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Isoxaben
CASRN 82558-50-7
Contents
0339
Isoxaben; CASRN 82558-50-7
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 Isoxaben
File On-Line 09/26/1988
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) on-line 04/01/1991
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 -- Isoxaben
CASRN -- 82558-50-7
Primary Synonym -- EL-107
Last Revised -- 04/01/1991
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
-------------------- ----------------------- ----- --- ---------
Increased BUN; NOEL: 125 ppm 100 1 5E-2
decreased serum AP (5 mg/kg/day, males; mg/kg/day
and AST; decreased 6.2 mg/kg/day, females)
food consumption
efficiency; increased LEL: 1250 ppm
heart/body weight (50.7 mg/kg/day, males;
61.8 mg/kg/day, females)
2-Year Rat Feeding
Study
Elanco Products, 1985a
*Conversion Factors: Actual doses tested
___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
Elanco Products Company. 1985a. MRID No. 00164553. Available from EPA.
Write to FOI, EPA, Washington, DC 20460.
Fisher 344 rats, 60/sex/group (2 replicates of 30/sex/group), were fed
isoxaben in the diet for 2 years at levels of 0, 125, 1250, or 12,500 ppm
(actual doses 0, 5, 50.7, and 526.5 mg/kg/day in males; 0, 6.2, 61.8, and
646.6 mg/kg/day in females). Observed effects included the following:
1) Mid dose (1250 ppm): Increased BUN, decreased serum levels of alkaline
phosphatase (AP) and aspartate aminotransferase (AST), decreased food
consumption efficiency (males and females); increased heart-to-body weight
(males)
2) High dose (12,500 ppm): Decreased body weight and body weight gains;
increase in alkaline phosphatase; increased liver-to-body weight ratios,
kidney-to-body weight, and brain-to-body weight (males and females); increased
creatinine, decreased prostate weights, increased liver weights, and increased
heart-to-body weight (males)
No effects were observed at the lowest dose tested (125 ppm) and is considered
the NOEL for systemic toxicity.
___I.A.3. UNCERTAINTY AND MODIFYING FACTORS (ORAL RfD)
UF -- An uncertainty factor of 100 was used, 10 each 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 minimum
2) 1-Year Feeding - dog: NOEL=10 mg/kg/day; LEL=100 mg/kg/day (increased
alkaline phosphatase; liver-to-brain weight ratio elevated in males and
females, liver-to-body weight ratio elevated in females, some liver
microsomal enzyme induction in high dose males); core grade minimum (Elanco
Products Company, 1985b)
3) 3-Generation Reproduction - rat: Maternal NOEL=500 ppm (25 mg/kg/day);
Maternal LEL=2500 ppm (125 mg/kg/day) (lowered body weight, body weight gains,
increased liver/body weight in males and females); Reproductive NOEL=2500 ppm
(125 mg/kg/day); Reproductive LEL=12500 ppm (625 mg/kg/day) (decreased number
viable pups F2a, F2b; lowered body weight of progeny on postpartum day 21);
Developmental NOEL=2500 ppm (125 mg/kg/day); Developmental LEL=12500 ppm (625
mg/kg/day) (decreases in viable fetuses/litter, increased hydroureter,
microphthalmia); core grade minimum (Elanco Products Company, 1984a)
4) Teratology - rat: Maternal NOEL=320 mg/kg/day; Maternal LEL=1000 mg/kg/day
(decreased body weight gain); Developmental NOEL=320 mg/kg/day; Developmental
LEL=1000 mg/kg/day (increased preimplantation loss, increased resorptions,
smaller litter size, increased number of runt fetuses); core grade minimum
(Elanco Products Company, 1984b)
5) Teratology - rabbit: Maternal and Developmental NOEL=1000 mg/kg/day (HDT);
Maternal and Developmental LEL=none; core grade minimum (Elanco Products
Company, 1984c)
Other Data Reviewed:
1) 2-Year Feeding (oncogenic) - mice: Systemic NOEL=100 ppm (14 mg/kg/day);
