Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Information from public copy of a correspondance letter to US EPA, reliability not known but contributing to a weight of evidence assessment.

Data source

Reference
Reference Type:
other: Public copy of a correspondance letter to US EPA
Title:
Unnamed
Year:
2002
Report Date:
2002

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: OECD Guideline 415 (One-Generation Reproduction Toxicity Study)
Principles of method if other than guideline:
A one-generation reproduction study was conducted in which the test substance was administered in the feed to groups of male and female rats (10/group), at dietary concentrations of 0, 300, 1500, 5000 ppm. Rats were fed for two weeks prior to cohabitation (premating period), during the cohabitation period (up to 2 weeks), and during gestation and lactation.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): Anthranilamide

Test animals

Species:
rat
Strain:
not specified

Administration / exposure

Route of administration:
oral: feed
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Length of cohabitation: up to 2 weeks
Duration of treatment / exposure:
- Rats were fed for two weeks prior to cohabitation (premating period), during the cohabitation period (up to 2 weeks), and during gestation and lactation.
- The F1 generation rats were not exposed after postnatal day 21.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 300, 1500, 5000 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
10 animals per dose group
Control animals:
yes, plain diet

Examinations

Maternal examinations:
- Cage site observations for mortality and moribundity were performed daily. Clinical signs were recorded weekly.
- Body weights were recorded weekly during premating and cohabitation and on days 0, 7, 14, 21 of gestation and lactation for P1 generation rats.
- Food consumption was recorded with body weights, except for the P1 cohabitation and lactation periods, when food consumption was not determined.
-A functional observation battery (FOB) and motor activity (MA) were evaluated in P1 male and female rats at the end of the 2-week premating period.
- Necropsy: P1 females on lactation day 21. Uterus, ovaries, thyroid, and liver were weighed and retained for possible histopathological examination. The number of uterine implantation sites was recorded in P1 females.
Fetal examinations:
- Body weights were recorded weekly for F1 generation rats beginning at weaning on postnatal day (PND) 21.
- F1 pups were counted by sex and individually weighed at birth, and on PND 4, 7, 14, and 21.
- F1 pups were culled to 8 per litter on PND 4 and unselelected pups were discarded without further evaluation.
- On PND 21, 1 pup/sex/litter was randomly selected and retained to comprise the F1 generation.
- On PND 21, unselected weanling pups (3/sex/litter) underwent a gross pathological examination.
- At postnatal day 60 remaining animals were necropsied
- Testes epididymides, prostate, seminal vesicles, uterus, ovaries, thyroid, and liver were weighed and retained for possible histopathological examination.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Details on maternal toxic effects:
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
- At the high dose level, three females were found dead on the second day of the study. They were replaced with three extra females; one of these females was found dead the next morning. This animal was replaced with an extra female, which survived the first day of diet administration and thereafter. No clinical signs of toxicity were observed in the P1 generation rats.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
- In P1 females fed 5000 ppm, body weight gain and food consumption on days 7-14 of gestation were 79 % and 90 % of control, respectively. Overall gestation body weight gain was 89 % of control in P1 females at 5000 ppm.

FUNCTIONAL OBSERVATION BATTERY AND MOTOR ACTIVITY
- There was no effect on functional observation battery parameters or motor activity in P1 rats.

REPRODUCTION PARAMETERS
- There were no compound-related effects on the following reproduction parameters: mating and fertility indices, gestation length, number of uterine implantation sites, implantation efficiency, number of pups born, born alive, and alive on PND 4, 7, 14, and 21. Litter sex ratio, gestation index, percent pups born alive, lactation index, and litter survival were unaffected at any dose level.

ORGAN WEIGHTS (PARENTAL ANIMALS)
- Liver weight was significantly increased in P1 female rats at the mid and high dose level.

HISTOPATHOLOGY (PARENTAL ANIMALS)
- Hepatocellular hypertrophy, characterized by cells with an enlarged and homogeneously eosinophilic cytoplasm, was observed at all dose levels in female rats. Hepatocellular hypertrophy was considered and adaptive physiologic response to exposure to a xenobiotic and not biologically adverse.
- Follicular thyroid hypertrophy and/or colloid depletion were observed at the mid and high dose level in P1 female rats. Follicular hypertrophy was characterized by follicles lined with columnar, rather than cuboidal epithelium. Colloid depletion was diagnosed when the usually eosinophilic follicular colloid was markedly pale and/or absent.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
300 ppm
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
300 ppm
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
VIABILITY (OFFSPRING)
- A statistically significant reduction in 0-4 Day viability of F1 pups was observed at the mid and high dose levels (97-98% vs. 100% in control group).

CLINICAL SIGNS (OFFSPRING)
- No clinical signs of toxicity were observed in F1 generation rats, or in the F1 litters during lactation

BODY WEIGHT (OFFSPRING)
- F1 pup weights were significantly reduced on PND 0-4 and 0-7 at the mid and high dose, respectively (91-94 % of control). In the F1 generation, body weight gain was significantly reduced at the high dose level on PND 21-28 in males (88 % of control) and PND 28-42 in females (82-84 % of control.)

FOOD CONSUMPTION (OFFSPRING)
- Food consumption was significantly reduced in F1 males at the mid and high dose level (86-90 % of control) on PND 21 -35.

SEXUAL MATURATION (OFFSPRING)
- The mean age at preputial separation and vaginal opening in F1 generation rats were unaffected at any dose level.

ORGAN WEIGHTS (OFFSPRING)
- Thyroid weight was decreased in F1 females, but not in F1 males, at the mid and high dose level. Other organ weights were unaffected in F1 generation rats.

HISTOPATHOLOGY (OFFSPRING)
- Follicular thyroid hypertrophy was observed in 1 and 2 F1 males at the mid and high dose level, respectively.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Applicant's summary and conclusion