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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
March - April 1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report Date:
1991

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
EPA OPP 83-3 (Prenatal Developmental Toxicity Study)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Test material form:
solid

Test animals

Species:
rat
Strain:
other: Crl:CD BR Sprague-Dawley
Details on test animals and environmental conditions:
Source: Charles River Breeding Laboratories, Inc., Portage, MI
Age: 83 days on first day of mating
Weight: 206-276 g on GD 0
Males used: Resident, untreated, sexually mature
Animal husbandry: Food (#5002: Purina Certified Rodent Chow) and tap water were available ad libitum throughout the study. A 12-h light/dark cycle was maintained. Temperature and humidity ranges were 70-75°F and 33-74%, respectively. Fresh air changes were 10-15/h.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Doses were administered daily via gavage from GD 6 through 15 in a volume of 5 mL/kg. The most recently recorded body weights were used to calculate the concentration of the doses. Dosing suspensions were not adjusted for active ingredient; were prepared once during the study; and were stored at room temperature. Prior to study initiation, homogeneity (low- and high-dose groups) and concentration (all dose groups) of the test substance in the vehicle were determined. Stability (low- and high-dose groups) was determined at the end of the study by analyzing the suspensions on the last day of dosing. Duplicate samples of the dosing solutions were analyzed by gas chromatography/flame ionization detection.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentrations of all dose levels were verified analytically prior to the initiation of dosing. Duplicate samples of the dosing solutions were analyzed by gas chromatography/flame ionization detection.
Details on mating procedure:
Following 12 d of acclimatization, females were mated 1:1 with males of the same strain and source. Females were checked daily for the presence of vaginal sperm or a (copulatory plug). The day on which mating was confirmed was designated Day 0 of gestation.
Duration of treatment / exposure:
GD 6 through 15, inclusive
Frequency of treatment:
Single daily dose
Duration of test:
10 d
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 10, 75, and 175 mg/kg bw/day
Basis:
nominal conc.
No. of animals per sex per dose:
25/female/group
Control animals:
yes, concurrent vehicle
Details on study design:
Concentrations of the doses were selected based upon the results of a range-finding study conducted in the same strain of eight mated rats per group at dose levels of 0, 10, 25, 75, or 150 mg/kg bw/day. In the range-finding study, maternal toxicity, evident at 150 mg/kg bw/day, was manifested as increased liver weight and clinical signs and slightly (non-significant) decreased body weight gain from GD 6 through 9. Developmental toxicity was not observed.

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes

DETAILED CLINICAL OBSERVATIONS: Yes

BODY WEIGHT: Yes

FOOD CONSUMPTION: Yes

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation Day 20
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
- External examinations: Yes
- Soft tissue examinations: Yes
- Skeletal examinations: Yes
- Head examinations: Yes
Statistics:
-Maternal body weight and bodyweight change, fetal body weight, food consumption, gravid uterus and organ weights, and numbers of corpora
lutea, implantation sites, and live fetuses--ANOVA and Dunnett’s test
-Litter proportions of intra-uterine data--Kruskal Wallis test
-Early and late resorption, dead fetuses, postimplantation losses-Mann-Whitney U-test
-Fetal sex ratios--Chi-square test with Yate’s correction factor
-Malformations and variations--Fischer’s exact test
Historical control data:
Yes

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
A body weight loss was recorded in animals at 175 mg/kg bw/day for the first three days of treatment, and a moderate decrease in body weight gain was observed for the overall treatment period. Gravid uterine weights were slightly decreased at the high dose compared to control. Food consumption was severely decreased at 175 mg/kg bw/day during the first 3 d of treatment, but returned to near control levels for the remainder of the study. Body weights and food consumption were unaffected at 10 and 75 mg/kg bw/day. Other evidence of maternal toxicity at 175 mg/kg bw/day included hair loss on various body surfaces and decreased defection and urination. No treatment-related clinical signs were observed at 10 and 75 mg/kg bw/day.

Effect levels (maternal animals)

open allclose all
Dose descriptor:
dose level: 175 mg/kg bw
Effect level:
175 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
clinical signs
body weight and weight gain
food consumption and compound intake
organ weights and organ / body weight ratios
early or late resorptions
Dose descriptor:
LOEL
Effect level:
75 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
organ weights and organ / body weight ratios
early or late resorptions
Dose descriptor:
NOEL
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
organ weights and organ / body weight ratios

