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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
2013
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study; well-performed and well-documented

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
gas under pressure: refrigerated liquefied gas

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Details on mating procedure:
After 14 days of treatment the both male and female, animals were paired (1:1) for a maximum of 14 days. The subsequent morning onwards the vaginal smears of females were checked to confirm the evidence of mating. After the confirmation of the mating, females were separated and housed individually.
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
28 days for males, up to 54 days for females
Frequency of treatment:
once per day
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 250, 750 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
piloerection, nasal discharge, eye closure at 250 and 750 mg/kg bw
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
only reproduction organs investigated
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
750 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant systemic effect up to highest applied dose. No effect on the reproduction organ and no effect on the reproduction performance.

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
750 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effect found for all parameters related to developmental toxicity

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

No mortality occurred in the control or any of the dose groups during the treatment period of this study.

At 250 and 750 mg/kg/day, signs of discomfort such as pushing the head through the bedding material and salivation were observed throughout the study in males and females. Occasionally, piloerection, nasal discharge and eye closure were also observed.

Food consumption and body weight and body weight gain were not affected by the treatment with the test item.

Gross pathological examination of male and females at scheduled necropsy did not revealed any treatment-related findings.

Absolute and relative weight of uterus, ovaries, testis, epididymides and prostate were not affected by the treatment with the test item.

The histopathologic examination of male and female reproductive organs did not indicate any test item-related changes. Two females of the control group, one female treated at 100 mg/kg/day, two females treated at 250 mg/kg/day and one female treated at 750 mg/kg/day were found not to be pregnant at terminal sacrifice. As there was no dose relationship, this was not considered to be treatment-related.

The litter weight was not affected by the treatment with the test item either at birth or on postnatal day 4.

No treatment related effect was observed on the total number of pups born per litter, and on the sex ratio. No external findings and no gross abnormalities were observed in pups at necropsy.

Fertility, delivery and viability indexes were similar within the group and were not indicative of any effect of the test item. Precoital interval and duration of the gestation were also not affected by the treatment with the test item.

Mean number of corpora lutea and of implantation sites were not considered to be affected by the treatment with the test item. Incidence of pre- and post-implantation losses was also not affected by the treatment with the test item.

Litter size and sex ratio were not affected by the treatment with the test item either at birth or on PND 4. Gross necropsy of dead pups revealed no treatment-related findings.

Applicant's summary and conclusion

Conclusions:
The reproduction toxicity of the registration substance was investigated according to the Guideline OECD 421. The NOAEL of 750 mg/kg bw, corresponding to highest applied dose, was obtained for parental and for developmental effects.
Executive summary:

The reproduction toxicity of the registration substance was investigated according to the Guideline OECD 421. The rats were treated via gavage at doses of 0, 100, 250, and 750 mg/kg bw.

At doses of 250 and 750 mg/kg bw signs of discomfort were observed but no severe clinical signs. No effects were observed in food consumption and body weight. Macroscopic and histopathologic parameters and evaluation of litter data did not induce any test item-related effect.

The NOAEL of 750 mg/kg bw was obtained for parental and for developmental effects.