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Apollo
CASRN 74115-24-5
Contents
0008
Apollo; CASRN 74115-24-5
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 Apollo
File On-Line 01/31/1987
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) on-line 11/01/1989
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 -- Apollo
CASRN -- 74115-24-5
Last Revised -- 11/01/1989
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 effects; organ NOEL: 50 ppm 100 1 1.3E-2
weight changes (1.25 mg/kg/day) mg/kg/day
1-Year Feeding Dog LEL: 1000 ppm
Study (25 mg/kg/day)
BFC Chemicals, Inc.,
1984
*Conversion Factors: 1 ppm = 0.025 mg/kg/day (assumed dog food consumption)
___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
BFC Chemicals, Inc. 1984. MRID No. 00149491, 00159080. Available from EPA.
Write to FOI, EPA, Washington D.C. 20460.
Four groups of 6 male and 6 female dogs were given diets containing 0, 50,
l000, or 20,000 ppm Apollo for l year. All test animals were observed during
the study for appearance of clinical signs or mortality, body weight, food
consumption, ophthalmological observations, electrocardiograms, hematology,
blood biochemistry, and urine analysis. At necropsy the tissues and organs
were grossly examined and lesions were noted. Organ weights were determined
and microscopic examinations were conducted on tissues. Apollo affected the
liver of dogs given dietary levels of l000 and 20,000 ppm. The effects
included hepatocyte enlargement with eosinophilic cytoplasm; increased liver,
thyroid, and adrenal weights; and elevated serum cholesterol, triglycerides,
and alkaline phosphatase.
___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)
Final reports on long-term studies in rats and mice are pending. Interim
reports for both studies (at 1 year for rats and mice and 18 months for rats)
have been submitted and reviewed. From these reports it is considered that
the dog appears to be the most sensitive species.
Data Considered for Establishing the RfD:
1) 1-Year Feeding - dog: Principal study (see description above); core grade
minimum
2) 2-Year Feeding (oncogenic) - rat: NOEL=40 ppm (2 mg/kg/day); LEL=400 ppm
(20 mg/kg/day) [increased liver weights and liver-to-body weight ratio
(males); increased thyroxine levels; centrilobular hypertrophy and vacuolation
of hepatocytes, focal cystic degeneration of hepatocytes, and diffuse
distribution of fat deposits in liver (males)]; core grade minimum (Nor-Am
Chemical Co., 1986)
3) 3-Generation Reproduction - rat: Reproductive NOEL=400 ppm (20 mg/kg/day)
(HDT); Systemic NOEL=40 ppm (2 mg/kg/day); Systemic LEL=400 ppm (centrilobular
hepatocyte hypertrophy, increased liver weight); core grade minimum (BCF
Chemicals, 1984)
4) Teratology - rat: Teratogenic NOEL=3200 mg/kg/day; Fetotoxic NOEL=3200
mg/kg/day (HDT); Maternal NOEL=1280 mg/kg/day, Maternal LEL=3200 mg/kg/day
(differential staining and slight enlargement of the centrilobular
hepatocytes); core grade minimum (BCF Chemicals, 1982)
5) Teratology - rabbit: Teratogenic NOEL=3000 mg/kg/day (HDT); Fetotoxic
NOEL=1000 mg/kg/day; Fetotoxic LEL=3000 mg/kg/day (bw reduction); Maternal
NOEL=1000 mg/kg/day; Maternal LEL=3000 mg/kg/day (bw reduction, reduced food
intake); core grade minimum (BCF Chemicals, 1983)
Other Data Reviewed:
1) 105-Week (oncogenic) - mice: Systemic NOEL=500 ppm (75 mg/kg/day);
Systemic LEL=5000 ppm (750 mg/kg/day) [reversible decreases in body weight,
decreased body weight gain (15 to 22%), increased incidence of eosinophalic
areas or foci of hepatocytes in males; in females increased incidence of
basophilic and/or eosinophilic foci or areas of hepatocytes, an increased
mortality during weeks 78 to 105 with amyloidosis identified as a contributing
factor to deaths]; core grade minimum (BCF Chemicals, 1983)
Data Gap(s): none
___I.A.5. CONFIDENCE IN THE ORAL RfD
Study -- High
Data Base -- High
RfD -- High
The principal study appears to be of good quality and is given a high
confidence rating. The additional studies are of fair to good quality, are
comprehensive, and quantitatively support the choice of a NOEL; thus, 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
Pesticide Registration Files/ New Chemical
Agency Work Group Review -- 04/22/1986, 09/16/1987
Verification Date -- 04/22/1986
___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 -- Apollo
CASRN -- 74115-24-5
Not available at this time.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Apollo
CASRN -- 74115-24-5
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 an increase in thyroid gland follicular cell tumors in male
rats and supportive findings in pituitary/thyroid hormone activity.
