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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

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

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rat
Strain:
other: Crl:CD(SD)
Sex:
male/female

Administration / exposure

Route of administration:
inhalation: gas
Type of inhalation exposure (if applicable):
whole body
Vehicle:
other: air and supplemental oxygen
Details on exposure:
The animals were exposed approximately 2 weeks for 6 hours/day, 5 days/week. Due to technical issue, exposures were suspended for 2 weeks and resumed on test day 29. Following resumption of exposures, animals were exposed 6 hours/day, 5 days/week for approximately a 2-week premating period, followed by a cohabitation period of approximately 2 weeks (6 hours/day, 7 days/week). This exposure schedule continued during a gestation period of approximately 3 weeks for females with evidence of mating. Gestation dams were not exposed after gestation day 19 or during the approximately 4-day lactation period. Females without evidence of mating continued to be exposed for 24 days (6 hours/day, 7 days/week) after the end of the cohabitation period. Exposures for parental males continued until the day prior to euthanasia on test days 77-78.
Details on mating procedure:
Cohabitation was started on test day 49 and lasted until evidence of copulation was observed or the cohabitation period (2 weeks) had ended, at which time the mating pairs were separated.
Each female was continuously housed on a 1:1 basis with a randomly selected, nonsibling male of the same exposure concentration level.
Analytical verification of doses or concentrations:
yes
Remarks:
gas chromatography
Duration of treatment / exposure:
Males: 78 days
Females: 63 days (with evidence of mating) or 66 days (without evidence of mating)
Frequency of treatment:
6 hours/day, 5 days/week (during the pre-mating period) and 7 days/week (at the commencement of cohabitation)
Doses / concentrationsopen allclose all
Dose / conc.:
0 ppm
Dose / conc.:
2 500 ppm
Dose / conc.:
10 000 ppm
Dose / conc.:
50 000 ppm
No. of animals per sex per dose:
10 rats/sex/dose
Control animals:
yes
Details on study design:
A neurobehavioral assessment was also performed.
Positive control:
No

Examinations

Parental animals: Observations and examinations:
-Daily animal health observations and general clinical observations. Detailed clinical observations (evaluation of fur, skin, eyes etc.) were recorded once during pretest and at least weekly thereafter.
-Regular measurement of body weight (during premating: twice weekly for the first 2 weeks and then weekly; during cohabitation: weekly; during gestation: on 0, 7, 14 and 19 gestation day; during lactation: on 0 and 4 lactation day; during post-cohabitation: weekly and at terminal sacrifice) and food consumption & food efficiency (during premating: weekly; during cohabitation: none; during gestation: on 0, 7, 14 and 19 gestation day; during lactation: on 0 and 4 lactation day; during post-cohabitation: none)
-Neurobehavioral evaluation consisting of abbreviated functional observational battery (FOB) assessments and motor activity (MA) was conducted throughout the study (at baseline, on test days 44 and 45)
-Clinical pathology evaluation (hematology and coagulation, clinical chemistry, urinalysis) was performed on test day 48.
Oestrous cyclicity (parental animals):
During cohabitation (test day 49), daily examination of each female for an intravaginal copulation plug in the vaginal lavage sample
Sperm parameters (parental animals):
During cohabitation (test day 49), daily examination of each female for sperm in the vaginal lavage sample
Litter observations:
During gestation (gestation day 20), female rats were observed at least twice daily for signs of delivery and offspring.
During lactation (lactation day 0 and 4), offspring were individually handled and examined for abnormal behavior and appearance; any dead or abnormal pups were recorded.
If litters died prior to day 4 of lactation, the dam was sacrificed. If the dam died prior to day 4 of lactation, the litter was examined externally, sacrificed and discarded.
Postmortem examinations (parental animals):
The necropsy included examination of the external surface, all orifices and the cranial, thoracic, abdominal and pelvic cavities (including viscera).
The uteri from all reproduction subset females were examined for the presence and number of implantation sites and the ovaries were examined for the number of corpora lutea.
The following organs were weighed fresh at necropsy from all adult animals: adrenals, brain, heart, kidneys, liver, lungs, spleen, thymus, ovaries, uterus, testes, epididymides, prostate, seminal vesicles, accessory sex organs.
Microscopic evaluation of all tissues collected from adult rats (liver, lungs, trachea, thyroid gland etc.) as well as of the reproductive organs from all male and female P1 rats suspected of impaired reproductive performance was done.
Postmortem examinations (offspring):
Pups found dead or euthanized in moribund condition underwent a gross examination to the extent possible.
Statistics:
Yes
Reproductive indices:
mating index (%), fertility index (%), gestation index (%), pre-implantation loss (%), post-implantation loss (%)
Offspring viability indices:
Pups born alive (%), viability index (%)

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
No test substance-related clinical signs of toxicity were observed in males or females at any exposure concentration during the premating, gestation, or lactation periods.
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Test substance-related mortality did not occur in the animals assigned to the Reproduction Subset.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
No adverse, test substance-related effects on body weight or weight gain were observed for males or females exposed to any concentration of the test substance during the premating, gestation, or lactation periods.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No test substance-related effects or statistically significant differences in food consumption were observed for males or females exposed to any concentration of the test substance during the premating, gestation, or lactation periods.

