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Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented publication which meets basic scientific principles.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
GLP compliance:
no
Limit test:
no
Species:
rat
Strain:
other: COBS, CD, albino
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River
- Age at study initiation: no data
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: five per cage in suspended wire-bottom cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): no data
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: 2 weeks
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- Further matings after two unsuccessful attempts: no data
- After successful mating each pregnant female was caged: the male was removed from the cage, a nesting pan was introduced and the female was allowed to litter
- Any other deviations from standard protocol: no data
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
The parent generation was treated for 264-268 days.
All offspring were killed after 5 weeks of weaning.
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
0.002, 0.2, 2.0% (8, 80 and 800 mg/kg bw/day)
Basis:
actual ingested
No. of animals per sex per dose:
15
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: no data
- Rationale for animal assignment: random
Positive control:
None
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: no data


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: no data


BODY WEIGHT: Yes
- Time schedule for examinations: prior to treatment, twice during the first week of feeding and weekly thereafter


FOOD CONSUMPTION AND COMPOUND INTAKE :
- Food consumption for each animal determined and mean daily diet consumption calculated as mg food/rat/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data
Oestrous cyclicity (parental animals):
No data
Sperm parameters (parental animals):
No data
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: no


PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
insemination, fertility, gestation, viability, lactation, average gestation (days), average litter size, sex (M/F), mean mortality at birth, mean mortality 0-8 weeks


GROSS EXAMINATION OF DEAD PUPS:
No data
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals after 265-268 days of treatment when it was certain no additional matings were necessary.
- Maternal animals: All surviving animals after 265-268 days of treatment when it was certain no additional matings were necessary.


GROSS NECROPSY
- Gross necropsy consisted of: no data


HISTOPATHOLOGY / ORGAN WEIGHTS
organ weights, hematocrit, hemoglobin concentration, total and differential white cell counts, serum glutamic oxalacetic transaminase, serum alkaline phosphatase, urea nitrogen, lactic acid dehydrogenase, serum glucose, serum total protein, triglyceride and cholesterol.
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring were sacrificed at 5 weeks after weaning.
- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows:


GROSS NECROPSY
- Gross necropsy consisted of: no data


HISTOPATHOLOGY / ORGAN WEIGTHS
No data
Statistics:
Data in all studies were analyzed statistically by analysis of variance, Duncan's multiple range ste, or Student's T-test p<0.05.
Reproductive indices:
Yes
Offspring viability indices:
Yes
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
> 2 other: %
Sex:
male/female
Basis for effect level:
other: Dose was converted to 800 mg/kg bw/day using default values. No treatment related effects were observed.
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Dose descriptor:
NOAEL
Effect level:
> 800 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: No treatment-related effects.
Remarks on result:
not determinable due to absence of adverse toxic effects
Clinical signs:
no effects observed
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Ophthalmological findings:
not specified
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not examined
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 2 other: %
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
> 800 mg/kg bw/day
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Reproductive effects observed:
no

No apparent differences in reproductive indices were seen between controls and treated groups of parents. Mean gestation period, litter size, sex ratio, and mortality of pups and parents were unaffected by the test substance.

Hematology and clinical chemistry done after 255 days of treatment revealed no toxicologic differences between control and high dose group. None of the organ weights (neither absolute nor relative) of the treated groups were significantly different from control. Microscopic examination of tissues of high dose and control F0 and F1b animals revealed no morphological changes that were attributable to ingestion of the test substance.

Ingestion of the test substance had no effect on body weight gain of the pups.

Based on default values in the REACH guidance Chapter R.8: Characterisation of dose [concentration]-response for human health (Table R8 -17); using the daily intake of 20 gram/day: and the average body weight of the rats of 0.5 kg (data of the 90 day study), the NOAEL of > 2% is converted to > 800 mg/kg bw/day.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No studies have specifically conducted with D,L-alpha-tocopherol. Therefore, data from the structurally related vitamine E derivative D-alpha-tocopheryl poly(ethylene glycol) 10000 succinate were used. Please see read-across justification section 13.

