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Avermectin B1
CASRN 65195-55-3
Contents
0381
Avermectin B1; CASRN 65195-55-3
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 Avermectin B1
File On-Line 07/01/1989
Category (section) Status Last Revised
----------------------------------------- -------- ------------
Oral RfD Assessment (I.A.) on-line 07/01/1989
Inhalation RfC Assessment (I.B.) no data
Carcinogenicity Assessment (II.) no data
_I. CHRONIC HEALTH HAZARD ASSESSMENTS FOR NONCARCINOGENIC EFFECTS
__I.A. REFERENCE DOSE FOR CHRONIC ORAL EXPOSURE (RfD)
Substance Name -- Avermectin B1
CASRN -- 65195-55-3
Primary Synonym -- Abamectin
Last Revised -- 07/01/1989
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
-------------------- ----------------------- ----- --- ---------
Increased retinal NOEL: 0.12 mg/kg/day 300 1 4E-4
folds in weanlings, mg/kg/day
decrease viability LEL: 0.40 mg/kg/day
and lactation indices,
decreased pup body
weight, increase of
dead pups at birth
2-Generation Rat
Reproduction Study
Merck and Co., 1984
*Conversion Factors: Actual dose tested
___I.A.2. PRINCIPAL AND SUPPORTING STUDIES (ORAL RfD)
Merck and Company. 1984. MRID No. 00164151. Available from EPA. Write to
FOI, EPA, Washington, DC 20460.
Avermectin was given orally by gavage to randomized groups of 30 male and 30
female Sprague-Dawely rats at dosages of 0 (vehicle), 0.05 mg/kg/day, 0.12,
and 0.40 mg/kg/day for two generations with two litters/generation.
Intubation with either the vehicle or the test material was initiated daily
when these rats were 39 days old and had individual body weights ranging from
142 to 194 g (male rats) and from 113 to 151 g (female rats). Daily dosing
was continued until death.
At 0.40 mg/kg/day several effects were observed including increased retinal
folds in weanlings, increase of dead pups at birth, decrease viability and
lactation indices, and decreased pup body weight. Therefore, the NOEL for
this study is 0.12 mg/kg/day based on the effects observed at 0.40 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. An additional UF of 3 was used to account for the
following: 1) the severity of the effects at the LEL dose observed in the
critical study, and 2) maternal toxicity (mortality) and developmental
toxicity (cleft palate) observed in the mouse teratology studies (Delta-8,9-
Isomer).
MF -- None
___I.A.4. ADDITIONAL COMMENTS (ORAL RfD)
Avermectin B1 (technical) is composed of 80% Avermectin B1a and 20% Avermectin
B1b. The difference structurally between B1a and B1b is that B1a has a C2H5-
group and the B1b has a CH3-group attached to one of the ring structures.
Therefore, the only chemical difference between B1a and B1b is a methylene
(-CH2) group.
When Avermectin B1 is applied to plants, a plant photoproduct forms which is
not present in animals. This plant photoproduct is the delta-8,9-isomer.
which possesses Avermectin B1-like toxicological activity. Further
photodegradtion of Avermectin B1 results in polar degradates in plants but not
in animals. The polar degradates do not possess Avermectin B1-like
toxicological properties.
The parent compound, Avermectin B1, and the delta-8,9-isomer are regulated
toxicologically (tolerance expression in food has both). Although the polar
degradates are also present in food, they are not regulated toxicologically
since they are toxicologically insignificant.
Data Considered for Establishing the RfD
1) 2-Generation Reproduction - rat: Principal study - see previous
description; core grade minimum
2) 2-Year Feeding (oncogenic) - rat: Systemic NOEL=1.5 mg/kg/day; Systemic
LEL=2.0 mg/kg/day (HDT; treatment-induced tremors in both sexes); core grade
minimum (Merck and Co., 1985a)
3) 52-Week Feeding - dog: NOEL=0.25 mg/kg/day; LEL=0.5 mg/kg/day (mydriasis);
core grade guideline (Merck and Co., 1987)
4) Teratology - rat: Maternal, Teratogenic, and Fetotoxic NOEL=1.6 mg/kg/day
(HDT); Maternal, Teratogenic, and Fetotoxic LEL=none; core grade minimum
(Merck and Co., 1982a)
5) Teratology - rabbit: Maternal NOEL=1 mg/kg/day; Maternal LEL=2 mg/kg/day
(decreases in body weight, food consumption and water consumption); core grade
minimum (Merck and Co., 1982b)
6) Teratology - mouse: (Avermectin B1a) Teratogenic NOEL=0.2 mg/kg/day;
Teratogenic LEL=0.4 mg/kg/day (cleft palate); Maternal toxicity NOEL=none
(mortality); core grade minimum (Merck and Co., 1982c)
7) Teratology - mouse: (Avermectin B1b) Maternal NOEL=0.05 mg/kg/day; Maternal
LEL=0.075 mg/kg/day (HDT; mortality in 2 mice after 6 doses); Developmental
NOEL=0.075 mg/kg/day); Developmental LEL=none; core grade minimum (Merck and
Co., 1985b)
Other Data Reviewed:
1) 94-Week Feeding (oncogenic) - mouse: Systemic NOEL=4 mg/kg/day; Systemic
LEL=8 mg/kg/day (increased incidence of skin dermatitis in males, increase
