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Phosphine
CASRN 7803-51-2
Contents
0090
Phosphine; CASRN 7803-51-2
Health assessment information on a chemical substance is included in IRIS only
after a comprehensive review of chronic toxicity data by U.S. EPA health
scientists from several Program Offices and the Office of Research and
Development. The summaries presented in Sections I and II represent a
consensus reached in the review process. Background information and
explanations of the methods used to derive the values given in IRIS are
provided in the Background Documents.
STATUS OF DATA FOR Phosphine
File On-Line 01/31/1987
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) on-line 12/01/1993
Inhalation RfC Assessment (I.B.) on-line 07/01/1995
Carcinogenicity Assessment (II.) on-line 12/01/1996
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Phosphine
CASRN -- 7803-51-2
Last Revised -- 12/01/1993
The oral Reference Dose (RfD) is based on the assumption that thresholds exist
for certain toxic effects such as cellular necrosis. It is expressed in units
of mg/kg-day. In general, the RfD is an estimate (with uncertainty spanning
perhaps an order of magnitude) of a daily exposure to the human population
(including sensitive subgroups) that is likely to be without an appreciable
risk of deleterious effects during a lifetime. Please refer to the Background
Document for an elaboration of these concepts. RfDs can also be derived for
the noncarcinogenic health effects of substances that are also carcinogens.
Therefore, it is essential to refer to other sources of information concerning
the carcinogenicity of this substance. If the U.S. EPA has evaluated this
substance for potential human carcinogenicity, a summary of that evaluation
will be contained in Section II of this file.
___I.A.1. ORAL RfD SUMMARY
Critical Effect Experimental Doses* UF MF RfD
-------------------- ----------------------- ----- --- ---------
Body weight and NOEL: 0.51 mg/kg food 100 1 3E-4
clinical parameters converted to 0.026 mg/kg/day
mg/kg/day
Rat Chronic Oral
Study LOAEL: none
Hackenburg, 1972
*Dose Conversion Factors & Assumptions: Food consumption of 5% bw/day;
thus, 0.51 mg/kg of diet x 0.05 kg of diet/kg bw/day = 0.026 mg/kg bw/day
___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
Hackenburg, U. 1972. Chronic ingestion by rats of standard diet treated with
aluminum phosphide. Toxicol. Appl. Pharmacol. 23(1): 147-153.
This study reported a no effects dose level for rats fed diet fumigated with
phastoxin over a 2-year period. The mean phosphine concentration during that
time period was 0.51 mg/kg of feed. Based on an average 5% food consumption
and average rat body weight of 610.4 g (reported in the study), the phosphine
dose can be calculated as 0.026 mg/kg bw/day. Hackenburg (1972) found a
slight, statistically insignificant tendency for test females to gain weight
faster than their control counterparts. There were no other differences
between controls and treated rats in hemoglobin content, hematocrit,
differential white blood cell count, glucose levels, SGPT, serum urea,
prothrombin time, organ weights, or tissue histopathology. Survival rates and
tumor incidences were similar between controls and experimental animals.
___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF -- Application of an uncertainty factor of 100 (10 for intraspecies
extrapolation and 10 for sensitive population) to the rat NOEL of 0.026 mg/kg
yields an RfD of 0.02 mg/day.
MF -- None
___I.A.4. ADDITIONAL COMMENTS (ORAL RfD)
The ACGIH (1984) has recommended a TLV of 0.3 ppm (0.42 mg/cu.m) for
phosphine, based principally on an epidemiologic study by Jones et al. (1964).
In this study, workers exposed intermittently to about 10 ppm phosphine gas
experienced gastrointestinal, cardiorespiratory, and central nervous system
symptomatology. Based on the TLV, an RfD of 0.021 mg/kg/day can be
recommended. However, the Hackenburg (1972) study was a 2-year study in rats
which explored a number of functional and morphologic endpoints. This study
forms a better basis for an RfD.
___I.A.5. CONFIDENCE IN THE ORAL RfD
Study -- Medium
Data Base -- Medium
RfD -- Medium
Confidence in the study can be considered medium to low because only a
moderate number of animals/dose and one dose group was used, but an extensive
methodology was employed to assure proper administration of the test compound
and an extensive number of parameters were measured. The data base can be
considered medium to low because the effectiveness and safety of this chemical
has long been reported, but few experimental oral studies are available.
Thus, the overall rating for the RfD can be considered medium to low.
___I.A.6. EPA DOCUMENTATION AND REVIEW OF THE ORAL RfD
Source Document -- This assessment is not presented in any existing U.S. EPA
document.
