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Assure
CASRN 76578-14-8
Contents
0335
Assure; CASRN 76578-14-8
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 Assure
File On-Line 09/26/1988
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) on-line 09/26/1988
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 -- Assure
CASRN -- 76578-14-8
Last Revised -- 09/26/1988
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
-------------------- ----------------------- ----- --- ---------
Liver cell enlargement NOEL: 25 ppm 100 1 9E-3
(0.9 mg/kg/day, males; mg/kg/day
2-Year Rat Feeding 1.1 mg/kg/day, females)
Study
LEL: 100 ppm
du Pont, 1985 (3.7 mg/kg/day, males;
4.6 mg/kg/day, females)
*Conversion Factors: Actual doses tested
___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
E.I. du Pont de Nemours and Company, Inc. 1985. MRID No. 00146682. Available
from EPA. Write to FOI, EPA, Washington, DC 20460.
Groups of CD-rats (50/sex/dose) were fed assure at nominal concentrations of
0, 25, 100, and 400 ppm (0, 0.9, 3.7, and 15.5 mg/kg/day, males; 0, 1.1, 4.6,
and 18.6 mg/kg/day, females) for 104 weeks. Satellite groups of 35
rats/sex/dose were reserved for interim sacrifices which were carried out at
weeks 26, 52, and 78. Ten rats/sex/dose were killed during each interim
sacrifice except at week 78 at which time all surviving animals from the
satellite groups were sacrificed. An increased incidence of hepatocyte
enlargement was observed in high dose males and females, 15.5 and 18.6
mg/kg/day respectively, at interim and terminal sacrifices. A slight increase
in the incidence of hepatocyte enlargement was also observed in 3.7 mg/kg/day
males at interim and terminal sacrifices. The LEL was established at 3.7
mg/kg/day; the NOEL, 0.9 mg/kg/day.
___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF -- An uncertainty factor of 100 was used to account for the inter- and
intraspecies differences.
MF -- None
___I.A.4. ADDITIONAL COMMENTS (ORAL RfD)
Data Considered for Establishing the RfD:
1) 2-Year Feeding (oncogenic) - rat: Principal study - see previous
description; core grade guideline
2) 52-Week Feeding - dog: NOEL=400 ppm (10 mg/kg/day) (HDT; no compound
related effects were observed); core grade minimum (Nissan Chemical Industries
Ltd., 1985)
3) 2-Generation Reproduction - rat: Developmental NOEL=25 ppm (1.25
mg/kg/day); Developmental LEL=100 ppm (2.5 mg/kg/day) (increased liver weight
and increased incidence of eosinophilic changes in the liver of offspring);
Maternal NOEL=100 ppm (5 mg/kg/day); Maternal LEL=400 ppm (20 mg/kg/day)
(decreased body weights of F0 and F1 males); core grade minimum (E.I. du Pont
de Nemours and Co., Inc., 1985b)
4) Teratology - rat: Maternal NOEL=30 mg/kg/day; Maternal LEL=100 mg/kg/day
(decreases in body weight and food consumption, increases in liver weights,
and decrease in corpora lutea); Teratogenic NOEL=300 mg/kg/day (HDT);
Teratogenic LEL=none; core grade minimum (E.I. du Pont de Nemours and Co.,
Inc., 1983a)
5) Teratology - rabbit: Maternal NOEL=60 mg/kg/day (HDT); Maternal LEL=none;
Fetotoxic NOEL and LEL could not be determined because critical data on
embryonic implantation and resorption were missing; core grade supplementary
(E.I. du Pont de Nemours and Co., Inc., 1983b)
Other Data Reviewed:
1) 18-Month Study (oncogenic) - mouse: When groups of CD-1 mice were fed
assure at dietary concentrations of 0, 2, 10, 80, and 320 ppm for 18 months,
increased liver weight, changes in clinical chemistry parameters (albumin,
alkaline phosphatase, and total protein) and in histomorphology were found.
