htm [accessed Nov. 23, 2010].
NIOSH (National Institute for Occupational Safety and Health). 2005. NIOSH Pocket
Guide to Chemical Hazards: Phosphorus Oxychloride. U.S. Department of
Health and Human Services, Centers for Disease Control and Prevention, Na-
tional Institute for Occupational Safety and Health, Cincinnati, OH. September
2005 [online]. Available: http://www.cdc.gov/niosh/npg/npgd0508.html [ac-
cessed 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.
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244 Acute Exposure Guideline Levels
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 oxychloride. P. 1318
in The Merck Index: An Encyclopedia of Chemicals and Drugs, 13th Ed. White-
house Station, NJ: Merck.
Rosenthal, T., G.L. Baum, U. Fraud, and M. Molho. 1978. Poisoning caused by inhala-
tion of hydrogen chloride, phosphorus oxychloride, phosphorus pentachloride, ox-
alyl chloride, and oxalic acid. Chest 73(5):623-626.
RTECS (Registry of Toxic Effects of Chemical Substances). 2009. Phosphoryl chloride.
RTECS No. TH4897000. National Institute for Occupational Safety and Health
[online]. Available: http://www.cdc.gov/niosh-rtecs/TH4AB8E8.html [accessed
Nov. 29, 2010].
Sassi, C. 1954. Occupational poisoning by phosphorus oxychloride [in Italian]. Med.
Lav. 45(3):171-177.
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, West Virginia. HHE 78-90-739.
U.S. Department of Health and Human Services, Centers for Disease Control, Na-
tional Institute for Occupational Safety and Health, Cincinnati, OH.
Velsicol Chemical Corporation. 1978. Letter from Velsicol Chemical Corporation to U.S.
EPA Submitting Information on Phosphorus Oxychloride with Attachments. EPA
Document No. 88-7800080. Microfiche No. OTS 0200064. U.S. Environmental
Protection Agency, Washington, DC.
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. Hum. Toxicol. 24(4):275-
276.
Wason, S., I. Gomolin, P. Gross, S. Mariam, F.H. Lovejoy, Jr. 1984. Phosphorus trichlo-
ride toxicity: Preliminary report. Am. J. Med. 77(6):1039-1042.
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. Assoc. J. 25:470-475.
WHO (World Health Organization). 1989. Phosphorus Trichloride and Phosphorus Oxy-
chloride. Health and Safety Guide No. 35. IPCS International Programme on
Chemical Safety. Geneva: World Health Organization [online]. Available: http://
www.inchem.org/documents/hsg/hsg/hsg035.htm [accessed Dec. 1, 2010].
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245
Phosphorus Oxychloride
APPENDIX A
DERIVATION OF AEGL VALUES FOR
PHOSPHORUS OXYCHLORIDE
Derivation of AEGL-1
AEGL-1 values are not recommended because insufficient data. Absence
of AEGL-1 values does not imply that exposure below the AEGL-3 values are
without adverse effects.
Derivation of AEGL-2
AEGL-2 values are not recommended because of insufficient data. Ab-
sence of AEGL-2 values does not imply that exposure below the AEGL-3 values
are without serious or possibly irreversible adverse effects.
Derivation of AEGL-3
Key study: Weeks et al. 1964
Toxicity end point: Lethality threshold of 16.1 ppm in rats, estimated by
3-fold reduction in 4-h LC50 of 48.4 ppm.
