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avermectin (Agri-Mek, Affirm) E.P.A. Pesticide Fact Sheet 9/89





E.P.A. Pesticide Fact Sheet 

Name of Chemical:  Avermectin B1

Reason for Issuance:  Update - First Food Use (Cotton)

Date Issued:  May 1989

Fact Sheet Number:  89.1

                1. DESCRIPTION OF CHEMICAL

Generic Name:  Avermectin B1 [A mixture of avermectins containing > 80%
               avermectin B1a (5-0-dimethyl avermectin A1a) and < 20%
               avermectin B1b (5-0-demethyl-25-de(1-methylpropyl)-25-
               (1-methylethyl) avermectin A1a)]
Common Name:  None assigned

Trade Names:  Affirm, Agrimec, Avid, MK-936, Zephyr

Other Name:  Abamectin

EPA Shaughnessy Code:  0122804

Chemical Abstracts Service (CAS) Numbers:  65195-55-3 and
                                           65195-56-4

Year of Initial Registration:  1986

Pesticide Type:  Insecticide/Miticide

Chemical Family:  Avermectins (macrocylic lactones isolated from soil
                  organism Streptomyces avermitilis).

U.S. Producers:  Merck and Co., Inc.

               2. USE PATTERNS AND FORMULATIONS

Application Sites
     Control of imported fire ants on turf, lawns, and other non-crop 
areas; control of mites and other insects on shadehouse, greenhouse, ant 
field-grown flowers, foliage plants, and other ornamentals, and on 
cotton.

Type of Formulations
     0.011% insecticide bait, 2.0% Spray (0.15% EC), 70% technical.

Method of Application
     Bait broadcast (ground or air application) and individual mound to 
mound treatment (fire ants).  Foliar spray (ground application) mixed 
with water for use on field grown flowers, foliage plants and 
ornamentals.  Foliar spray (ground or air application) mixed with water 
for use on cotton.

Rates of Application
     For Fire Ants - Use rate is 50mg active ingredient (ai) per acre 
(1 pound (lb) product/acre); 
     For Field Grown Flowers and Ornamentals - use rate is 0.005 to 0.01 
lb ai/acre (4 to 8 oz product/acre); 
     For Cotton - Use rate is 0.01 to 0.02 lb ai/acre (8 to 16 oz 
product/acre) and 3 applications per season.

Usual Carriers:  Pregelled defatted corn grit carrier and water.

                     3 SCIENCE FINDINGS

Summary Science Statement

     Technical avermectin exhibits high mammalian acute toxicity.  It is 
not considered to be mutagenic and does not sensitize skin.  It is not 
readily absorbed by mammals and the majority of the residue is excreted 
in the feces within 2 days.  The 24-month rat chronic feeding/ 
oncogenicity study and 94-week mouse chronic toxicity oncogenicity study 
were negative for oncogenic potential.  The results of a series of 
developmental toxicity studies (rat, rabbit, mouse) have been evaluated 
and showed that avermectin B1 produces developmental toxicity (cleft 
palate) in the CF1 mouse.  Toxicology data were also evaluated for the 
delta-8,9-isomer of avermectin B1 which is a plant photodegradate that 
can range between 5 and 20 percent of the residue on/in cottonseed.  
This isomer possesses avermectin-like toxicological activity.  It was 
concluded that the delta 8,9-isomer also produces developmental toxicity 
(cleft palate) in mice, but not in rats.

     In addition to avermectin and its delta 8,9-isomer, toxicology data 
were also evaluated for the "polar degradates" of avermectin, which 
constitute a large percentage (up to 70%) of the total residue on 
cottonseed.  Review of the toxicology data indicated that these polar 
degradates do not possess avermectin-like toxicological activity and for 
this reason need not be included in the tolerance expression for 
residues in/on cottonseed.

     Sufficient data are available to characterize avermectin from an 
environmental fate and ecological standpoint.  Avermectin is extremely 
toxic to mammals and aquatic invertebrates and highly toxic to fish and 
bees.  Avermectin is relatively non-toxic to birds.  Based upon 
terrestrial residue analysis, aquatic runoff modeling and cluster 
analysis it appears that certain endangered species may be impacted by 
the use of avermectin on cotton.  EPA and the Fish and Wildlife Service 
are in the process of updating the cotton cluster. The results when 
available will be applicable to the registration of avermectin on 
cotton.

     Avermectin undergoes rapid photolysis, is readily degraded by soil 
microorganisms and, due to its binding properties and low water 
solubility, is expected to exhibit little or no potential for leaching; 
however, a complete assessment cannot be made until additional leaching 
and soil dissipation data are submitted.