NOEL=10 ppm (1.5 mg/kg/day); LEL=80 ppm (12 mg/kg/day); core grade guideline
(E.I. du Pont de Nemours and Co., Inc., 1985c)
2) 90-Day Feeding - rat: NOEL=40 ppm (2 mg/kg/day); LEL=128 ppm (6.4
mg/kg/day) (liver weight increases and liver lesions); core grade minimum
(E.I. du Pont de Nemours and Co., Inc., 1982a)
3) 6-Month Feeding - dog: NOEL=100 ppm (2.5 mg/kg/day); LEL=400 ppm (10
mg/kg/day) (atrophy of seminiferous tubules, pylelitis and others); core grade
guideline (E.I. du Pont de Nemours and Co., Inc., 1984)
4) 90-Day Feeding - mice: NOEL=none; LEL=100 ppm (15 mg/kg/day) (LDT; liver
changes were seen at all dosage levels); core grade minimum (E.I. du Pont de
Nemours and Co., Inc., 1982b)
Data Gap(s): Rabbit Teratology Study (A new study is currently under review)
___I.A.5. CONFIDENCE IN THE ORAL RfD
Study -- High
Data Base -- High
RfD -- High
The critical study is of good quality and is given a high confidence rating.
Additional studies are supportive and of good quality and 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 -- 01/21/1988
Verification Date -- 01/21/1988
___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 -- Assure
CASRN -- 76578-14-8
Not available at this time.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Assure
CASRN -- 76578-14-8
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 -- D; not classifiable as to human carcinogenicity
Basis -- Based on no human data and inadequate animal data.
___II.A.2. HUMAN CARCINOGENICITY DATA
None.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Inadequate. The carcinogenicity of Assure could not be adequately
evaluated based on data obtained from mouse and rat studies. In a study
conducted by Nissan Chemical Industries and reported by Hazleton Laboratories
America (reviewed in U.S. EPA, 1987a,b), 70 CD-1 mice/sex/group were fed 0, 2,
10, 80 or 320 ppm Assure for 78 weeks. Groups of 10 mice/sex/group were
killed at 26 and 52 weeks for interim evaluation. The incidence of an unusual
luteoma of the ovary was 0/51 in the controls and 3/50 at the high dose. An
additional granulosa cell tumor was also observed at the high dose only. The
incidences of the luteoma and the combined incidences of luteoma and granulosa
cell tumor were significantly elevated when compared with historical controls
(0/196 for luteoma and 1/196 for the combined incidences of luteomas and
granulosa) but they were not statistically different from the concurrent
controls. In the livers of the high-dose male mice the incidence of adenomas,
carcinomas and combined tumors were 5/68, 10/68 and 15/68, respectively; in
the controls the incidences were 3/70, 4/70 and 7/70, respectively. For
adenomas and carcinomas combined, there was no statistically significant trend
and no significant pairwise difference by the Peto prevalevence test, which
accounts for survival differences. The incidences of carcinomas increased
with dose, but these data were not examined by the Peto prevalence test.
Liver tumors were apparent in males killed at 26 and 52 weeks, suggesting a
reduced latency. The highest dose tested in male mice exceeded the MTD as
indicated by reduced survival (39% male mice survived compared with 59% for
the controls), testicular atrophy and hepatotoxic effects.
In a 24-month rat oncogenicity study conducted by Huntingdon Research
Centre (reviewed in U.S. EPA, 1987a,b), groups of 50 Charles River SD
rats/sex/dose were fed Assure at 0, 25, 100 and 400 ppm in the diet. Assure
produced a statistically significant positive trend for hepatocellular
carcinomas in female rats, but the low increases in carcinomas were not
considered biologically significant because no neoplastic lesions were
observed and the increase did not exceed the historical control incidences for
liver carcinomas reported by the test laboratory (U.S. EPA, 1987b).
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Assure was not mutagenic in reverse mutation assays for Salmonella
typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 or for Escherichia
coli WP-2. DNA damage assays in Bacillus subtilis strains M45 and H17, a
chromosome abberation assay in CHO cells and an unscheduled DNA synthesis
assay in rat hepatocytes were also negative. No materials structurally
related to Assure have been found to be carcinogenic (reviewed in U.S. EPA,
1987a).