Other EPA Documentation -- None
Agency Work Group Review -- 08/19/1985
Verification Date -- 08/19/1985
___I.A.7. EPA CONTACTS (ORAL RfD)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
__I.B. REFERENCE CONCENTRATION FOR CHRONIC INHALATION EXPOSURE (RfC)
Substance Name -- Phosphine
CASRN -- 7803-51-2
Last Revised -- 07/01/1995
The inhalation Reference Concentration (RfC) is analogous to the oral RfD and
is likewise based on the assumption that thresholds exist for certain toxic
effects such as cellular necrosis. The inhalation RfC considers toxic effects
for both the respiratory system (portal-of-entry) and for effects peripheral
to the respiratory system (extrarespiratory effects). It is expressed in
units of mg/cu.m. In general, the RfC is an estimate (with uncertainty
spanning perhaps an order of magnitude) of a daily inhalation exposure of the
human population (including sensitive subgroups) that is likely to be without
an appreciable risk of deleterious effects during a lifetime. Inhalation RfCs
were derived according to the Interim Methods for Development of Inhalation
Reference Doses (EPA/600/8-88/066F August 1989) and subsequently, according to
Methods for Derivation of Inhalation Reference Concentrations and Application
of Inhalation Dosimetry (EPA/600/8-90/066F October 1994). RfCs can also be
derived for the noncarcinogenic health effects of substances that are
carcinogens. Therefore, it is essential to refer to other sources of
information concerning the carcinogenicity of this substance. If the U.S. EPA
has evaluated this substance for potential human carcinogenicity, a summary of
that evaluation will be contained in Section II of this file.
___I.B.1. INHALATION RfC SUMMARY
Critical Effect Exposures* UF MF RfC
-------------------- ----------------------- ----- --- ---------
Decreased body weight NOAEL: 1.4 mg/cu.m 1000 1 3E-4
(1.0 ppm) mg/cu.m
Mouse Subchronic NOAEL(ADJ): 0.25 mg/cu.m
Inhalation Study NOAEL(HEC): 0.25 mg/cu.m
Barbosa et al., 1994 LOAEL: 6.3 mg/cu.m (4.5 ppm)
LOAEL(ADJ): 1.12 mg/cu.m
LOAEL(HEC): 1.12 mg/cu.m
*Conversion Factors and Assumptions: MW = 34. Assuming 25 C and 760 mmHg,
NOAEL (mg/cu.m) = NOAEL (ppm) x MW/24.45 = 1.4. NOAEL(ADJ) = 1.4 mg/cu.m x (6
hours/24 hours) x (5 days/7 days) = 0.25 mg/cu.m. The NOAEL(HEC) was
calculated for a gas:extrarespiratory effect, assuming periodicity was
attained. Because the lambda values are unknown for the experimental animal
species (a) and humans (h), a default value of 1.0 is used for this ratio.
NOAEL(HEC) = NOAEL(ADJ) x lambda(a)/(h) = 0.25 mg/cu.m.
___I.B.2. PRINCIPAL AND SUPPORTING STUDIES (INHALATION RfC)
Barbosa, A., E. Rosinova, J. Dempsey and A.M. Bonin. 1994. Determination of
genotoxic and other effects in mice following short-term, repeated-dose, and
subchronic inhalation exposure to phosphine. Environ. Molec. Mutagenesis.
24: 81-88.
Four groups of 24 Balb-c mice each (12/sex) were exposed to either air
(control), 0.3, 1.0, or 4.5 ppm phosphine, 6 hours/day, 5 days/week for 13
weeks. After duration adjustment and conversion, these concentrations
corresponded to 0.00, 0.07, 0.25, and 1.12 mg/cu.m, respectively. Exposures
were conducted by diluting concentrated phosphine gas with ambient air and
metering the appropriate mixture into the individual cages. Endpoints
evaluated were body weight and organ weights. Mice exposed to the highest
concentration showed signs of itching around the face, tail, and feet during
exposure and were less active at the end of each exposure than were other
groups. No neurological disturbances were noted in this group. At the end of
the exposure, there was a statistically significant inverse linear
relationship between body weight and concentration, independent of sex.
Biological significance, however, was attained only among females at the
highest exposure, where the average body weight following the 13-week exposure
period was 10% less than that of the corresponding control. Alterations in
some organ weights were noted, but they were not clearly related to dose and
could have been due to the variability in body weights. No other noncancer
endpoints were investigated or reported. A LOAEL of 4.5 ppm and a NOAEL of 1
ppm are designated based on this 10% decrease in final body weight, in
comparison with controls.
It is assumed that phospine is an in vivo inhibitor of oxidative
phosphorylation. This designation is not meant to imply a direct causal
relationship between the observed alteration in body weight and inhibition of
oxidative phosphorylation. It is, however, well established that the chronic
toxicity of other inhibitors of oxidative phosphorylation, such as cyanide
(Philbrick et al., 1979), dinitrophenol (Horner, 1942), pentachlorophenol
(Schwetz et al., 1978), and rotenone (U.S. Fish and Wildlife Service, 1983),
does include alterations in body weights. Thus, although the effects of
chronic phosphine exposure are still unknown, the actual adverse effects
reasonably may be expected to include body weight alterations such as those
observed in this subchronic study in mice and in the subchronic study of
Newton et al. (1993) with rats.