Chemical Characteristics (Technical Grade):

Physical State:  Crystalline powder
Color:  Yellowish-white 
Odor:  Odorless 
Melting Point:  155 - 157 degrees C 
Vapor Pressure:  Being tested, expected to be extremely low 
Density:  1.16 plus or minus 0.05 at 21 degrees C 
Solubility:  Insoluble in water (less than or equal to 5 ug/mL),
             readily soluble in organic solvents 
pH:  NA.  The avermectin molecule has neither acidic nor basic
          functional groups 
Octanol/Water Partition Coefficient:  9.9 x 10 to the third

Toxicological Characteristics

Technical Grade Avermectin B1

- Dermal Sensitization: Negative for skin sensitization
- Acute Oral LD50 - Rat:  10.6 mg/kg (males),
                          11.3 mg/kg (females)
- 14-Week Oral Study - Rat:  NOEL is greater than or equal to
                             0.4 mg/kg/day (HDT)
- 18-Week Oral Study - Dog:  NOEL = 0.25 mg/kg/day
- Teratology Study - Rat:  Negative for terata up to 1.0 mg/kg/day.
- Teratology Study - Rabbit:  Negative for terata up to 1.0 mg/kg/day.
- Teratology Studies - Mouse:  Teratogenic LEL = 0.4 mg/kg/day
                               (cleft palate); Teratogenic NOEL =
- Maternotoxicity Studies - Mouse:  LEL = n.075 mg/kg/ day (lethality);
                                    NOEL = 0.05 mg/k~/day
- 2-Generation Reproduction Study - Rat:  NOEL = 0.12 mg/kg/day;
             LEL = 0.40 mg/kg/day (increased retinal folds in weanlings,
             increased dead pups at birth, decreased viability indices,
             decreased lactation indices, decreased pup body weights)
- 1-Year Oral Study - Dog:  NOEL = 0.25 mg/kg/day; LEL = 0.50 mg/kg/ day 
(mydriasis in males and females)
- 94-Week Chronic Toxicity/Oncogenicity Study - Mice:  Oncogenic
  potential:  Negative up to 8 mg/kg/day (HDT); Systemic NOEL = 4
  mg/kg/day; Systemic LEL = 8 mg/kg/day (Dermatitis in males,
  extramedullary hematopoiesis in the spleen in males, increased
  mortality in males, tremors and body weight loss in females)
- 2-Year Chronic Toxicity/Oncogenicity Study - Rats: Oncogenic
  potential:  Negative up to 2.0 mg/kg/day (HDT); Systemic NOEL = 1.5
  mg/kg/day; Systemic LEL = 2.0 mg/kg/day tremors in both sexes)
- Metabolism Study - Rat: The metabolic T 1/2 in rats is 1.2 days
- Ames Mutagenicity Assay:  Negative
- Mutagenicity Assay for Chromosomal Aberrations in vitro in Chinese
  hamster Ovary Cells
- Rat Hepatocyte Mutagenicity Study:  Under conditions of the study,
  abamectin (0.3 and 0.6 mM) caused an induction of single strand DNA
  breaks in rat hepatocytes in vitro; no effect was observed when the
  assay was carried out on hepatocytes from rats dosed in vivo at the
  LD50 dose level (10.6 mg/kg)
- In Vivo Bone Marrow Mutagenicity Cytogenic Study:  Negative in male
  mice at doses of 1.2 and 12.0 mg/kg

Toxicity Studies on the Delta-8,9-Isomer of Avermectin

- Acute Oral LD50 - Mouse:  > 80 mg/kg (HDT) (males and females)
- Teratology Study - Rat:  Negative for terata up to 1.0 mg/kg/day (HDT)
- Teratology Studies - Mouse:  Teratogenic LEL = 0.10 mg/kg/day 
  (cleft palate); Teratogenic NOEL = 0.06 mg/kg/day
- Maternotoxicity Studies - Mouse:  LEL = 0.50 mg/kg/ day (lethality);
  NOEL = 0.10 mg/kg/day
- 1-Generation Reproduction Study - Rat:  NOEL = 0.4 mg/kg/day (HDT)
- Ames Mutagenicity Assay:  Negative

Toxicity Studies on the "Polar Degradates" of Avermectin

- Acute Oral LD50 - Mouse:  > 5000 mg/kg (HDT)
- Teratology Study - Mouse:  Negative for terata up to 1.0 mg/kg/day
  (HDT)
- Teratology Study (polar degradates derived from , citrus-treated
  fruit) - Mouse:  Negative for terata up to 1.0 mg/kg/day (HDT)
- Ames Mutagenicity Assay:  Negative