Systemic LEL=143 mg/kg/day) (lowered body weight, body weight gain in males;
hepatocellular hyperplasia, hepatocellular cytomegaly); core grade minimum
(Elanco Products Company, 1985c)
2) 1-Year Feeding - rat: NOEL=125 ppm (6.25 mg/kg/day); LEL=1250 ppm (62.5
mg/kg/day) (decreased body weight, body weight gain, food efficiency in high
dose females; liver microsomal enzyme induction in high-dose males and
females, mid-dose females [6, 12 months], and mid-dose males [3, 6 months];
serum glucose increase in males and females at 6 months); core grade minimum
(Elanco Products Company, 1984d)
3) 90-Day Feeding - dog: Systemic NOEL=110 mg/kg/day; Systemic LEL=500
mg/kg/day (increased liver weight, liver-to-body weight ratio); core grade
minimum (Elanco Products Company, 1984e)
1) 2-Year Feeding (oncogenic) - mice: Systemic NOEL=100 ppm (14 mg/kg/day);
Systemic LEL=143 mg/kg/day) (lowered body weight, body weight gain in males;
hepatocellular hyperplasia, hepatocellular cytomegaly); core grade minimum
(Elanco Products Company, 1985c)
2) 1-Year Feeding - rat: NOEL=125 ppm (6.25 mg/kg/day); LEL=1250 ppm (62.5
mg/kg/day) [decreased body weight, body weight gain, food efficiency in high
dose females; liver microsomal enzyme induction - high dose males and females,
mid-dose females (6, 12 months), mid-dose males (3, 6 months); serum glucose
increase in males and females at 6 months]; core grade minimum (Elanco
Products Company, 1984d)
3) 90-Day Feeding - dog: Systemic NOEL=110 mg/kg/day; Systemic LEL=500
mg/kg/day (increased liver weight, liver/body weight ratio); core grade
minimum (Elanco Products Company, 1984e)
Data Gap(s): None
___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 -- 10/14/1987
Verification Date -- 10/14/1987
___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 -- Isoxaben
CASRN -- 82558-50-7
Primary Synonym -- EL-107
Not available at this time.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Isoxaben
CASRN -- 82558-50-7
Primary Synonym -- EL-107
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 -- Based on a statistically significant increased incidence of benign
liver tumors in one species.
___II.A.2. HUMAN CARCINOGENICITY DATA
None.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Limited. There was a statistically significant increased incidence of a
single tumor type in both sexes of one species. Isoxaben was fed to 60 B6C3F1
mice/sex/group at 0, 100, 1000, and 12,500 ppm for 2 years (Elanco, 1985).
Decreased survival observed in the low-dose males and the mid-dose females did
not contribute to any significant dose-related survival disparities for either
sex. The OPP Peer Review committee agreed that, based on hepatic toxicity,
the MTD was reached or slightly exceeded at the high dose (Rinde, 1987).
There was also a statistically significant positive trend in hepatocellular
adenoma incidence with dose for both sexes. In the high-dose group there was
a statistically significant increase in this tumor type in both male and
female mice when compared to their respective controls. The incidences of
hepatocellular adenomas in male mice were 3/44, 1/41, 3/47 and 12/48 in the
control, low-, mid- and high-dose groups, respectively, and in female mice
were 0/52, 3/52, 2/46 and 7/52 in the control, low-, mid- and high-dose
groups, respectively (Swentzel, 1989). There was no statistically significant
increase in hepatocellular carcinoma incidence nor a dose-related trend in
either sex for this tumor type. The incidence of hepatocellular carcinomas in
the control, low-, mid- and high-dose males was 9/56, 5/49, 5/55 and 5/55,
respectively; the incidence of hepatocellular carcinomas in females receiving
the same doses was 0/52, 1/52, 0/46 and 2/52, respectively (Swentzel, 1989).
