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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:
No data
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
This study was selected as the key study because the information provided for the hazard endpoint is sufficient for the purpose of classification and labeling and/or risk assessment. GLP guideline study with acceptable restrictions. Restrictions : no english data on study design, no details on functional observational battery tests.

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1999

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 2,2'-AZOBIS(2-METHYLPROPIONITRILE)
- Physical state: white crystal
- Analytical purity: 99.9%
- Lot/batch No.: no data
- Expiration date of the lot/batch: no data
- Storage condition of test material: no data

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals and environmental conditions:
Not available in English language

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on exposure:
Not available in English language
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Males were exposed for 42 days.
Females were exposed from 14 days prior to mating to day 3 of lactation.
Terminal killing at day 43 for males and on day 4 of lactation for females.
Frequency of treatment:
No English data
Duration of test:
Day four of lactation
No. of animals per sex per dose:
13
Control animals:
yes, concurrent vehicle
Details on study design:
See below

Examinations

Maternal examinations:
See chapter 7.8.1
Ovaries and uterine content:
See chapter 7.8.1
Fetal examinations:
See chapter 7.8.1

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Abnormal nursing behavior was noted in 3 animals from the 50 mg/kg group.

Effect levels (maternal animals)

Dose descriptor:
NOEL
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes. Remark: At a maternally toxic dose level

Details on embryotoxic / teratogenic effects:
The findings in offspring showed that ABMPN had no effects on the parturition index, live pup delivery index, overall delivery index, or the
sex ratio and body weight on Day 0. In the 50 mg/kg group, the offspring viability index and body weight on Day 4 of lactation showed a
tendency to decrease. No offspring from the ABMPN groups showed any morphological anomaly.

Effect levels (fetuses)

Dose descriptor:
NOEL
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

CLINICAL SIGNS AND MORTALITY

Males : Temporary salivation after each administration was observed in the 10 mg/kg or more groups.

Females : One female died on post-partum day 3 in the 50 mg/kg group. Abnormal nursing behavior was noted in 3 animals from the 50 mg/kg group.

BODY WEIGHT AND WEIGHT GAIN

Males : Suppression of body weight gain during the early administration period was noted in the 50 mg/kg group.

Females : Slight decreases in body weight gain and food consumption during the early administration period were observed in the 10 mg/kg or moregroups. In addition, body weight gain and food consumption were decreased during pregnancy in the 50 mg/kg group.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)

Males : Suppression of food consumption during the early administration period was noted in the 50 mg/kg group.

Females : No effects.

HAEMATOLOGY Males : Elevated platelet and white blood cell counts were apparent after the administration of the compound at the dose level of 50 mg/kg.

Females : No effects.

CLINICAL CHEMISTRY

Males : Increases in total protein and concentrations of albumin, total cholesterol, Ca and inorganic phosphorus and decreases in the A/G ratio an Cl concentration were apparent after the administration of the compound at the dose level of 50 mg/kg.

Females : No effects.

ORGAN WEIGHTS

Males : Increases in the kidney weights in all the treated groups and in the liver weights in the 10 mg/kg or more groups were observed at autopsy. Females : Liver and kidney weights showed a tendency for increase in the 50 mg/kg group (observed at autopsy on post-partum day 4).

GROSS PATHOLOGY No effects.

HISTOPATHOLOGY: NON-NEOPLASTIC

Males : Increased eosinophilic bodies and basophilic changes of the renal tubular epithelial cells in the kidneys of males treated with the compound atany dose levels tested were noted, as well as granular casts in the lower nephrons. Centrilobular hypertrophy of hepatocytes was also detected in the 10 mg/kg or more groups.

Females : Centrilobular hypertrophy of hepatocytes was observed in the 10 mg/kg or more groups.

No effects on the copulation index or fertility index at 50 mg/kg or lower doses. ABMPN did not affect the length of the gestation period or delivery index in maternal animals, either. No abnormal parturition was observed. Abnormal nursing behavior was noted in 3 animals from the 50 mg/kg group.

The abnormal lactation behavior and subsequent effects on offspring on day 4, are considered secondary to maternal toxicity.

Applicant's summary and conclusion

Conclusions:
NOEL for reproduction/developmental toxicity is 50 mg/kg/day in males and 10 mg/kg/day in females (abnormal lactation behavior) and offspring (viability index and body weight decrease on day 4 of lactation). The abnormal lactation behavior and subsequent effects on offspring on day 4, are considered secondary to maternal toxicity.
Executive summary:

No reproductive toxicity data are available for the registered substance. A reproductive/developmental screening study in rats with 2,2’-azobis(isobutyronitrile) was used as a read-across to fulfill the data gap for the test substance. The underlying hypothesis for the read-across between the test substance and 2,2’-azobis(isobutyronitrile) is that the two substances are similar in physicochemical properties, have common effects seen at acute exposures, and are similar in metabolic pathway.Additional documentation, provided within the IUCLID Assessment Reports section, supports the read-across approach.

An OECD 422 repeated dose, reproductive/developmental toxicity screening study with 2,2’-azobis(isobutyronitrile) was evaluated in male and female rats after gavage administration at doses of 0, 2, 10 and 50 mg/kg/day until day 43 for males and day 4 of post-partum for females. Reduced body weight gain and feed consumption was observed in females at ≥10 mg/kg. At 50 mg/kg, reduced weight gain and feed consumption were also observed during gestation, and one animal died 3 days after parturition. Increased liver and kidney weights were observed, and histopathological examinations suggested centrilobular hypertrophy of hepatocytes at ≥10 mg/kg.

No effects were observed on copulation index, fertility index, length of gestation, delivery index, parturition index, live pups delivered, overall delivery index, or sex ratio and body weight of pup on Day 0. Abnormal nursing behaviour was noted in 3 animals from the 50 mg/kg group.

Abnormal nursing behaviour was noted in 3 animals from the 50 mg/kg group.

The findings in offspring showed no effects on the parturition index, live pup delivery index, overall delivery index, or the sex ratio and body weight on Day 0 at all dose-levels. In the 50 mg/kg group, the offspring viability index and body weight on Day 4 of lactation showed a tendency to decrease. This was attributed to maternal toxicity at the 50 mg/kg/day dose level.No offspring from the treated groups showed any morphological anomaly.

Based on these results, the NOEL for reproductive and developmental toxicity was 50 mg/kg/day in males and 10 mg/kg in females and in pups.The abnormal lactation behavior and subsequent effects on offspring on day 4, are considered secondary to maternal toxicity.