Ecological Characteristics:

Avian Oral (Bobwhite quail):  LD50 > 2000 mg/kg; LC50 = 3102 ppm
Avian Dietary (Mallard duck):  LC50 = 383 ppm
Freshwater Fish (Bluegill):  LC50 = 9.6 ppb
Rainbow trout:  LC50 = 3.2 ppb
Estuarine Fish (Fathead minnow):  LC50 = 15 ppb
Oyster Embryo Larvae:  LC50 = 430 ppb.
Acute Freshwater Invertebrate (Daphnia):  LC50 = 0.22 ppb
Acute Estuarine Invertebrate (Shrimp, mysid):  LC50 = 0.02 ppb

Environmental Characteristics:

     Avermectin is stable to hydrolysis at ph 5, 7, and 9 and thus is 
not expected to hydrolyze in the environment.  It photodegrades rapidly 
in water and soil with half-lives of less than 12 hours and 1 day 
respectively.  Soil metabolism studies conducted in darkness indicate 
degradation does occur with a half-life of 2 weeks to 2 months under 
aerobic conditions.  Anaerobic degradation is slower.  It is not 
expected to accumulate in fish.  Avermectin's solubility in water is 
determined to be 7.8 ppb.  The field dissipation study indicates that 
avermectin, when applied in the bait formulation directly to the soil, 
dissipates with a half-life of about a week but may persist longer if 
the bait is shaded.  Due to its binding properties and low water 
solubility, Avermectin is expected to exhibit little or no potential for 
leaching; however, a determination cannot be made until the results of 
the analyses of the three remaining soil core replicates are submitted 
and evaluated.  Also an absorption/desorption leaching study must be 
conducted since avermectin has shown conflicting results in soil thin-
layer chromatographic (TLC) (immobile) and soil column studies.

Tolerance Assessment

     A Section 408 tolerance under the Federal Food, Drug, and Cosmetic 
Act has been established for residues of avermectin B1 and its delta 
8,9-isomer in/on the following raw agricultural commodity (RAC) (40 CFR 
180.___ )

         Commodity            ppm

        Cottonseed          0.005

     The acceptable daily intake (ADI), based on a NOEL of 0.12 
mg/kg/day from a 2-generation rat reproduction study and safety factor 
of 300, is 0.0004 mg/kg/body weight (bwt) day.

     Because of developmental effects seen in animal studies the Agency 
used the rat reproduction study with a 300 fold safety factor to assess 
chronic dietary exposure and establish an ADI.  The 300 fold safety 
factor was employed to account for (l) inter- and intra-species 
differences (2) and pup death observed in the reproduction study. 
(3) maternal toxicity (lethality) NOEL = 0.05 mg/kg/day, and (4) cleft 
palate in the mouse teratology study with the isomer, NOEL = 0.06 
mg/kg/day.  The theoretical maximum residue contribution (TMRC) from the 
proposed tolerance as well as pending tolerances on celery, pears and 
tomatoes and temporary tolerances on citrus with secondary residues in 
meat and milk is 0.000052 mg/kg/day.  This is equivalent to about 13 
percent of the ADI.  This analysis used tolerance level residues and 100 
percent of crop treated.  The TMRC from cotton only is .000001 
representing less than 0.1 of the ADI.

     Because of adverse developmental effects seen in animal studies 
detailed acute dietary exposure analysis for this tolerance and pending 
tolerances for this chemical was also conducted using a NOEL of 0.06 
mg/kg body weight for developmental effects.  The food uses evaluated 
were the same as those evaluated in the chronic exposure analysis.  The 
acute exposure analysis estimated the distribution of single-day 
exposures for the overall U.S. population and certain population 
subgroups.  The analysis evaluated the individual food consumption, as 
reported by respondents in the 1977-78 USDA Food Consumption Survey, and 
accumulated exposure to avermectin for each food consumed for which a 
tolerance is being evaluated.  Each analysis assumed that avermectin 
residues were present at tolerance level in all foods consumed.  The 
toxicologic endpoint pertained to developmental toxicity.  The subgroup 
of interest in this analysis was women aged 13 and above, which has the 
subgroup most closely approximating women of child-bearing age.  Based 
upon this analysis the Margin of Safety (MOS) for the average woman of 
child bearing age was calculated to be 1579.  None of the target 
population is expected to have a MOS less than 250.

     The nature of the residue in cottonseed is adequately defined.  The 
residue of concern is the parent and its delta 8,9-isomer.  Based on 
(1) no accumulation of avermectin in tissues or milk (from a ruminant 
metabolism study) (2) absence of measurable residues (<2 ppb) in 
cottonseed treated at exaggerated application rates and (3) feeding 
restrictions for cotton foliage the Agency has concluded that there is 
no reasonable expectation of finite residues in milk, eggs, meat, or 
poultry and no processing data or food/feed additive tolerances are 
needed for the use on cotton.