___I.B.3. UNCERTAINTY AND MODIFYING FACTORS (INHALATION RfC)
UF -- Full factors of 10 each are used for sensitive human subpopulations and
the use of a subchronic study. A partial factor of 3 is applied for
deficiencies in the data base (i.e., lack of multigenerational reproduction
studies). Newton et al. (1993) reported an absence of effects in respiratory
tract tissues subchronically exposed to phosphine. A partial factor of 3 also
is used for interspecies extrapolation due to the use of dosimetric
adjustments. The total uncertainty factor is 1000.
MF -- None
___I.B.4. ADDITIONAL STUDIES / COMMENTS (INHALATION RfC)
Acute exposure to phosphine can result in neurological, gastrointestinal,
and respiratory effects in humans (Price and Chambers, 1990; WHO, 1988; Gupta
et al., 1995). Twenty-two workers (mean age of 48 years) were examined after
fumigating with aluminum phosphide (Misra et al., 1988). Mean phosphine
concentration in the breathing zone of six workers during fumigation ranged
from 0.78-0.98 ppm (1.1-1.4 mg/cu.m, respectively). Respiratory symptoms
included suffocation, breathing difficulty, and chest tightness lasting from
15 minutes to 3 hours. Neurological symptoms, most commonly headaches (31.8%
of the workers), and gastrointestinal effects also were reported. After
touching the tablets, numbness and paraesthesia in the fingers were reported
in 13.6% of the workers. Alcohol consumption and smoking was reported in 50
and 68% of workers, respectively. These results are difficult to interpret
because no information regarding control groups, if any were employed, was
given.
Crew members aboard a grain freighter were exposed to phosphine gas
(Wilson et al., 1980). Symptoms that were prevalent in the exposed crew
included shortness of breath, cough, vomiting, fatigue, headache, drowsiness,
paresthesias, and tremor. The levels of phosphine in the ship ranged from
0.5-30 ppm. Gastrointestinal findings also were reported following phosphine
exposure. Platelet and erythrocyte count were reduced in an individual
poisoned by phosphine [Verga and Belloni, 1958 (cited in WHO, 1988)]. The
hemoglobin concentration was 55%. The patient recovered, and the
hematological levels returned to normal. Interpretation of these studies is
limited due to experimental protocol deficiencies. Also, the exposures in
these case studies are not to pure phosphine gas, but to reaction products of
metal phosphides that have not been chemically or toxicologically
characterized.
Barbosa and Bonin (1994) examined a small cohort of 31 fumigators who had
worked with phosphine for a mean of 11.6 years (range = 1.5-32 years).
Phosphine concentration in the breathing zone of fumigators was recorded
during eight fumigations, with the highest level recorded being 2.4 ppm/hour
(3.3 mg/cu.m/hour), although more typical concentrations were <0.1 ppm/hour.
These workers and 21 controls matched by sex, age, and smoking habit had
hematological profiles, whole serum and blood cholinesterase activities, and
several clinical biochemistry measures monitored. No significant effects were
seen in any parameter monitored, including genotoxic endpoints. These results
show no association between exposure and toxic effects at adjusted phosphine
concentrations of up to 0.2 mg/cu.m (3.3 mg/cu.m divided by 8 hours and
factored by 10/20 cu.m of air).
Newton et al. (1993) exposed Fischer 344 rats (30/sex/group) to either 0,
0.3, 1.0 or 3.0 ppm phosphine for 6 hours/day, 5 days/week (converted and
duration adjusted to 0, 0.07, 0.25, or 0.75 mg/cu.m, respectively), for 13
weeks. Ten animals/sex/group were sacrificed at the following intervals: 4
weeks (interim sacrifice), 13 weeks (terminal sacrifice), and 18 weeks
(recovery period). Because no major effects were observed in the 3-ppm group,
additional groups (10/sex/group) exposed to 5 or 10 ppm (1.75 or 3.50 mg/cu.m,
respectively, converted and duration adjusted) were included with
corresponding control groups. Animals were monitored for cage-side
observations, weight gain, and food consumption. Hematology and clinical
chemistry were performed. Histopathology was performed only in animals exposed
to 3, 5, or 10 ppm phosphine. Tissues examined included all major organs,
bone (sternum and femur), spleen, bone marrow, and the entire respiratory
tract, including the nasopharyngeal region (number of sections not specified).
Death came to 4/10 females on the third day of exposure to 10 ppm; the
remaining six animals were sacrificed on this day. There were no deaths in
the other exposed groups, including the males exposed to 10 ppm phosphine.