incidence of extramedullary hematopoiesis in the spleen of males, increased
mortality in males and tremors and body weight decrease in females); core
grade minimum (Merck and Co., 1985c)
2) 14-Week Feeding - rat: NOEL=0.4 mg/kg/day (HDT; rats used in this study
had previously been exposed in utero to the test material); LEL=none; core
grade minimum [Merck and Co., n.d.(a)]
3) 18-Week Feeding - dog: NOEL=0.25 mg/kg/day; LEL=0.5 mg/kg/day (tremors,
one death, pathology of the liver, decreased body weight); core grade minimum
[Merck and Co., n.d.(b)]
4) Teratology - rat: (Delta-8,9-Isomer) Maternal and Developmental NOEL=1.0
mg/kg/day (HDT); core grade minimum (Merck and Co., 1988a)
5) Teratology - mouse: Three mouse teratology studies conducted with the
Delta-8,9-Isomer of Avermectin yielded the following results: Study No. 84-
722-1: Maternal NOEL=0.1 mg/kg/day; Maternal LEL=0.5 mg/kg/day (mortality);
Teratogenic NOEL=0.05 mg/kg/day; Teratogenic LEL=0.1 mg/kg/day (cleft palate);
core grade minimum (Merck and Co., 1985d); Study No. 85-710-0: Maternal
NOEL=0.6 mg/kg/day; Maternal LEL=none; Teratogenic NOEL=0.06 mg/kg/day; core
grade minimum (Merck and Co., 1985d) Study No. 85-710-1: Maternal NOEL=0.1
mg/kg/day; Maternal LEL=0.5 mg/kg/day (mortality); Teratogenic NOEL=0.03
mg/kg/day; Teratogenic LEL=0.1 mg/kg/day (cleft palate); core grade minimum
(Merck and Co., 1985d) Based on the above studies, the NOEL for maternal
toxicity in mice is 0.1 mg/kg/day, and the LEL is 0.5 mg/kg/day. The NOEL for
teratogenic toxicity is 0.06 mg/kg/day (based on the highest NOEL observed),
and the LEL is 0.1 mg/kg/day. This latter NOEL of 0.06 mg/kg/day, if divided
by a 100-fold uncertainty factor, would essentially yield the same RfD as
verified.
6) Teratology - mouse: (Citrus-Derived Polar Degradates) Maternal,
Developmental, and Teratogenic NOEL=1.0 mg/kg/day (HDT); core grade minimum
(Merck and Co., Inc. 1988b)
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 data 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 -- 04/20/1989
Verification Date -- 04/20/1989
___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 -- Avermectin B1
CASRN -- 65195-55-3
Primary Synonym -- Abamectin
Not available at this time.
_II. CARCINOGENICITY ASSESSMENT FOR LIFETIME EXPOSURE
Substance Name -- Avermectin B1
CASRN -- 65195-55-3
Primary Synonym -- Abamectin
This substance/agent has not undergone a complete evaluation and determination
under US EPA's IRIS program for evidence of human carcinogenic potential.
_VI. BIBLIOGRAPHY
Substance Name -- Avermectin B1
CASRN -- 65195-55-3
Primary Synonym -- Abamectin
Last Revised -- / /
__VI.A. ORAL RfD REFERENCES
Merck and Company. 1982a. MRID No. 00130819. Available from EPA. Write to
FOI, EPA, Washington D.C. 20460.
Merck and Company. 1982b. EPA Accession No. 249152. Available from EPA.
Write to FOI, EPA, Washington D.C. 20460.
Merck and Company. 1982c. EPA Accession No. 246894. Available from EPA.
Write to FOI, EPA, Washington D.C. 20460.
Merck and Company. 1984. MRID No. 00164151. Available from EPA. Write to
FOI, EPA, Washington D.C. 20460.
Merck and Company. 1985a. MRID No. 40069601, 40375511, 40517801. Available
from EPA. Write to FOI, EPA, Washington D.C. 20460.
Merck and Company. 1985b. EPA Accession No. 265572. Available from EPA.
Write to FOI, EPA, Washington D.C. 20460.
Merck and Company. 1985c. MRID No. 40069602, 40375512, 40517802. Available
from EPA. Write to FOI, EPA, Washington D.C. 20460.
Merck and Company. 1985d. EPA Accession No. 265564. Available from EPA.
Write to FOI, EPA, Washington D.C. 20460.
Merck and Company. 1987. MRID No. 00164022, 40375510. Available from EPA.
Write to FOI, EPA, Washington D.C. 20460.
Merck and Company. 1988a. MRID No. 40713403. Available from EPA. Write to
FOI, EPA, Washington D.C. 20460.
Merck and Company. 1988b. MRID No. 40912701. Available from EPA. Write to
FOI, EPA, Washington D.C. 20460.
Merck and Company. No date, a,b. EPA Accession No. 246895. Available from
EPA. Write to FOI, EPA, Washington D.C. 20460.
__VI.B. INHALATION RfD REFERENCES
None
__VI.C. CARCINOGENICITY ASSESSMENT REFERENCES
None
_VII. REVISION HISTORY
Substance Name -- Avermectin B1
CASRN -- 65195-55-3
Primary Synonym -- Abamectin
-------- -------- --------------------------------------------------------
Date Section Description
-------- -------- --------------------------------------------------------
07/01/1989 I.A. Oral RfD summary on-line
07/01/1989 VI. Bibliography on-line
VIII. SYNONYMS
Substance Name -- Avermectin B1
CASRN -- 65195-55-3
Primary Synonym -- Abamectin
Last Revised -- 07/01/1989
65195-55-3
ABAMECTIN
ANTIBIOTIC C 076B1a
AVERMECTIN A1a, 5-O-DEMETHYL-
AVERMECTIN B1
AVERMECTIN B1a
5-O-DEMETHYLAVERMECTIN Ala
Last updated: 5 May 1998
URL: http://www.epa.gov/iris/SUBST/0381.HTM
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