Rabiolabeled Assure, when administered orally to rats, is readily absorbed
from the gastrointestinal tract. The material is taken up in the blood and
distributed to the liver and kidney. The biological half-life is 18-27 hours
for blood and tissues of both sexes. In males, the major route of elimination
is in the feces, whereas in females equal amounts of administered
radioactivity are eliminated in the urine and feces. In fecal samples
collected within 48 hours, unchanged parent compound accounted for
approximately 23% of the high oral dose (160 mg/kg) and <7% of the low oral
dose (1.5 mg/kg). The major metabolite is the corresponding acid of Assure
(U.S. EPA, 1987b).
__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 -- Quest, 1988; U.S. EPA, 1987a,b
The Office of Pesticide Programs (Health Effects Division of U.S. EPA) peer
reviewed the data pertaining to possible carcinogenicity of assure.
(Memorandum from J. Quest to R. Taylor, Peer Review of Assure following SAP
Meeting, March 17, 1988).
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 01/21/1988, 09/22/1988
Verification Date -- 09/22/1988
___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 -- Assure
CASRN -- 76578-14-8
Last Revised -- 06/01/1991
__VI.A. ORAL RfD REFERENCES
E.I. du Pont de Nemours and Company, Inc. 1982a. EPA Accession No. 250071.
Available from EPA. Write to FOI, EPA, Washington D.C. 20460.
E.I. du Pont de Nemours and Company, Inc. 1982b. EPA Accession No. 250073.
Available from EPA. Write to FOI, EPA, Washington D.C. 20460.
E.I. du Pont de Nemours and Company, Inc. 1983a. EPA Accession No. 250071.
Available from EPA. Write to FOI, EPA, Washington D.C. 20460.
E.I. du Pont de Nemours and Company, Inc. 1983b. EPA Accession No. 073905.
Available from EPA. Write to FOI, EPA, Washington D.C. 20460.
E.I. du Pont de Nemours and Company, Inc. 1984. EPA Accession No. 250553.
Available from EPA. Write to FOI, EPA, Washington D.C. 20460.
E.I. du Pont de Nemours and Company, Inc. 1985a. MRID No. 00146682.
Available from EPA. Write to FOI, EPA, Washington D.C. 20460.
E.I. du Pont de Nemours and Company, Inc. 1985b. EPA Accession No. 074017.
Available from EPA. Write to FOI, EPA, Washington D.C. 20460.
E.I. du Pont de Nemours and Company, Inc. 1985c. EPA Accession No. 255982.
Available from EPA. Write to FOI, EPA, Washington D.C. 20460.
Nissan Chemical Industries Ltd. 1985. EPA Accession No. 073536. Available
from EPA. Write to FOI, EPA, Washington D.C. 20460.
__VI.B. INHALATION RfD REFERENCES
None
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Quest, J. 1988. U.S. EPA, Washington, DC. Memorandum to R. Taylor, U.S.
EPA, Washington, DC. March 17. Peer Review of Assure following SAP Meeting.
U.S. EPA. 1987a. Peer Review of Assure. Office of Pesticides and Toxic
Substances, Washington, DC. February 6.
U.S. EPA. 1987b. Second Peer Review of Assure. Office of Pesticides and
Toxic Substances, Washington, DC. September 9.
_VII. REVISION HISTORY
Substance Name -- Assure
CASRN -- 76578-14-8
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
09/26/1988 I.A. Oral RfD summary on-line
10/01/1989 VI. Bibliography on-line
06/01/1991 II. Carcinogenicity assessment on-line
06/01/1991 VI.C. Carcinogenicity references added
07/01/1991 II.D.2. Work group review date corrected
10/01/1993 II.D.3. Primary contact changed; secondary's phone no. changed
VIII. SYNONYMS
Substance Name -- Assure
CASRN -- 76578-14-8
Last Revised -- 09/26/1988
76578-14-8
Assure
2-(4-((6-chloro-2-quinoxalinyl)oxy)phenoxy)propanoic acid ethyl ester
DPX-Y 6202
EXP 3864
FBC 32197
NC 302
NCI 96683
pilot
propanoic acid, 2-(4-((6-chloro-2-quinoxalinyl)oxy)phenoxy)-, ethyl ester
quinofop-ethyl
quizalofop-ethyl
terga
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0335.HTM
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