Maternal abnormalities

Abnormalities:
not specified
Localisation:
not specified

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
Fetal body weights were slightly decreased at 175 mg/kg bw/day. No effects on fetal body weight were observed at other dose levels. Post implantation loss was increased at 75 and 175 mg/kg bw/day (1.0 and 1.3 postimplantation losses/dam, respectively) compared to the concurrent control value (0.5 losses/dam). However, both treatment values were within historical control range. Twenty percent of the historical control studies had post-implantation values equal to or greater than the value at 75 mg/kg bw/day. Therefore, the effect at 75 mg/kg bw/day was not considered related to treatment. The post-implantation loss at 175 mg/kg bw/day was at the upper end of the historical control range and only 3% of the studies had equal or greater values. The effect at 175 mg/kg bw/day was considered equivocal. There were no treatment-related effects on the number of implantations, fetal viability or sex ratios at any dose level. Total malformations (external, visceral and skeletal) occurred in 2, 5, 0, and 7 fetuses in 2, 4, 0 and 5 litters from the 0, 10, 75 and 175 mg/kg bw/day groups, respectively. The fetal and litter incidence rates at the high dose were not statistically higher than concurrent control, but were outside of historical control range. The malformations observed at 175 mg/kg bw/day was primarily observed in three of the seven affected fetuses and no single malformation was statistically increased compared to control. A dose of 175 mg/kg bw/day was considered to have produced an equivocal effect on malformations. The malformation incidence observed at 10 mg/kg bw/day was not considered related to treatment due to the lack of an effect at 75 mg/kg bw/day. Several external malformations occurred with a single incidence at the high dose only including: umbilical herniation of the intestine, fetal anasarca, micromelia, bradydactyly, omphalocele and tarsal flexure. Five fetuses in three litters at 175 mg/kg bw/day exhibited tail anomalies (curly, filamentous or bent). Visceral malformations observed as a single incidence at the high dose and not seen in the control were situs inversus and interrupted aortic arch. Malpositioned uteri and ovaries were noted in two high dose fetuses in two litters, and this litter incidence was outside of historical control range. The skeletal malformation, vertebral agenesis, occurred in two fetuses in two litters at the high dose, and this litter incidence was outside of historical control range. There were no external variations in any group, and there were no visceral variations considered related to treatment. One skeletal variation, sternebrae #1, 2, 3 and/or 4 unossified was increased in incidence for fetuses and litters at the high dose. There were no treatment-related increases in skeletal variations at lower dose levels.

Effect levels (fetuses)

open allclose all
Dose descriptor:
LOEL
Effect level:
175 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
fetal/pup body weight changes
other: delayed ossification in the sternebrae at a significantly increased litter rate
Dose descriptor:
NOEL
Effect level:
75 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
fetal/pup body weight changes
other: specific malformations

Fetal abnormalities

Abnormalities:
effects observed, treatment-related
Localisation:
other: An equivocal increase in the incidence of total (external, visceral and skeletal) malformations and an increase in one skeletal variation (vertebral agenesis)

Overall developmental toxicity

Developmental effects observed:
yes
Lowest effective dose / conc.:
175 mg/kg bw/day (actual dose received)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects as a secondary non-specific consequence of maternal toxicity effects

Any other information on results incl. tables

Test substance analysis: Analysis conducted on dosing suspensions for concentration and homogeneity ranged from 93.4% to 100% of target. Stability of low and high-dose suspensions after 20 d in room temperature revealed values from 84.3% to 106% of target.

Applicant's summary and conclusion

Conclusions:
Under the conditions of the study, the NOELs of MON 13900 for maternal and developmental toxicity were found to be 10 and 75 mg/kg bw/day, respectively in rats.
Executive summary:

A study was to evaluate the developmental toxicity potential of MON 13900 according to the EPA OPP 83-3 Guideline in compliance with GLP.

 

The test substance in the vehicle, corn oil, was administered orally by gavage once daily at the dose levels of 0, 10, 75, and 175 mg/kg bw/day to 4 groups of 25 mated female Charles River CD(SD)BR rats during gestation days 6 through 15. These dose levels were selected based on results from a pilot rat teratology study. Analytical concentrations of the test substance were acceptably close to target levels. Homogeneity and stability of dosing solutions were also acceptable. Maternal toxicity was evidenced at 175 mg/kg bw/day by an initial body weight loss and a decreased body weight gain for the overall treatment period, by various clinical signs and by increased liver weights. Liver weights were also increased at 75 mg/kg bw/day. Developmental toxicity was indicated at 175 mg/kg bw/day by decreased fetal weights, an equivocal increase in post-implantation loss, an equivocal increase in the incidence of total (external, visceral and skeletal) malformations and an increase in one skeletal variation.

Therefore, the NOEL for developmental toxicity was 75 mg/kg bw/day and the NOEL for maternal toxicity was 10 mg/kg bw/day.