|
Acephate
CASRN 30560-19-1
Contents
0354
Acephate; CASRN 30560-19-1
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 Acephate
File On-Line 09/07/1988
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) on-line 02/01/1990
Inhalation RfC Assessment (I.B.) no data
Carcinogenicity Assessment (II.) on-line 10/01/1993
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Acephate
CASRN -- 30560-19-1
Last Revised -- 02/01/1990
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
-------------------- ----------------------- ----- --- ---------
Inhibition of brain NOEL: None 30 1 4E-3
ChE mg/kg/day
LEL: 2 ppm
90-Day Rat Feeding (0.12/0.15 mg/kg/day, M/F)
Study
Chevron Chemical Co.,
1987a
*Conversion Factors: Actual dose tested
___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
Chevron Chemical Company. 1987a. MRID No. 40504819. Available from EPA.
Write to FOI, EPA, Washington, DC 20460.
Five groups of 60 Sprague-Dawley rats (30 male and 30 female) were dosed with
nominal dietary concentrations of 0, 2, 5, 10, and 150 ppm (Males: 0, 0.12,
0.28, 0.58, 8.90 mg/kg/day; Females: 0. 0.15, 0.36, 0.76, 11.48 mg/kg/day)
acephate for 13 weeks. The rats were approximately 45 days old at the start
of dosing.
Although there was still some statistically significant brain cholinesterase
inhibition at 13 weeks at 2 ppm (0.12 mg/kg/day in males and 0.15 mg/kg/day in
females), it was concluded that this level essentially represented a threshold
i.e., the dose response curve in this area was very flat becoming essentially
parallel to the x-axis. At 150 ppm (8.9 mg/kg/day in males and 11.48 in
females), in both the brain and RBC ChE there was statistically significant
inhibition. Plasma ChE determinations varied widely and only one subset
showed statistical significance (females after 13 weeks of dosing with the 150
ppm diet). The NOEL for RBC and plasma ChE is 10 ppm (0.58 mg/kg/day in males
and 0.76 in females). A NOEL for brain cholinesterase inhibition was not
found in this study.
Human subjects were dosed with graded levels of Monitor:Acephate mixtures
(1:4, 1:9) at 0.1, 0.2, 0.3 or 0.4 mg/kg/day for a total of 37 to 73 days. No
effects on erythrocyte ChE activity, hematology, blood chemistry, blood
pressure, pulse rate, pupil size, light reflex, eye accommodation, chest
sound, muscle tone, knee jerk, tongue tremor, and finger tremor were observed.
Plasma ChE activities were inhibited significantly in the 1:4 and 1:9 groups.
The inhibition in the 1:4 group was first noted at the 0.2 mg/kg/day level
after 16 days of dosing and occurred in all subjects studied. The depression
was greater than 2 standard deviations below mean pretest activity for
consecutive determinations. The first significant inhibition in the 1:9 group
was observed at the 0.3 mg/kg/day level after 21 days of dosing and only in
males subjects. At the 0.4 mg/kg/day level, 2 out of 3 female subjects tested
exhibited a significant ChE depression after 10 days of dosing. All inhibited
ChE activities returned to the pretreatment levels during the 7-day recovery
periods (Chevron Chemical Co., 1973).
___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF -- The human study and the comparative in vitro studies were considered by
the RfD Work Group when evaluating the data base for acephate. The human
study was not found to be adequate as the basis for the RfD because it was 1)
carried out by IBT and 2) because brain ChE inhibition seems a more sensitive
endpoint than RBC or plasma ChE for acephate, and brain ChE was not measured
in the human study. In vitro studies on the affinity of acephate to human
brain, RBC and plasma ChE, show differences of less than 10-fold. Upon
reconsideration and discussion the Agency concluded that both the human study
and the in vitro data could be used to support a modification of the customary
100-fold uncertainty factor used for brain cholinesterase inhibition. This
100-fold factor was reduced to 10 (e.g., the 10-fold factor from animal to man
was not considered necessary). Furthermore, a 3-fold factor was used because
a NOEL was not determined in the critical study. This intermediate factor of
3 was considered as more appropriate than 10 because the LEL dose was
concluded to represent a threshold dose. Finally, the 10-fold factor normally
used to estimate an RfD using subchronic data was not considered necessary,
since the results after subchronic exposure are similar in both severity and
magnitude as for chronic studies.