Food efficiency:
effects observed, non-treatment-related
Description (incidence and severity):
No test substance-related effects or statistically significant differences in food efficiency were observed for males or females exposed to any concentration of the test substance during the premating, gestation, or lactation periods.
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no exposure-related changes in group mean hematology parameters in male or female rats at any concentration tested.
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
There were no exposure-related changes in group mean clinical chemistry parameters in male or female rats at any concentration tested.
Urinalysis findings:
no effects observed
Description (incidence and severity):
There were no statistically significant differences in group mean urinalyses parameters in male or female rats at any concentration tested.
Behaviour (functional findings):
effects observed, non-treatment-related
Description (incidence and severity):
Under the conditions of the study, no test substance-related or adverse effects were observed on neurobehavioral parameters for the reproduction subset.
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
There were no test substance-related organ weight effects. All individual and mean organ weight differences were considered spurious and unrelated to test substance exposure.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no test substance-related gross observations in any of the P1 adults. All gross observations, recorded at necropsy, were consistent with normal background lesions in rats of this age and strain.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
There were no test substance-related microscopic findings in any of the P1 adults. All microscopic findings in these animals were consistent with normal background lesions in rats of this age and strain.
Histopathological findings: neoplastic:
no effects observed
Description (incidence and severity):
There were no test substance-related microscopic findings in any of the P1 adults. All microscopic findings in these animals were consistent with normal background lesions in rats of this age and strain.
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
effects observed, non-treatment-related
Description (incidence and severity):
There were no test substance-related reproductive failures in this study.
Reproductive function: sperm measures:
effects observed, non-treatment-related
Description (incidence and severity):
There were no test substance-related reproductive failures in this study.
Reproductive performance:
effects observed, non-treatment-related
Description (incidence and severity):
There were no test substance-related reproductive failures in this study.

Details on results (P0)

"P1" in the study corresponds to "P0" in IUCLID.

Effect levels (P0)

Key result
Dose descriptor:
NOAEC
Effect level:
ca. 50 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
food consumption and compound intake
food efficiency
haematology
clinical biochemistry
urinalysis
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic
histopathology: neoplastic
reproductive function (oestrous cycle)
reproductive function (sperm measures)
reproductive performance

Results: F1 generation

General toxicity (F1)

Clinical signs:
no effects observed
Description (incidence and severity):
No test substance-related effects on the offspring clinical signs occurred at any exposure concentration.
Dermal irritation (if dermal study):
not examined
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
No test substance-related effects on the number of offspring born, born alive, percentage born alive, number of offspring surviving to lactation day 4, percentage surviving to lactation day 4 occurred at any exposure concentration
The viability index for the 50,000 ppm group was 96.5% compared to 100% for the control group. The 96.5% value is within the historical control range of 91.1-100% (Appendix SSS). Therefore, the significantly lower viability index for the 50,000 ppm group was within the range of normal biological variation and not considered to be test substance-related. One litter in the control group was euthanized on lactation day 0 due to the death of dam 159, as a result of dystocia.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No test substance-related effects on the offspring body weight on lactation days 0 and 4 occurred at any exposure concentration.
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Sexual maturation:
no effects observed
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no test substance-related gross observations in pups.
Histopathological findings:
not specified
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not examined

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not examined

Effect levels (F1)

Key result
Dose descriptor:
NOAEC
Generation:
F1
Effect level:
ca. 50 000 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
viability
sexual maturation
clinical signs
mortality
body weight and weight gain
gross pathology

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
Under the conditions of the study, the no-observed-adverse-effect concentration (NOAEC) of Zyron 116 (perfluoroethane) for systemic toxicity in male and female rats was 50,000 ppm, the highest concentration tested, based on the absence of effects in all endpoints. The NOAEC for reproductive effects was 50,000 ppm based on the absence of effects on reproductive endpoints and on offspring at the highest concentration tested.

"P1" in the study corresponds to "P0" in IUCLID.