___II.A.2. HUMAN CARCINOGENICITY DATA
None.
___II.A.3. ANIMAL CARCINOGENICITY DATA
Limited. There was an increase in the incidence of a single tumor type in
male rats. Charles River Sprague-Dawley rats (70/sex/group) were fed Apollo
in the diet at 0, 10, 40 or 400 ppm for 27 months. Twenty animals/sex/dose
were treated as satellite groups and killed at 12 months (FBC/Nor-Am Chemical
Co., 1985a). In male rats there was a statistically significant dose-related
trend in the incidence of both benign and malignant follicular cell tumors in
the thyroid gland. There was also a statistically significant increase in the
incidence of combined benign and malignant thyroid gland tumors in the male
rats in the high-dose group; the incidences were 2/68, 2/65, 2/66 and 8/63 in
the 0, 10, 40 and 400 ppm dose groups, respectively (Gardner, 1988). (Animals
that died before week 52 were excluded because these animals are not at the
same type of risk; the denominators reflect numbers of animals at risk.)
Historical data for combined tumors from two studies conducted at the same
laboratory ranged from 3/40 to 6/40, indicating that survival was not affected
by the doses used in this study. Although both the Toxicology Branch Peer
Review Committee and the FIFRA Scientific Advisory Panel concluded that the
maximum tolerated dose (MTD) had not been achieved in this study, they decided
that the study was not compromised. In a 90-day study in rats (BFC Chemicals,
Inc., 1981) at dietary doses of 0, 40, 400 and 4000 ppm, Apollo produced liver
changes (increased liver weight, morphologic changes, and increased clinical
chemistry values) that were not life threatening and without body weight was
not suppressed even at the highest dose tested.
Charles River CD-1 Swiss mice (52/sex/dose) were fed Apollo in the diet at
levels of 0, 50, 500 and 5000 ppm for 105 weeks (FBC/Nor-Am Chemical Co.,
1985b). Incidences of malignant and combined benign/malignanthepatocellular
tumors were significantly increased in the 500 ppm males but not in high-dose
males (no dose-response relationship). The incidences of malignant liver
tumors in 0, 50, 500 and 5000 ppm males were 14/50, 16/46, 24/48 and 19/48,
respectively; the incidence of combined benign and malignant tumors were
19/50, 20/46, 33/48 and 25/48, respectively (U.S. EPA, 1988a). No significant
increase in these tumors was observed at any dose in the females (Peto
prevalence procedures were employed in the tumor analysis of female mice).
The male mice showed no change in survival with increased dose, while
mortality increased with increased dose in the female mice. The dose
selection for the male mice was indeed adequate based on body weight loss at
the high dose. The doses administered to the females did not appear to reach
the MTD respect to toxic effects, yet mortality was significantly increased at
the high dose. The OPP Health Effects Division Peer Review Committee (Quest,
1988; Gardner, 1988) and the FIFRA Scientific Advisory Panel (U.S. EPA, 1988)
agreed, based on the results of this study, that there were no compound-
related effects on tumor incidence.
___II.A.4. SUPPORTING DATA FOR CARCINOGENICITY
Several short-term studies in rats (reviewed in U.S. EPA, 1988a,b) have
implicated the thyroid gland as the target organ for Apollo. Follicular
hypertrophy, diminished colloid, and possible hyperplasia were characteristic
of the histomorphological effects and were reversible when dosing stopped.
Blood concentrations of thyroxine, tri-iodothyroxine, and thyroid-stimulating
hormone (TSH) levels were increased; iodine uptake was also increased. The
normal expectation for a goitrogenic material would be to have reduced thyroid
hormone and increased TSH. Further studies revealed that Apollo increased
bile flow rate and shifted the pattern of thyroxine excretion to the feces,
suggesting that Apollo may enhance clearance of thyroid hormones.
The proposed mechanisms postulated that Apollo increased bile flow,
causing an increase in metabolism and excretion of thyroxine. The reduced
circulating thyroxine stimulated the pituitary gland through the hypothalamus
to produce increased TSH. The elevated TSH stimulated the follicular cells
and resulted in increased thyroxine and decreased colloid, follicular cell
hyperplasia, hypertrophy and neoplasia in the male rat at the termination of
the chronic study.
Apollo was negative in a Salmonella typhimurium mutagenicity test with or
without hepatic homogenates. Results of a mutagenicity assay in a mouse
lymphoma cell line with and without activation were equivocal. It was
negative in a micronucleus test in mice at doses of up to 3200 mg/kg and did
not produce gene conversion or mitotic recombination in Saccharomyces
cerevisiae strain D7. At dietary doses of up to 400 ppm for 10 weeks, it did
not produce dominant lethal effects in male rats (reviewed in U.S. EPA,
1988a).