There was, however, a significant dose-related trend for combined
hepatocellular adenomas/carcinomas in both sexes. There was an increase in
these combined tumors in the high-dose females only (9/52) when compared to
the female control group (0/52).
Isoxaben was fed to Fischer 344 rats (60/sex/group) at 0, 125, 1250 or
12,500 ppm for 2 years (Elanco, 1985). The OPP Peer Review Committee
concluded that, although the MTD was slightly exceeded in the rat study (as
indicated by observation of glomerulonephrosis and >10% decrease in body
weight) these toxic effects did not compromise the relevance of the tumor data
(Rinde, 1987). The Scientific Advisory Panel (SAP) also considered the doses
in the rat study to have exceeded the MTD (U.S. EPA, 1988). A significant
increasing trend in mortality with dose was found for male rats. There was an
apparent increase in benign adrenal pheochromocytomas in males at the high
dose when compared to controls; a statistically significant positive trend was
found. The incidences of benign adrenal medulla pheochromocytomas in male
rats were 10/59, 9/59, 9/59 and 18/59 in the control, low-, medium- and high-
dose groups, respectively (Rinde, 1987). There were no significant findings
in females.
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Isoxaben was negative in a Salmonella assay for reverse mutation both with
and without activation (Elanco, 1983a). It was also negative in a forward
mutation assay in mouse lymphoma both with and without activation (Elanco,
1983c) and in an unscheduled DNA repair assay using rat hepatocytes (Elanco,
1983b).
Isoxaben was weakly positive in a male mouse micronucleus study (Elanco,
1984); however, this study was later evaluated as inconclusive by OPP because
only a single dose level, not shown to be the MTD, was used and females were
not tested (Rinde, 1987). A repeat study in male mice using 0, 800, 2000 or
5000 mg/kg confirmed the earlier presumptive positive result in males
(Dearfield, 1988). Micronuclei were increased at all dose levels in the
repeat study.
A SEARCH of several data bases showed no structurally-related compounds of
toxicological interest.
The OPP Peer Review committee designated isoxaben a Group C compound on
the basis of a statistically significant increase in benign liver tumors in
male and female mice. In contrast, the SAP classified isoxaben a Group D
compound because significant hepatocarcinogenesis was observed only at the
highest dose, a level at which hepatotoxicity (elevated serum enzymes, nodular
hyperplasia, fatty degeneration) occurred. In a follow-up meeting, the Peer
Review committee reiterated its original opinion that the weight of evidence
is adequate for a Group C classification based on the following: 1) although
chronic compound-induced hepatotoxicity can cause histopathological
alterations, the mechanism involved in the compound-induced histopathological
alterations is not the primary issue of consideration, 2) an MTD was not
exceeded solely because there was target organ toxicity, and 3) the noted
liver tumors are most likely compound-induced (Swentzel, 1989).
__II.B. QUANTITATIVE ESTIMATES OF CARCINOGENIC RISK FROM ORAL EXPOSURE
Not available.
__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 -- Rinde, 1987; Swentzel, 1989
The Office of Pesticide Programs (Health Effects Division, U.S. EPA) peer
reviewed data pertaining to the potential carcinogenicity of Isoxaben
(Memorandum from K.C. Swentzel to R. Mountfort, Peer Review of Isoxaben-
Reevaluation Following the September 7, 1988 Science Advisory Panel Review.
01/04/1989).
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 05/03/1989
Verification Date -- 05/03/1989
___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 -- Isoxaben
CASRN -- 82558-50-7
Primary Synonym -- EL-107
Last Revised -- 10/01/1991
__VI.A. ORAL RfD REFERENCES
Elanco Products Company. 1984a. Accession No. 073297, 073298. Available
from EPA. Write to FOI, EPA, Washington DC 20460.
Elanco Products Company. 1984b. Accession No. 073229. Available from EPA.
Write to FOI, EPA, Washington DC 20460.
Elanco Products Company. 1984c. Accession No. 073299. Available from EPA.
Write to FOI, EPA, Washington DC 20460.