Cn × t = k (n = 3 for extrapolating from longer to
Scaling:
shorter exposure periods and n = 1 for extrapolating
from shorter to longer exposure periods)
(16.1 ppm)1 × 4 h = 64.4 ppm-h
(16.1 ppm)3 × 4 h = 16,693.12 ppm-h
Uncertainty factors: 10 for interspecies variability
3 for intraspecies variability
10-min AEGL-3 1.1 ppm, set equal to the 30-min AEGL-3
C3 × 0.5 h = 16,693.12 ppm-h
30-min AEGL-3
C = 32.2 ppm
30-min AEGL-3 = 32.2 ppm/30 = 1.1 ppm
C3 × 1 h = 16,693.12 ppm-h
1-h AEGL-3
C = 25.56 ppm
1-h AEGL-3 = 25.56 ppm/30 = 0.85 ppm
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246 Acute Exposure Guideline Levels
C3 × 4 h = 16,693.12 ppm-h
4-h AEGL-3
C = 16.1 ppm
4-h AEGL-3 = 16.1 ppm/30 = 0.54 ppm
C1 × 8 h = 64.4 ppm-h
8-h AEGL-3
C = 8.05 ppm
8-h AEGL-3 = 8.05 ppm/30 = 0.27 ppm
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Phosphorus Oxychloride
APPENDIX B
ACUTE EXPOSURE GUIDELINES FOR
PHOSPHORUS OXYCHLORIDE
Derivation Summary for Phosphorus Oxychloride
AEGL-1 VALUES
10 min 30 min 1h 4h 8h
Not Not Not Not Not
recommended recommended recommended recommended recommended
Reference: Not applicable
Test Species/Strain/Number: Not applicable
Exposure Route/Concentrations/Durations: Not applicable
Toxicity End Point: Not applicable
Time Scaling: Not applicable
Concentration/Time Selection/Rationale: Not applicable
Uncertainty Factors/Rationale: Not applicable
Modifying Factor: Not applicable
Animal to Human Dosimetric Adjustments: Not applicable
Data Adequacy: Neither quantitative exposure-response data nor odor threshold
data were available for assessing AEGL-1 type effects for phosphorus oxychloride.
Therefore, AEGL-1 values are not recommended. The absence of AEGL-1
values does not imply that exposure below AEGL-3 levels is without effect.
AEGL-2 VALUES
10 min 30 min 1h 4h 8h
Not Not Not Not Not
recommended recommended recommended recommended recommended
Reference: Not applicable
Test Species/Strain/Number: Not applicable
Exposure Route/Concentrations/Durations: Not applicable
Toxicity End Point: Not applicable
Time Scaling: Not applicable
Concentration/Time Selection/Rationale: Not applicable
Uncertainty Factors/Rationale: Not applicable
Modifying Factor: Not applicable
Animal to Human Dosimetric Adjustments: Not applicable
(Continued)
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248 Acute Exposure Guideline Levels
AEGL-2 VALUES Continued
10 min 30 min 1h 4h 8h
Not Not Not Not Not
recommended recommended recommended recommended recommended
Data adequacy: Exposure-response data on nonlethal toxic responses were not
available for developing AEGL-2 values for phosphorus oxychloride. The absence
of such data precludes estimating AEGL-2 values by reducing AEGL-3 values.
Therefore, AEGL-2 values are not recommended. The absence of AEGL-2 values
does not imply that exposure below AEGL-3 levels is without serious or possibly
irreversible effect.
AEGL-3 VALUES
10 min 30 min 1h 4h 8h
1.1 ppm 1.1 ppm 0.85 ppm 0.54 ppm 0.27 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. Assoc. J. 25:470-475.
Test Species/Strain/Number: Rats (strain not specified)/20 per group
Exposure Route/Concentrations/Durations: Inhalation/concentrations varied but not
specified/4 h
Toxicity End Point: 4-h LC50 (48.4 ppm) for guinea pigs
Time Scaling: Cn × t = k, n = 3 for extrapolating from longer to shorter exposure
periods and n = 1 for extrapolating from shorter to longer exposure periods
Concentration/Time Selection/Rationale: A 3-fold reduction of 4-h LC50 (48.4 ppm/
3 = 16.1 ppm) for rats (the more sensitive species) was considered an estimate of the
lethality threshold
Uncertainty Factors/Rationale:
Total Uncertainty: 30
Interspecies: 10
Intraspecies: 3 was considered sufficient because the primary mechanism of action
involves a direct effect on respiratory epithelium which is unlikely to vary greatly
among individuals. The factor also is considered to be adequate for the protection of
individuals with moderately compromised respiratory function. Additional reduction
of the AEGL-3 values by a greater uncertainty factor would result in AEGL-3 values
that are inconsistent with occupational data and other guidelines.
Modifying Factor: None applied
Animal-to-Human Dosimetric Adjustments: Insufficient data
Data Adequacy: LC50 values available for only two species. These data were
considered sufficient for developing AEGL-3 values. Interspecies variability remains
uncertain because of the lack of data in additional species and definitive exposure
data in humans.
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Phosphorus Oxychloride
APPENDIX C
FIGURE 5-1 Category plot for phosphorus oxychloride.