Neither Apollo nor its urinary metabolites were found to be structurally
related to any known carcinogen (reviewed in U.S. EPA, 1988a).
__II.B. QUANTITATIVE ESTIMATE 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 -- Gardner, 1988, 1990; Quest, 1988; U.S. EPA, 1988
The Office of Pesticide Programs (Health Effects Division, U.S. EPA) peer
reviewed data pertaining to potential carcinogenicity of Apollo (Memorandum
from R. Gardner to D. Edwards, Third Peer Review of Apollo 04/16/1990).
___II.D.2. REVIEW (CARCINOGENICITY ASSESSMENT)
Agency Work Group Review -- 11/09/1988, 02/08/1990
Verification Date -- 02/08/1990
___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 -- Apollo
CASRN -- 74115-24-5
Last Revised -- 06/01/1991
__VI.A. ORAL RfD REFERENCES
BFC Chemicals, Inc. 1982. MRID No. 00114270, 00159095. Available from EPA.
Write to FOI, EPA, Washington DC 20460.
BFC Chemicals, Inc. 1983. MRID No. 00130761. Available from EPA. Write to
FOI, EPA, Washington DC 20460.
BFC Chemicals, Inc. 1984a. MRID No. 00149491, 00159080. Available from EPA.
Write to FOI, EPA, Washington DC 20460.
BFC Chemicals, Inc. 1984b. MRID No. 00147884, 00159070, 40289801. Available
from EPA. Write to FOI, EPA, Washington DC 20460.
BFC Chemicals, Inc. 1985. MRID No. 00147885, 00159094, 40302001. Available
from EPA. Write to FOI, EPA, Washington DC 20460.
Nor-Am Chemical Company. 1986. MRID No. 00147883, 00159081. Available from
EPA. Write to FOI, EPA, Washington DC 20460.
__VI.B. INHALATION RfC REFERENCES
None
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
BFC Chemicals, Inc. 1981. EPA Accession Nos. 070963, 071384, 071859.
Available from EPA. Write to FOI, EPA, Washington, DC 20460.
FBC/Nor-Am Chemical Company. 1985a. EPA Accession Nos. 262261, 262262.
Available from EPA. Write to FOI, EPA, Washington, DC 20460.
FBC/Nor-Am Chemical Company. 1985b. EPA Accession Nos. 262263, 262264.
Available from EPA. Write to FOI, EPA, Washington, DC 20460.
Gardner, R. 1988. U.S. EPA, Washington, DC. Memorandum to D.H. Edwards,
U.S. EPA, Washington, DC, July 27. Second Peer Review of Apollo
(Clofentizine).
Gardner, R. 1990. U.S. EPA, Washington, DC. Memorandum to D.H. Edwards,
U.S. EPA, Washington, DC, April 16. Third Peer Review of Apollo
(Clofentizine).
Quest, J.A. 1988. U.S. EPA, Washington, DC. Memorandum to D.H. Edwards,
U.S. EPA, Washington, DC., April 12. Peer Review of Apollo (Clofentizine).
U.S. EPA. 1988. Memorandum. Federal Insecticide, Fungicide, and
Rodenticide Act. Scientific Advisory Panel Report. Stephen L. Johnson
(Executive Secretary).
_VII. REVISION HISTORY
Substance Name -- Apollo
CASRN -- 74115-24-5
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
03/01/1988 I.A.3. Text revised
03/01/1988 I.A.4. Data gaps revised
03/01/1988 I.A.4. Study description added
03/01/1988 I.A.4. Data added to 'Other Data Reviewed'
03/01/1988 I.A.5. Confidence levels revised
03/01/1988 I.A.6. Dates corrected
06/30/1988 I.A.6. Work Group review date added
11/01/1989 I.A. Principal study year corrected
11/01/1989 VI. Bibliography on-line
03/01/1990 II. Carcinogen assessment now under review
06/01/1991 II. Carcinogenicity assessment on-line
06/01/1991 VI.C. Carcinogenicity references added
10/01/1993 II.D.3. Primary contact changed; secondary's phone no. changed
VIII. SYNONYMS
Substance Name -- Apollo
CASRN -- 74115-24-5
Last Revised -- 01/31/1987
74115-24-5
88025-82-5
Apollo
Apollo 50W
3,6-Bis(2-chlorophenyl)-1,2,4,5-tetrazine
Bisclofentezin
Bisclofentezine
Clofentezine
NC 21314
1,2,4,5-Tetrazine, 3,6-bis(2-chlorophenyl)-
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0008.HTM
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