MF -- None
___I.A.4. ADDITIONAL COMMENTS (ORAL RfD)
Data Considered for Establishing the RfD
1) 13-Week Feeding - rat: Principal study - see previous description; core
grade acceptable
2) Subchronic Feeding - human: Plasma ChE NOEL=0.1 mg/kg/day; ChE LEL= 0.2
mg/kg/day; see previous description; core grade supplementary (Chevron
Chemical Co., 1973)
3) 28-Month Feeding (oncogenic) - rat: ChE NOEL=not established; ChE LEL=5
ppm (0.25 mg/kg/day) (inhibition of ChE activities in brain, plasma, and RBC);
Systemic NOEL=50 ppm (2.5 mg/kg/day); Systemic LEL=700 ppm (35 mg/kg/day)
(HDT; weight loss in male rats); core grade minimum (Chevron Chemical Co.,
1981)
4) 2-Year Feeding - dog: NOEL=30 ppm (0.75 mg/kg/day); LEL=100 ppm (2.5
mg/kg/day) (HDT; brain, plasma, and RBC ChE activity); Systemic LEL=100 ppm
(2.5 mg/kg/day); core grade minimum (Chevron Chemical Co., 1972)
5) 2-Generation Reproduction - rat: Maternal NOEL=50 ppm (2.5 mg/kg/day);
Maternal LEL=500 ppm (25 mg/kg/day) [decreased body weight gain for adults and
pups; increases in food consumption relative to body weight in adults;
clinical signs in males (alopecia and loose stools); decreases in litter size
(25-30%) for 4 of the 5 litter groups]; Reproductive NOEL=50 ppm (2.5
mg/kg/day); Reproductive LEL=500 ppm (25 mg/kg/day) (decreased viability
index); core grade guideline (Chevron Chemical Co., 1987b)
6) Teratology - rat: Teratogenic NOEL=200 mg/kg/day [slightly more resorption
sites per female at 200 mg/kg/day level than in controls; less weight gain at
100 mg/kg/day level (25%) and 200 mg/kg/day (29%) by female during gestation];
core grade minimum (Chevron Chemical Co., 1971)
7) Teratology - rabbit: Teratogenic and Fetotoxic NOEL=10 mg/kg/day (HDT);
Maternal NOEL=3 mg/kg/day; Maternal LEL=10 mg/kg/day (HDT; increase in nasal
discharge and 2/16 abortions); core grade guideline (Chevron Chemical Co.,
1980)
Other Data Reviewed:
1) 2-Generation Reproduction - rat: Reproductive NOEL=not established;
Various reproductive effects (fetal losses, decreased litter weights) were
observed at 50 ppm (2.5 mg/kg/day) (LDT); Systemic NOEL=not established;
Weight loss by females and decreased food utilization by males and females was
observed at 50 ppm; core grade minimum (Chevron Chemical Co., 1983)
Data Gap(s): None
___I.A.5. CONFIDENCE IN THE ORAL RfD
Study -- Medium
Data Base -- High
RfD -- High
The critical study is of adequate quality and is given a medium confidence
rating. Additional studies are also of good quality; therefore, the data base
is given a high confidence rating. High confidence in the RfD follows.
___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 -- Pesticide Registration Files
Agency Work Group Review -- 04/08/1986, 11/25/1986, 01/18/1989
Verification Date -- 01/18/1989
___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 -- Acephate
CASRN -- 30560-19-1
Not available at this time.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Acephate
CASRN -- 30560-19-1
Last Revised -- 10/01/1993
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 -- C; possible human carcinogen.
Basis -- The classification is based on increased incidence of hepatocellular
carcinomas and adenomas in female mice.
___II.A.2. HUMAN CARCINOGENICITY DATA
None.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Limited. Technical grade acephate was administered in the diet of Charles
River CD-1 mice (75/sex/dose) at 0, 50, 250 and 1000 ppm for 105 weeks
(Chevron Chemical, 1982a). Ten male and female mice of each dose group were
killed at 52 weeks and necropsies were performed; the remaining mice were
killed at 105 weeks. There was a statistically significant increase in
incidence of hepatocellular carcinomas and adenomas (15/61) and hyperplastic
nodules (15/61) in the high-dose female group at terminal sacrifice, as
compared to controls (1/62 and 2/62). There were no such increases in the
lower-dose female groups nor were there increased tumor incidences in any of
the male groups. There was no increase in tumor incidence observed at the 52-
week sacrifice. Survival was not affected by the occurrence of tumors. There
were toxic effects at the mid-dose, and the MTD may have been exceeded at the
high dose.