     There are no Canadian or Mexican tolerances and no Codex Maximum 
Residue Limits (MRLS) have been established for avermectin B1 and its 
delta 8,9-isomer in/on cotton. Therefore, no compatibility problem 
exists.

          4. SUMMARY OF REGULATORY POSITION AND RATIONALE

     The Agency has determined that it should allow the conditional 
registration of abamectin for agricultural use to control mites on 
cotton.  Adequate data are available to assess the acute and chronic 
toxicological effects of abamectin to humans.  However since long-term 
fish, aquatic and mammalian data are lacking and additional leaching and 
soil dissipation data are required, the registration is being 
conditionally approved with an expiration date of March 31, 1992.  Due 
to the conditional status of the registration the Agency is also 
establishing the tolerance for this pesticide on cottonseed with an 
expiration date of March 31, 1993 to cover residues expected to be 
present during and for one year after the period of conditional 
registration.

      In view of the high toxicity of technical abamectin to fish, 
aquatic invertebrates and mammals and the potential hazard associated 
with exposure from the use on cotton the risk criteria for restricted 
use classification is exceeded and thus the Agency, is restricting use 
on cotton to certified applicators.

     Additional data are required to more adequately define the hazards 
to mammals, fish, and aquatic invertebrates.  According to EPA's 
Ecological Effects Standard Evaluation Procedures presumption of 
unacceptable risk is triggered when the estimated environmental 
concentration (EEC) exceeds the bird or mammal LC50, or 1/2 the aquatic 
LC50 or EC50.  According to EPA's assessments, these criteria are 
exceeded for mammals and aquatic invertebrates for the cotton use 
(mammal 1-day LC50 = 2.5 ppm, EEC = 4.8 ppm, aquatic invertebrate 
(freshwater) EC50 = 0.22 ppb, EEC = 0.6 ppb; estuarine invertebrate EC50  
0.02 ppb, EEC = 0.6 ppb).

     Because of adverse developmental effects seen in animal studies 
non-dietary exposure analysis was also conducted with respect to 
exposure to mixer/loaders, applicators and harvesters. Based upon 
surrogate exposure data; persons wearing long pants, long-sleeved 
shirts, rubber gloves and dermal absorption data in the monkey, the 
calculated MOS for cotton crop applicators and workers were found to 
exceed 100 in all instances.  This MOS is sufficient to adequately 
protect these workers.

                     5. SUMMARY OF DATA GAPS

                                 Reference
Name of Study                      Number            Due Date
_____________                    _________         _____________

Fish Life Cycle Test             Sect.72-5         October 1991

Mesocosm Aquatic Study           Sect.72-7         October 1991

Simulated Mammal Field Test      Sect.71-5         October 1991

Soil Absorption/Desorption       Sect.163-1        June 1990

Results of the Analysis of the
Remaining Soil Core Samples for
the Field Dissipation Study      Sect.164-1        July 1989


                 6. REQUIRED UNIQUE LABELING SUMMARY

     All products registered for use on cotton must bear the following 
restricted use labeling statements:

                      RESTRICTED USE PESTICIDE
          Toxic to Fish, Mammals and Aquatic Organisms
     For Retail sale to and use only by Certified Applicators or Persons 
under their direct supervision and only for those uses covered by the 
Certified Applicator's certification

     The following use limitations must appear on products registered 
for use on cotton:

- Do not apply more than 48 fl oz per acre per year.
- Do not apply within 20 days of harvest.
- Do not graze or feed cotton foliage.
- Do not reenter treated areas until sprays have dried.
- Do not apply when weather conditions favor drift from target areas.
- Do not apply this product through any type of irrigation system.

     Personal protective equipment and work safety statements must 
appear on the label of products registered for use on cotton and shade 
house, greenhouse and field grown flowers, foliage plants and 
ornamentals.

                   6. CONTACT PERSON AT EPA

George T. LaRocca
Product Manager 15
Insecticide-Rodenticide Branch
Registration Division (H7505C)
Office of Pesticide Program
U.S. Environmental Protection Agency
401 M Street SW.
Washington, DC 20460

Office location and telephone number:

Rm. 204, CM #2
1921 Jefferson Davis Highway
Arlington, VA 22202
(703) 557-2400

DISCLAIMER:  The information presented in this Chemical Information Fact 
Sheet is for informational purposes only and may not be used to fulfill 
data requirements for pesticide registration and reregistration.