Mortality exhibited an extremely sharp concentration response, animals exposed
to 10 ppm for 18 hours died, whereas others exposed to 3 ppm for 13 weeks
exhibited few toxicological consequences. This sharp response has been
documented by Klimmer (1969) in rats and several other species. The animals
exposed to 5 ppm phosphine were exposed for only 13 days, with a 4-week
recovery period. Renal tubular necrosis was noted in animals but only those
exposed at the lethal concentration of 10 ppm. Congested lungs were noted in
the four females that died of exposure to 10 ppm phosphine. Hemoglobin
concentration, hematocrit, and erythrocyte count were decreased in male rats,
but the changes were slight (<10%) and, under these exposure conditions, were
not considered toxicologically significant. There were no biologically
significant effects on organ weights in any exposure group. Minor effects
that were of questionable toxicological significance and not concentration
related were noted in the nasopharynx (submucosal glandular concretions) of
both treated and control animals. Minor decreases in body weight gain
(relative to controls) were noted in both sexes. The decrease noted at the
highest concentration was approximately 7% for males and 4% for females.
Although these alterations did not achieve biological significance, they do
support the decreased body weight gain reported in the Barbosa et al. (1994)
study. The histopathology performed on the nasal tract tissues provides the
minimum data base requirements for the derivation of an RfC.
In a series of inhalation experiments with widely ranging durations and
concentrations of phosphine exposures, Klimmer (1969) elucidated a sharp
concentration response for phosphine-related mortality, proposed and presented
data for a concentration (C) x time (T) relationship for mortality, and
demonstrated this relationship to apply across a number of species. Exposure
of rats to either 25 ppm phosphine for a single 8-hour exposure or to 403 ppm
for 0.6 hour resulted in death; the C x T relationship being a parts per
million per hour value of 200 for the lower and 242 for the higher
concentration. This relationship was shown to closely predict mortality to
elevated concentrations of phosphine (5 ppm or greater) in other species
including cats, rabbits, and guinea pigs. When the phosphine concentration
was <5 ppm, however, mortality was not observed, despite extended exposure
periods. No mortality occurred in either cats, guinea pigs, or rats exposed
to 2.5 ppm phosphine for a parts per million per hour composite of 820, or
around fifty-five 6-hour exposures. Only minor toxicity was observed in
animals exposed to <5 ppm phosphine, although a number of endpoints, including
urine, blood, and liver function tests (cats only) were performed before, at
the midpoint, and at the end of the exposure periods. Gross and miscroscopic
histopathology is generally described for all major organs, including lungs
and brain. Mild, isolated cloudy swelling of renal tubular epithelium is
described in general for rats exposed to 2.5 ppm for a composite of 820 hours,
and mention is made of fatty liver in cats that also were exposed to this
regime. The general nature in which the results are presented in this study
precludes its selection as the principal study. The information provided on
mortality corroborates that reported by Newton et al. (1993).
Morgan et al. (1995) exposed groups of male and female B6C3F1 mice and
Fischer 344 rats (18/sex/group) to either 0 (air), 1.25, 2.50, or 5.00 ppm
phosphine gas for 6 hours/day, 5 days/week for up to 2 weeks (10 exposures).
When converted and duration adjusted, these concentrations correspond to 0,
0.31, 0.62, or 1.24 mg/cu.m. phosphine, respectively. Hematological and
clinical chemistry and body and organ weights were monitored. Histopathology,
including the nasal passages, larynx, and lung, was evaluated, but only in
animals exposed to the highest concentration. No mortality was noted. After
10 exposures, urea nitrogen levels were elevated slightly over control values
(13.2 mg/dL) at 1.25 ppm (20.2 mg/dL) and 5 ppm (21.1 mg/dL), but not at the
middle concentration. Lung weights of male rats and mice were significantly
decreased (21-29%), and heart weights of female rats and mice were
significantly increased (16-27%) after 10 exposures at the highest
concentration. Histopathology showed cardiomyopathy in controls (2/6 males,
1/6 females) and in the animals exposed to the highest concentration (1/6
males, 4/6 females), the only exposed group examined. The severity of this
lesion was minimal in all instances except for mild severity in one exposed
female. Based on an increase in heart weight and the severity of
cardiomyopathy in female rats, this study indicates a LOAEL of 1.24 mg/cu.m
and a probable NOAEL of 0.62 mg/cu.m.
In a study reported by Pazynich et al. (1984), male white rats (16/group)
were exposed either to air, 0.05, 0.20, 1.50, or 8.00 mg/cu.m phosphine for
1.5 months. The duration of the daily exposure is not stated. No other
experimental details are available. The authors claimed significant decreases
occurred in erythrocyte count and hemoglobin content at all concentration
levels, although no data are presented. A number of other endpoints of
questionable toxicological significance are examined and reported. No
scientific conclusions could be made from this report.
Waritz and Brown (1975) exposed six male Charles River-CD rats to 4 ppm
(5.6 mg/cu.m) phosphine, 4 hours/day for a total of 12 exposures over two
weeks. Pathology was performed and included histological examination of the
lungs, trachea, eyes, and kidneys. Mild respiratory irritation and
piloerection was observed in the exposed animals. No gross or histopathologic
effects were observed. Weight gain curves demonstrated an approximate 8%
decrease in body weight relative to controls that was followed by a normal
rate of weight gain during a 14-day recovery period.
