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Toxicological information

Toxicity to reproduction

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Administrative data

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, please refer to IUCLID section 13 for read across justification.

Data source

Reference
Reference Type:
publication
Title:
d-alpha-Tocopherol Poly(ethylene glycol) 1000 Succinate. Acute Toxicity, Subchronic Feeding, Reproduction, and Teratologic Studies in the rat.
Author:
Krasavage WJ and Terhaar CJ
Year:
1977
Bibliographic source:
J Agric Food Chem 25: 273-278

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 415 [One-Generation Reproduction Toxicity Study (before 9 October 2017)]
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
d-alpha-tocopheryl PEG succinate

d-alpha-tocopheryl poly(ethylene glycol) 10000 succinate, prepared from crystalline d-alpha-tocopheryl acid succinate and poly(ethylene glycol), average molecular weight 1000, providing 260 mg of d-alpha-tocopherol per g (387 IU); according to the authors, purity was >99% (tlc)

Test animals

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

Administration / exposure

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
Doses / concentrations
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

Examinations

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

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
no effects observed
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
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed

Effect levels (P0)

open allclose all
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:
other: Generation: P and F1 (migrated information)
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:
other: Generation: P and F1 (migrated information)

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 specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

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.

Applicant's summary and conclusion