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Repeated dose toxicity: dermal

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short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
February 1989
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP study in compliance with guidelines

Data source

Reference Type:
study report
Report date:

Materials and methods

Test guideline
according to guideline
EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
GLP compliance:
Limit test:

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
Name: Ametryn Tecnical (FL 840991)
Purity: 97,4 %

Test animals

New Zealand White
Details on test animals or test system and environmental conditions:
TEST SYSTEM: 22 male and 22 female New Zealand white rabbits were received from H.A.R.E., Inc. Hewitt, New Jersey on July 7, 1988. Upon arrival at the Safety Evaluation Facility (SEF), all animals were assigned to individual cages. The rabbits were acclimated to laboratory conditions for about three weeks prior to dosing. ,The rabbits were offered a daily ration of Purina Rabbit Chow 5325 and had tap water ad libitum via an automatic delivery system. The feed and drinking water were monitored for contaminants according to the Standard Operating Procedures (SOPs) of the SEP. Only those animals judged healthy on the basis of general observations, body weights, physical/auditory examinations, and clinical laboratory evaluations that were performed during the predose period were utilized for this study. Prior to the initiation of dosing, rabbits were randomly assigned to treatment groups via the Beckman TOXSYS (R) Computer System. Rabbits not assigned to the study were returned to stock. Animals were identified with Monel ear tags according to the SOPs of the SEP. Study animals were approximately 14-15 weeks of age and weighed 2.35 to 3.00 kg just prior to dosing.

ANIMAL QUARTERS: All rabbits in this study were housed at the Summit facilities in a single animal room in the SEP. The room was maintained at a daily temperature of 65 ± 5 °F and a relative humidity of 50 ± 20%, whenever possible. Room temperature and humidity were monitored throughout the study according to the SOPs of the SEP. In addition, the animal room was supplied daily with 12 hours of continuous artificial light and was closely monitored so that no unusual activities interfered with the conduct of the study.

Administration / exposure

Type of coverage:
Details on exposure:
Prior to dosing and as needed during the study, each rabbit was prepared by clipping the skin of the flank and back free of hair. Ametryn was weighed neat, moistened with sterile water, and applied daily to an area of intact skin comprising approximately 5 to 10% (approximately 120 to 240 sq. cm.) of the total body surface of the rabbits. A gauze dressing was applied over the test site and secured to the animal with adhesive wrapping. Following dosing, each animal was fitted with an Elizabethan collar and returned to its cage. The compound remained in contact with the skin for approximately 6 hours daily. One group of rabbits was similarly treated with sterile water and did not receive the test substance. Following the dosing period, the gauze dressing was removed, and the treatment site was gently washed with tap water and dried with a paper towel. Each animal was then returned to its cage overnight.
Analytical verification of doses or concentrations:
Details on analytical verification of doses or concentrations:
Not applicable
Duration of treatment / exposure:
21 days
Frequency of treatment:
The compound was applied to shaved skin for approximately 6 hours daily.
Doses / concentrations
Doses / Concentrations:
0 (G1), 10 (G2), 100 (G3), 1000 (G4) mg/kg
nominal per unit body weight
No. of animals per sex per dose:
40 animals: 5 male and 5 femal for each dose level
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:
The dermal LD50 of Ametryn Technical is greater than 2010 mg/kg . Twenty-one day dermal toxicity studies in rabbits have been completed for other triazine herbicides at high doses without any adverse effects. It was determined, therefore, that the rabbit would tolerate Ametryn Technical at a dermal dose of up to 1000 mg/kg/day in this study. The no observable effect level was projected to be at least 10 mg/kg.

- Rationale for animal assignment: randomly via computer system
Positive control:
not applicable


Observations and examinations performed and frequency:
see below
Sacrifice and pathology:
see below
Other examinations:
see below
see below

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
no effects observed
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
see below

Effect levels

open allclose all
Dose descriptor:
other: Maximum tolerated dose (MTD)
Effect level:
1 000 mg/kg bw/day
Basis for effect level:
other: overall effects
Dose descriptor:
Effect level:
100 mg/kg bw/day
Basis for effect level:
other: overall effects

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

1. Mortality, Clinical Signs, and Physical/Auditory Examinations

All animals survived the study. There were no clinical signs observed during the study, and physical/auditory examinations that were conducted at the end of the study were unremarkable.


2. Dermal Observations

There were no treatment-related dermal changes noted in any animal throughout the study.


3. Body Weight

There were no treatment-related effects on mean body weight data during the study or at the time of necropsy. A transient treatment-related decrease in mean percent body weight gain was noted in the high-dose males and females on test day 8; the change was statistically significant only in the males.


4. Food Consumption

A transient reduction in mean food consumption was noted in high-dose males and females on test day 8. This change was statistically significant only in the males. Food consumption for all animals throughout the remainder of the study were similar to controls.


5. Ophthalmoscopic Examination

No treatmentrelated ophthalmoscopic changes were observed at the end of the study.


6. Hematology

There were no treatment-related changes in any hematologic parameter at the end of the study. Statistically significant differences in percent neutrophils and lymphocytes were noted in the high-dose males when compared to the concurrent controls. These differences were considered to be incidental to treatment based upon the absence of a dose-response relationship and because these differences were also present during predose.


7. Biochemistry

Statistically significant increases in mean serum cholesterol and triglycerides were observed in the high-dose males and females at the end of the study. These differences did not correlate with any organ weight effects or gross and microscopic pathology and are not considered to be of any toxicologic significance. A statistically significant increase in gaituna glutainyl transpeptidase was noted in Group 3 and 4 males, but not females, on test day 20. Since individual values for this parameter showed variations predose that were similar to those on test day 20, the relationship of this change to treatment is unknown. A statistically significant decrease in mean serum alkaline phosphatase was observed in the low-dose females at the end of the study. Since there was no dose-response or any toxicologic significance to this change it is not considered related to dosing with Ametryn.


8. Organ Weights

There were no treatment-related changes in any of the organ weights taken at necropsy. A statistically significant alteration in liver (absolute and/or relative to body weight) weights was noted in Group 2 or 4 females. Mean relative lung weight (brain) was also statistically elevated in the group 3 females. These changes were considered to be incidental and unrelated to treatment based upon the lack of a dose-response relationship, absence of a similar effect in males, and no correlating biochemical or pathological changes.


9. Gross Pathology

No gross tissue alterations attributable to Ametryn were observed in any of the rabbits at necropsy. Gross lesions observed were considered to be spontaneous and/or incidental because of the absence of a dose-response and similarity to findings commonly encountered in this species.


10. Microscopic Pathology

Microscopic evaluations did not reveal any treatment-related findings.

Applicant's summary and conclusion