Pregnant Sprague-Dawley rats (24/group) inhaled 0.03, 0.30, 3.00, 5.00, or
7.50 ppm (0.04, 0.40, 4.20, 7.00, and 10.40 mg/cu.m, respectively) phosphine
during gestational days 6-15 for 6 hours/day (Newton et al., 1993). Control
animals were exposed to room air only. Dams were sacrificed on gestational
day 20. Because of excessive mortality in the high-concentration group, this
concentration level was eliminated. Changes to body weight, food consumption,
and clinical signs were not found in any of the exposed groups. An increase
in dilated renal pelvises were reported in all groups, but this effect does
not appear to be concentration related. There was an increase in the total
resorptions per dam in animals exposed to 0.03 mg/cu.m (1.3) as compared with
controls (0.5) but not at any other higher concentration. No major treatment-
related fetal malformations were observed. A NOAEL of 5 ppm (7 mg/cu.m)
phosphine is determined for maternal, reproductive, or developmental toxicity.
The high incidence of maternal deaths at 7.5 ppm designates this level to be
an FEL. The proximity of the NOAEL and the FEL concentrations indicates that
this compound has an extremely steep concentration-response curve and provides
further corroboration for the results of Klimmer (1969) and the other portions
of the Newton et al. (1993) study.
To evaluate effects of inhaled phosphine on male germ cells, Kligerman et
al. (1994) exposed 50 male B6C3F1 mice for 6 hours/day for 10 days over a 12-
day period to 5 ppm (7 mg/cu.m) phosphine. These male mice were then mated to
groups of untreated female mice on each of six consecutive 4-day mating
intervals. None of the six groups of females exhibited a significant increase
in percent resorptions or implants/female, nor were any differences noted in
the percent of females impregnated by control or exposed males.
Phosphine is a reductant and, predictably, reacts with heavy metals such
as the iron in heme and the metals of metal-dependent enzymes present in cells
(Price and Chambers, 1990). In vitro experimental evidence has elucidated
extensive and specific information on the capability of phosphine to inhibit
mitochondrial respiration, apparently through this reductive capacity (Price
and Chambers, 1990). In studies with isolated mitochondria, Chefurka et al.
(1976) identified cytochrome c oxidase as the site in the electron transport
chain at which ATP synthesis is inhibited by phosphine. In vitro, phosphine
has been shown to react with the heme moiety of human hemoglobin in the
presence of oxygen (Potter et al., 1991). These authors reported that Heinz
bodies (aggregations of denatured hemoglobin) developed in human erythrocytes
following exposure to 1.25 ppm phosphine for 4 hours, with hemolysis observed
at 3 ppm. In vivo corroboration of these effects, however, is limited.
Inhibitory effects on mitochondrial respiration were not detected in insects
receiving a lethal dose of phosphine (Price and Chambers, 1990). No
biologically significant hematological alterations were noted in the in vivo
study of Biodynamics (1990). Klimmer (1969) noted marked decreases in blood
elements, but only at high (5 ppm) concentrations, and no effects at lower
concentrations in exposures extending for 24 weeks. Thus, the in vitro
effects on blood demonstrated by Potter et al. (1991) may not be manifest
under chronic in vivo exposure conditions. Isolated case reports have cited
red cell hemolysis. In a postmortem examination of a child poisoned by
phosphine, Wilson et al. (1980) reported hemolysis in conjunction with other
major pathology. Unstable hemoglobins are present in the human population
(Winterbourn, 1990), and there are no in vivo data to rule out a hypothesis
that these individuals would be at increased risk for adverse hematological
effects as a result of exposure to phosphine. The absence of a true chronic
study prevents evaluation of blood as a target tissue.
___I.B.5. CONFIDENCE IN THE INHALATION RfC
Study -- Medium
Data Base -- Low
RfC -- Low
The principal study was performed and reported in a thorough manner and
provided both a NOAEL and a LOAEL for an effect that was consistent with other
studies of phosphine (Newton et al., 1993) and with the effects of other known
inhibiters of oxidative phosphorylation. This analogy with other inhibitors
points out the potential for fallacy in relying solely on body weight
alterations to predict the array of toxicity that may actually occur in
response to chronic exposure. Other effects of chronic exposure to these
inhibitors included cataract formation for dinitrophenol, liver pathology for
pentachlorophenol, and myelin degeneration and thyroid effects for cyanide.
Confidence in the principal study is therefore no more than medium. The data
base is rated low because of the absence of chronic studies. Also, there
exist no multigenerational reproductive studies for this compound. It should
be noted that the experimental exposures on which this RfC is based are to
pure phosphine gas. Actual exposures, however, would most likely be to
reaction products of metal phosphides, which have not been chemically or
toxicologically characterized. A low confidence in the RfC follows.