Technical grade acephate was fed in the diet of Charles River (CD)
Sprague-Dawley rats (75 rats/sex/dose) at 0, 5, 50 and 700 ppm for 28 months
(Chevron Chemical, 1981). Although the incidence of pheochromocytomas was
elevated above the controls in the treated males, there was no evidence of a
dose-dependent increase. Furthermore, the incidence of pheochromocytomas was
within the range of historical incidences reported for controls in the testing
laboratory and in the literature for the strain tested. There was no evidence
of either increased malignancy of lesions or decreased latency in the treated
males and the pheochromocytoma incidence in acephate-treated female rats was
the same or lower than that observed in controls. The U.S. EPA (1985) thus
concluded that the observed increase in pheochromocytomas was not indicative
of a true carcinogenic effect in rats. These conclusions were in agreement
with those of a consulting veterinary pathologist based on histopathologic
reevaluation of the tissue.
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Acephate was mutagenic for Salmonella, Escherichia coli and Saccharomyces
cerevisiae. Generally weak responses were noted (Simmon, 1979; Moriya et al.,
1983; Mortelmans et al. 1980). Acephate has been reported to produce
mutations in mouse lymphoma cells, sister chromatid exchange in CHO cells and
mitotic recombination in Saccharomyces (Chevron Chemical, 1982b; Jotz and
Mitchell, 1980; Evans and Mitchell, 1980; Mortelmans et al., 1980). No
metabolism studies are available for mice, but one study did indicate that
rats excreted acephate largely in the urine and in an unchanged form.
Acephate is structurally related to methamidophos.
__II.B. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM ORAL EXPOSURE
___II.B.1. SUMMARY OF RISK ESTIMATES
Oral Slope Factor -- 8.7E-3/mg/kg/day
Drinking Water Unit Risk -- 2.5E-7/ug/L
Extrapolation Method -- Linearized multistage procedure, extra risk
Drinking Water Concentrations at Specified Risk Levels:
Risk Level Concentration
-------------------- -------------
E-4 (1 in 10,000) 4E+2 ug/L
E-5 (1 in 100,000) 4E+1 ug/L
E-6 (1 in 1,000,000) 4 ug/L
___II.B.2. DOSE-RESPONSE DATA (CARCINOGENICITY, ORAL EXPOSURE)
Tumor Type -- liver adenomas and carcinomas
Test Animals -- mouse/CD-1, female
Route -- diet
Reference -- Chevron Chemical, 1982a
Administered Human Equivalent Tumor
Dose (ppm) Dose (mg/kg)/day Incidence
------------ ---------------- ---------
0 0 1/62
50 0.63 3/61
250 3.33 0/62
1000 13.3 15/61
___II.B.3. ADDITIONAL COMMENTS (CARCINOGENICITY, ORAL EXPOSURE)
Twelve of 15 tumors in the high-dose group were carcinomas. The slope
factor of 6.6E-3 presented in a 1984 Health and Environmental Effects Profile
was based on carcinomas only and was not corrected for early mortality.
The unit risk should not be used if the water concentration exceeds 4E+4
ug/L, since above this concentration the slope factor may differ from that
stated.
___II.B.4. DISCUSSION OF CONFIDENCE (CARCINOGENICITY, ORAL EXPOSURE)
Adequate numbers of animals were treated and observed for a period
approximating the natural lifespan. It should be noted that oncogenic effects
were significantly elevated only at the high dose although toxic effects were
observed in the mid-dose group as well.
__II.C. QUANTITATIVE ESTIMATE OF CARCINOGENIC RISK FROM INHALATION EXPOSURE
Not available.
__II.D. EPA DOCUMENTATION, REVIEW, AND CONTACTS (CARCINOGENICITY ASSESSMENT)
___II.D.1. EPA DOCUMENTATION
Source Document -- U.S. EPA, 1985
The Toxicology Branch Peer Review Committee Office of Pesticide Programs,
reviewed data on acephate.
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 02/24/1988, 03/23/1988
Verification Date -- 03/23/1988
___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 -- Acephate
CASRN -- 30560-19-1
Last Revised -- 07/01/1989
__VI.A. ORAL RfD REFERENCES
Chevron Chemical Company. 1971. MRID No. 00014695. Available from EPA.