Elanco Products Company. 1984d. Accession No. 073295. Available from EPA.
Write to FOI, EPA, Washington DC 20460.
Elanco Products Company. 1984e. Accession No. 073293. Available from EPA.
Write to FOI, EPA, Washington DC 20460.
Elanco Products Company. 1985a. MRID No. 00164553. Available from EPA.
Write to FOI, EPA, Washington DC 20460.
Elanco Products Company. 1985b. Accession No. 265733. Available from EPA.
Write to FOI, EPA, Washington DC 20460.
Elanco Products Company. 1985c. Accession No. 265737, 265738. Available
from EPA. Write to FOI, EPA, Washington DC 20460.
__VI.B. INHALATION RfD REFERENCES
None
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
Dearfield, K. 1988. U.S. EPA, Washington, DC. Memorandum to M. Jones,
Office of Pesticide Programs, U.S. EPA, Washington, DC. Overview of submitted
mutagenicity studies on Isoxaben. June 17.
Elanco Products Company. 1983a. MRID No. 00132136. Available from EPA.
Write to FOI, EPA, Washington DC 20460.
Elanco Products Company. 1983b. MRID No. 00132137. Available from EPA.
Write to FOI, EPA, Washington DC 20460.
Elanco Products Company. 1983c. MRID No. 00132138. Available from EPA.
Write to FOI, EPA, Washington DC 20460.
Elanco Products Company. 1984. MRID No. 164555. Available from EPA. Write
to FOI, EPA, Washington DC 20460.
Elanco Products Comapny. 1985. MRID No. 164553. Available from EPA. Write
to FOI, EPA, Washington DC 20460.
Rinde, E. 1987. U.S. EPA, Washington, DC. Memorandum to R. Mountfort,
Office of Pesticide Programs, U.S. EPA, Washington, DC. Peer Review of
Isoxaben. October 5.
Swentzel, K.C. 1989. U.S. EPA, Washington, DC. Memorandum to R. Mountfort,
Office of Pesticide Programs, U.S. EPA, Washington, DC. Peer Review of
Isoxaben-Reevaluation Following the September 7, 1988 Science Advisory Panel
Review. January 4.
U.S. EPA. 1988. FIFRA Science Advisory Panel Executive Summary: A set of
Scientific Issues Being Considered by the Agency in Connection with the Peer
Review Classification of Isoxaben as a Class C Oncogen. Stephen L. Johnson,
Executive Secretary.
_VII. REVISION HISTORY
Substance Name -- Isoxaben
CASRN -- 82558-50-7
Primary Synonym -- EL-107
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
09/26/1988 I.A. Oral RfD summary on-line
12/01/1988 I.A.4. Study 4) LEL corrected
06/01/1989 II. Carcinogen assessment now under review
12/01/1989 VI. Bibliography on-line
04/01/1991 I.A. Text edited
09/01/1991 VI.C. Carcinogenicity assessment on-line
09/01/1991 VI.C. Carcinogenicity bibliography added
10/01/1991 VI.C. Carcinogenicity refs moved to correct biblio section
10/01/1993 II.D.3. Secondary contact changed
VIII. SYNONYMS
Substance Name -- Isoxaben
CASRN -- 82558-50-7
Primary Synonym -- EL-107
Last Revised -- 09/26/1988
82558-50-7
Benzamide, N-(3-(1-ethyl-1-methylpropyl)-5-isoxazolyl)-2,6-dimethoxy-
Caswell No. 419F
Compound 121607
EL-107
EPA Pesticide Chemical Code 125851
Isoxaben
N-(3-(1-Ethyl-1-methylpropyl)isoxazol-5-yl)-2,6-dimethoxybenzamide
N-(3-(1-Ethyl-methylpropyl)-5-isoxazolyl)-2,6-dimethoxybenzamide
N-(3-(1-Ethyl-1-methylpropyl)-5-isoxazolyl)-2,6-dimethoxybenzamide (9CI)
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0339.HTM
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