___I.B.6. EPA DOCUMENTATION AND REVIEW OF THE INHALATION RfC
Source Document -- This assessment is not presented in any existing U.S. EPA
document.
This assessment was peer reviewed by external scientists. This review was
completed on 03/29/1995. Their comments have been carefully evaluated and
considered in the revision and finalization of this IRIS summary. A record of
these comments is included in the IRIS documentation files.
Other EPA Documentation -- U.S. EPA, 1990
Agency Work Group Review -- 02/09/1993, 09/22/1993, 05/10/1995
Verification Date -- 05/10/1995
___I.B.7. EPA CONTACTS (INHALATION RfC)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Phosphine
CASRN -- 7803-51-2
Last Revised -- 12/01/1996
Section II provides information on three aspects of the carcinogenic
assessment for the substance in question; the weight-of-evidence judgment of
the likelihood that the substance is a human carcinogen, and quantitative
estimates of risk from oral exposure and from inhalation exposure. The
quantitative risk estimates are presented in three ways. The slope factor is
the result of application of a low-dose extrapolation procedure and is
presented as the risk per (mg/kg)/day. The unit risk is the quantitative
estimate in terms of either risk per ug/L drinking water or risk per ug/cu.m
air breathed. The third form in which risk is presented is a drinking water
or air concentration providing cancer risks of 1 in 10,000, 1 in 100,000 or 1
in 1,000,000. The rationale and methods used to develop the carcinogenicity
information in IRIS are described in The Risk Assessment Guidelines of 1986
(EPA/600/8-87/045) and in the IRIS Background Document. IRIS summaries
developed since the publication of EPA's more recent Proposed Guidelines for
Carcinogen Risk Assessment also utilize those Guidelines where indicated
(Federal Register 61(79):17960-18011, April 23, 1996). Users are referred to
Section I of this IRIS file for information on long-term toxic effects other
than carcinogenicity.
__II.A. EVIDENCE FOR CLASSIFICATION AS TO HUMAN CARCINOGENICITY
___II.A.1. WEIGHT-OF-EVIDENCE CLASSIFICATION
Classification -- D; not classifiable as to human carcinogenicity
Basis -- Based on inadequate data in animals and no tumor data in humans.
While phospine has not been associated with cancer in humans, there is some
evidence of chromosomal damage (transient chromatid deletions, gaps and
breaks, persistent chromosomal translocations). A relationship between these
genetic effects and the development of cancer in humans is sometimes
postulated.
___II.A.2. HUMAN CARCINOGENICITY DATA
None.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Inadequate. Hackenberg (1972) fed 30 Wistar rats/sex an aluminum
phosphide-fumigated diet, equivalent to 0.27 mg phosphine/kg (a range of 0.167
to 0.377 mg/kg was fed in several feed preparations), for weeks 1-16; and for
weeks 17-104, the feed contained 0.51 mg/kg (a range of 0.205 to 7.5 mg/kg was
fed in several feed preparations). Untreated control groups (30 Wistar
rats/sex) were fed a basal diet that was not fumigated. Fifteen
rats/sex/group were used at various interim time points for hematological,
blood-glucose, and urine analyses. Tissues from all rats that died during the
study and at least five treated rats/sex that were killed at termination (24
months) were examined macroscopically and microscopically for neoplasms.
Tumors were reported to occur infrequently at multiple sites in all groups of
rats. The authors reported no differences between tumor incidences in control
and treated rats. Adverse effects were not observed in this study, indicating
that the MTD had not been reached.
Cabrol Telle et al. (1985) provided 30 Sprague-Dawley rats/sex feed that
was fumigated with phosphine (average residue levels of 5 ppb dietary
phosphine) for less than or equal to 2 years. It is not clear if the
investigators estimated or measured the level of residual phosphine. After 1
year, 19-20 rats/sex/group were sacrificed for gross examination;
histopathologic examination was performed on approximately 10 rats/sex/group.
The investigators conducted similar examination of the 10 remaining
rats/sex/group that were sacrificed after 2 years. Survival appeared to be
similar in all groups. No tumors occurred in any group of rats sacrificed
after 1 year. Although a number of tumors were reported in treated and
control groups at termination, no significant differences in incidence were
observed. An MTD was not achieved in this study. U.S. EPA (1989) determined
that this study was inadequate for predicting the carcinogenicity of phosphine
to rats since only one dose level was evaluated and too few rats remained
after the interim sacrifice for potentially low excess tumor incidences to
achieve statistical significance.