Write to FOI, EPA, Washington D.C. 20460.
Chevron Chemical Company. 1972. MRID No. 00014699. Available from EPA.
Write to FOI, EPA, Washington D.C. 20460.
Chevron Chemical Company. 1973. MRID No. 00015160. Available from EPA.
Write to FOI, EPA, Washington D.C. 20460.
Chevron Chemical Company. 1980. MRID No. 00069684. Available from EPA.
Write to FOI, EPA, Washington D.C. 20460.
Chevron Chemical Company. 1981. MRID No. 00084017. Available from EPA.
Write to FOI, EPA, Washington D.C. 20460.
Chevron Chemical Company. 1983. MRID No. 00129508. Available from EPA.
Write to FOI, EPA, Washington D.C. 20460.
Chevron Chemical Company. 1987a. MRID No. 40504819. Available from EPA.
Write to FOI, EPA, Washington D.C. 20460.
Chevron Chemical Company. 1987b. MRID No. 40323401. Available from EPA.
Write to FOI, EPA, Washington D.C. 20460.
__VI.B. INHALATION RfD REFERENCES
None
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Chevron Chemical Corporation. 1981. MRID No. 00084017. Available from EPA.
Write to FOI, EPA, Washington D.C. 20460.
Chevron Chemical Corporation. 1982a. MRID No. 00105197. Available from EPA.
Write to FOI, EPA, Washington D.C. 20460.
Chevron Chemical Corporation. 1982b. (Cited in Acephate Assessment of
Chronic and Oncogenic Effects Summary, OPP, March, 1984, p. 28)
Evans, E. and A. Mitchell. 1980. Science Research Institute (SRI) at
Louisiana State University (LSU). Study no. 7558. (Cited in Acephate
Assessment of Chronic and Oncogenic Effects Summary, OPP, March, 1984)
Jotz, M. and A. Mitchell. 1980. Science Research Institute (SCI) at
Louisiana State University (LSU). Study no. 7558-21. (Cited in Acephate
Assessment of Chronic and Oncogenic Effects Summary, OPP, March, 1984)
Moriya, M., T. Ohta, K. Watanabe, T. Miyazawa, K. Kato and Y. Shirasu.
1983. Further mutagenicity studies on pesticides in bacterial reversion
assay systems. Mutat. Res. 116(3-4): 185-216.
Mortelmans, K. et al. 1980. Science Research Institute (SCI) at Louisiana
State University (LSU). Study no. 7558-20. (Cited in Acephate Assessment
of Chronic and Oncogenic Effects Summary, OPP, March, 1984)
Simmon, V.F. 1979. In vitro microbiological mutagenicity and unscheduled
DNA synthesis studies of eighteen pesticides. p. 177. EPA 600/1-79-041.
NTIS PB 80-133226. (CA 93:108605k)
U.S. EPA. 1985. Toxicology Branch Peer Review Committee, Memorandum on
acephate 05/08/1985.
_VII. REVISION HISTORY
Substance Name -- Acephate
CASRN -- 30560-19-1
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
09/07/1988 II. Carcinogen summary on-line
09/26/1988 II.C. 'Not available' message added
02/01/1989 II.D.3. Secondary contact's phone number corrected
05/01/1989 I.A. Oral RfD summary on-line
07/01/1989 I.A. Principal study clarified
07/01/1989 II. Principal studies clarified
07/01/1989 VI. Bibliography on-line
02/01/1990 I.A.3. Uncertainty factor text revised
01/01/1992 IV. Regulatory Action section on-line
10/01/1993 II.D.3. Primary contact changed; secondary's phone no. changed
VIII. SYNONYMS
Substance Name -- Acephate
CASRN -- 30560-19-1
Last Revised -- 09/07/1988
30560-19-1
75 SP
ACEPHAT
Acephate
ACETYLPHOSPHORAMIDOTHIOIC ACID O,S-DIMETHYL ESTER
CHEVRON RE 12,420
ENT 27822
N-(METHOXY(METHYLTHIO)PHOSPHINOYL)ACETAMIDE
ORTHENE
ORTHENE-755
ORTHO 12420
ORTRAN
ORTRIL
O,S-DIMETHYLACETYLPHOSPHOROAMIDOTHIOATE
PHOSPHORAMIDOTHIOIC ACID, N-ACETYL-, O,S-DIMETHYL ESTER
RE 12420
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0354.HTM
|