In a one-generation reproduction toxicity study (Krasavage 1977), rats were fed up to 2.0% D-alpha-tocopheryl poly(ethylene glycol) 10000 succinate (corresponding to 800 mg/kg bw/d (using default values of 20 g food /day and a body weight of 0.5 kg (REACH guidance Chapter R.8: Characterisation of dose [concentration]-response for human health (Table R8 -17)).

No apparent differences in reproductive indices were seen between controls and treated groups of parents. Mean gestation period, litter size, sex ratio, and mortality of pups and parents were unaffected by the test substance.

Hematology and clinical chemistry done after 255 days of treatment revealed no toxicologic differences between control and high dose group. None of the organ weights (neither absolute nor relative) of the treated groups were significantly different from control. Microscopic examination of tissues of high dose and control F0 and F1b animals revealed no morphological changes that were attributable to ingestion of the test substance. Ingestion of the test substance had no effect on body weight gain of the pups.

The one-generation study revealed no toxicological differences in rats treated with the vitamin E derivative compared to the control group and no effects were observed in rats of the treated group after microscopic examination or in body weight gain of the pups. Taken together, these data are considered sufficient to cover the endpoint effects on reproduction.


Short description of key information:
The results of a one-generation reproduction rat toxicity study (comparable to OECD 415) with the structurally related vitamin E derivative D-alpha-tocopheryl poly(ethylen glycol) 10000 succinate does not indicate that D,L-alpha-tocopherol has adverse effect on the reproductive function. The reproductive indices of the treated groups were unaffected and the offspring developed normally. The NOAEL in this study was > 800 mg/kg bw/d (corresponding to 2% in the feed).

Effects on developmental toxicity

Description of key information
In teratogenicity studies (OECD 414, pre-GLP) with rats and rabbits with the Vitamin E ester D,L-alpha tocopheryl acetate, no significant difference in malformations between the control and the treated groups. The NOAEL is >= 1600 mg/kg bw/d for both species.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

No studies have specifically been conducted with D,L-alpha-tocopherol. Therefore, data from the structurally related vitamine E ester D,L

-alpha-tocopheryl acetate were used. This compound is rapidly hydrolysed to the vitamin E active form D,L alpha-tocopherol under physiological conditions.

Please see read-across justification section 13.

In a teratogenicity study, rats were fed up to 1600 mg/kg bw/day D,L-alpha-tocopheryl acetate (Food&Drug Research Laboratory, 1973).

There were no significant differences in any parameter between the groups treated with the test substance. No dose-response relationship was noted. Malformations of the sternebrae, ribs, vertebrae, skull, and extremities were recorded. However, the incidences of these malformations in vitamin E-treated groups were not significantly different from those observed in sham-treated control. Soft tissue findings in the tocopheryl acetate groups were distributed over all treated groups without indicating any dose-response. These included cardiomegaly (3 fetuses), anophthalmia (1 fetus), hydrocephalus (3 fetuses), gastroschisis (2 fetuses), apulmonism (1 fetus), and petechiae (1 fetus). No soft tissues findings are reported for the sham-treated control fetuses. In the positive control group treated with Aspirin, the expected statistically significant increase in the incidence of skeletal malformations and soft tissue variations was observed.

Additionally, the teratogenic activity of D,L-alpha-tocopheryl acetate was investigated in rabbits (Food&Drug Research Laboratory, 1973). The test substance was administered by gavage at dose levels of 0 (sham-treated control group), 16, 74.3, 345, and 1600 mg/kg bw/d. The administration of up to 1600 mg/kg bw/d of the test material to pregnant rabbits for 13 consecutive days had no clearly discernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.

Justification for classification or non-classification

Based on the available data, vitamin E does not need to be classified for effects on fertility and developmental toxicity according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.