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Garry et al. (1989) reported that pesticide applicators exposed to
phosphine may have increased levels of genetic aberrations. The exposed
groups consisted of 9 men who were exposed to phosphine alone, 11 to phosphine
and other pesticides, and 4 who did not use phosphine. Two control groups
included 15 state grain workers and 24 community control subjects. As a
group, the pesticide applicators exhibited 3.58 times more total chromosome
aberrations (excluding gaps) than the controls (p<0.001). Phosphine-exposed
workers had a 5-fold increase in deletions compared with controls (p<0.001)
and a significant increase in gaps (p<0.02) and breaks (p<0.01). No increase
in sister chromatid exchanges was observed. Human lymphocytes exposed to
phosphine in vitro demonstrated similar patterns of chromosome damage in a
dose-related manner. However, when the human subjects were studied 6 weeks to
3 months after fumigation with phosphine had ceased, there was no difference
in the number of chromosome gaps, deletions or breaks between men exposed to
phosphine and control subjects. The only persistent change was that of
increased chromosome rearrangements (p<0.05) in the exposed group. The
authors were unable to state conclusively whether the chromosome
rearrangements were directly attributed to phosphine exposure but expressed
this as a distinct possibility.
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
None.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
None.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1989
The 1989 Health and Environmental Effects Document for Phosphine has received
Agency review.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 03/31/1992
Verification Date -- 03/31/1992
___II.D.3. U.S. EPA CONTACTS (CARCINOGENICITY ASSESSMENT)
Please contact the Risk Information Hotline for all questions concerning this
assessment or IRIS, in general, at (513)569-7254 (phone), (513)569-7159 (FAX)
or RIH.IRIS@EPAMAIL.EPA.GOV (internet address).
_VI. BIBLIOGRAPHY
Substance Name -- Phosphine
CASRN -- 7803-51-2
Last Revised -- 07/01/1995
__VI.A. ORAL RfD REFERENCES
ACGIH (American Conference of Governmental Industrial Hygienists). 1984. TLVs
Threshold limit values for chemical substances and physical agents in the
workroom environment with intended changes for 1984-1985. Cincinnati, OH.
p. 27.
Hackenburg, U. 1972. Chronic ingestion by rats of standard diet treated with
aluminum phosphide. Toxicol. Appl. Pharmacol. 23(1): 147-158.
Jones, A.T., R.C. Jones and E.O. Longley 1964. Environmental and clinical
aspects of bulk wheat fumigation with aluminum phosphide. Am. Ind. Hyg. Assn.
J. 25: 376-379.
__VI.B. INHALATION RfC REFERENCES
Barbosa, A., E. Rosinova, J. Dempsey and A.M. Bonin. 1994. Determination of
genotoxic and other effects in mice following short-term, repeated-dose, and
subchronic inhalation exposure to phosphine. Environ. Molec. Mutagenesis.
24: 81-88.
Barbosa, A. and A.M. Bonin. 1994. Evaluation of phosphine genotoxicity at
occupational levels of exposure in New South Wales, Australia. Occup.
Environ. Med. 51(10): 700-705.
Bio/dynamics, Inc. 1989. MRID No. 413770-02. Available from EPA. Write to
FOI, EPA, Washington, DC 20460. (Also reported in Newton et. al., 1993.)
Bio/dynamics, Inc. 1990. MRID No. 414131-01. Available from EPA. Write to
FOI, EPA, Washington, DC 20460. (Also reported in Newton et al., 1993.)
Chefurka, W., K.P. Kashi and E.J. Bond. 1976. The effect of phosphine on
electron transport in mitochondria. Pest. Biochem. Physiol. 6: 65-84.
Gupta, S., K. Sushil and K. Ahlawat. 1995. Aluminum phosphide poisoning - A
review. Clin. Toxicol. 33(1): 19-24.
Horner, W.D. 1942. Dinitrophenol and its relation to formation of cataracts.
Arch. Ophthal. 27: 1097-1112.
Kligerman, A.D., J.B. Bishop, G.L. Erexson, et al. 1994. Cytogenetic and
germ cell effects of phosphine inhalation by rodents: II. Subacute exposures
to rats and mice. Environ. Molec. Mutagen. 24: 301-306.
Klimmer, O. 1969. Study of action of phosphine (PH3). Chronic phosphine
poisoning. Arch Toxicol. 24: 164-187. (German trans.)
Misra, U., S. Bhargava, D. Nag, M. Kidwai and M. Lal. 1988. Occupational
phosphine exposure in Indian workers. Toxicol. Lett. 42(3): 257-263.
Morgan D.L., M.P. Moorman, M.R. Elwell, et al. 1995. Inhalation toxicity of
phosphine for Fisher 344 rats and B6C3F1 mice. Inhal. Toxicol. 7: 225-238.
Newton, P.E., R.E. Schroeder, J.B. Sullivan, W.M. Busey and D.A. Banas. 1993.
Inhalation toxicity of phosphine in the rat: Acute, subchronic, and
developmental. Inhal. Toxicol. 5(2): 223-239. (Also reported as
Bio/dynamics, Inc., 1989 and 1990.)
Pazynich, V.M., I.A. Mazur, A.V. Podloznyi, et al. 1984. Experimental
SUBSTantiation and prediction of marginally acceptable concentrations,
differentiated in time, of phosphine in atmospheric air. Gig. i. Sanit. 1:
13-15. (Russian trans.)
Philbrick, D.J., J.B. Hopkins, D.C. Hill, J.C. Alexander, and R.G. Thomson.
1979. Effects of prolonged cyanide and thiocyanate feeding in rats. J.
Toxicol. Environ. Health. 5: 579-592.
Potter, W.T., S. Rong, J. Griffith, J. White and V.F. Garry. 1991.
Phosphine-mediated Heinz body formation and hemoglobin oxidation in human
erythrocytes. Toxicol. Lett. 57(1): 37-45.
Price, N.R. and J. Chambers. 1990. Biochemistry of phosphines. In: The
Chemistry of Organophosphorus Compounds, Volume 1, F.R. Hartley, ed.
p. 643-661.
Schwetz, B.A., J.F. Quast, P.A. Keeler, C.G. Humiston and R.J. Kociba. 1978.
Results of a 2-year toxicity and reproduction studies on pentachlorophenol in
rats. In: Pentachlorophenol: Chemistry, Pharmacology and Environmental
Toxicology, K.R. Rao, ed. Plenum Press, NY. p. 301-309.
U.S. EPA. 1990. Health and Environmental Effects Document for Phosphine.
Prepared by the Environmental Criteria and Assessment Office, Cincinnati,
Ohio, for the Office of Solid Waste and Emergency Response, Washington, DC.
EPA No. 600/8-90/001.
U.S. Fish and Wildlife Service. 1983. MRID No. 00141408. Available from
EPA. Write to FOI, U.S. EPA, Washington, DC 20460.
Waritz, R.S. and R.M. Browm. 1975. Acute and subacute inhalation toxicities
of phosphine, phenylphosphine, and triphenylphosphine. Am. Ind. Hyg. Assoc.
J. 36: 452-458.
Wilson, R., F. Lovejoy, R. Jaeger and P. Landrigan. 1980. Acute phosphine
poisoning aboard a grain freighter. Epidemiologic, clinical, and pathological
findings. JAMA. 244(2): 148-150.
Winterbourn, C.C. 1990. Oxidative denaturation in congenital hemolytic
anemias: The unstable hemoglobins. Seminars in Hematology. 27(1): 41-50.
WHO (World Health Organization). 1988. Environmental Health Criteria 73:
Phosphine and selected metal phosphides. World Health Organization:
Distribution and Sales Service, 1211 Geneva 27, Switzerland. 100 p.
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Cabrol Telle, A.-M., G. De Saint Blanquat, R. Derache, E. Hollande, B.
Periquet and J.P. Thouvenot. 1985. Nutritional and toxicological effects of
long-term ingestion of phosphine-fumigated diet by the rat. Food Chem.
Toxicol. 23(11): 1001-1009.
Garry, V.F., J. Griffith, T.J. Danzl, et al. 1989. Human genotoxicity:
Pesticide applicators and phosphine. Science. 246: 251-255.
Hackenberg, U. 1972. Chronic ingestion by rats of standard diet treated with
aluminum phosphide. Toxicol. Appl. Pharmacol. 23(1): 147-158.
U.S. EPA. 1989. Health and Environmental Effects Document for Phosphine.
Prepared by the Office of Health and Environmental Assessment, Environmental
Criteria and Assessment Office, Cincinnati, OH for the Office of Solid Waste
and Emergency Response, Washington, DC.
_VII. REVISION HISTORY
Substance Name -- Phosphine
CASRN -- 7803-51-2
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
03/31/1987 I.A.6. Documentation corrected
09/30/1987 V. Supplementary Data section added
03/01/1988 I.A.5. Confidence levels revised
09/01/1989 VI. Bibliography on-line
01/01/1992 I.A.7. Primary contact changed
01/01/1992 IV. Regulatory actions updated
09/01/1992 II. Carcinogenicity assessment under review on 03/31/1992
09/01/1992 II. Carcinogenicity assessment on-line
09/01/1992 VI.C. Carcinogenicity assessment references on-line
03/01/1993 I.B. Inhalation RfC now under review
11/01/1993 I.A.2. Principal study: phosphate changed to phosphide
11/01/1993 VI.A. Hackenburg 1972 citation corrected
11/01/1993 I.B. Work group review date added
12/01/1993 I.A.4. Citation corrected
12/01/1993 VI.A. Reference corrected
06/01/1995 I.B. Work group review date added
07/01/1995 I.B. Inhalation RfC summary on-line
07/01/1995 VI.B. Inhalation RfC references on-line
12/01/1996 II.D.3. Primary contact removed
VIII. SYNONYMS
Substance Name -- Phosphine
CASRN -- 7803-51-2
Last Revised -- 01/31/1987
7803-51-2
CELPHOS
DELICIA
DETIA
DETIA GAS EX-B
FOSFOROWODOR
HYDROGEN PHOSPHIDE
Phosphine
PHOSPHORUS TRIHYDRIDE
PHOSPHORWASSERSTOFF
RCRA WASTE NUMBER P096
UN 2199
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0090.HTM
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