Registration Dossier

Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
disregarded due to major methodological deficiencies
Study period:
09 September 2011 - 20 December 2011
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: The study has many deviations and the information in the report is incomplete.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2012
Report Date:
2012

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
The study has many deviations and the information in the report is incomplete.
- The laboratory has no GLP accreditation.
- No details on animal housing and actual environmental conditions.
- It is not mentioned if water/diet is analyzed for contaminants.
- Animals were exposed for a limited time: from gestation day 6-15. The guideline is not intended to examine solely the period of organogenesis, (e.g. days 5-15 in the rodent) but also effects from preimplantation, when appropriate, through the entire period of gestation to the day before caesarean section.
- "The test substance was administered to the animals by gavage with a feeding needle." No further information on test item administration; preparation of dosing solution? volume administered? stability/homogenicity and frequency of preparation?
- Body weight determination frequency is not complete, is the dose to each animal based on the most recent individual body weight determination?
- Food consumption is not measured.
- Results for the individual animals are not presented in the report.
- For the pups 1/2 litter should be prepared for skeletal examinations and the other 1/2 for soft tissue alterations. in this study the litters were divided 2/3 and 1/3 for these examinations.
- It is mentioned in the report that dead fetuses were seen but this is not mentioned anywhere in the tables.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Name: α,α,α',α'-tetramethyl-m-xylene-α,α'-diol
Lot No.: 101155
odourless white solid

Test animals

Species:
rat
Strain:
Wistar

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
not specified
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: until detection of a vaginal plug
- After days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no data
- Verification of same strain and source of both sexes: no data
- Proof of pregnancy: vaginal plug referred to as day 0 of pregnancy
- Any other deviations from standard protocol: -
Duration of treatment / exposure:
GD 6-15
Frequency of treatment:
daily from GD 6-15
Duration of test:
start of mating, from GD 0 to day of c-section GD 20
Doses / concentrations
Remarks:
Doses / Concentrations:
40, 200 and 1000 mg/kg bw
Basis:

No. of animals per sex per dose:
25 females
Control animals:
other: yes, treated with corn oil

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
200 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

Abstract from study report:

Results

There were reductions in bodyweight during pre-mating period in F0 and F1 animals receiving 10000 ppm combined by reduced bodyweight in F1 and F2 pups. There were no effects of α,α,α',α'-tetramethyl -m-xylene-α,α'-diol on reproductive parameters and dose levels up to and including 10000 ppm.

Conclusions

There were no effects of α,α,α',α'-tetramethyl-m-xylene-α,α'-diol on reproductive parameters at dose levels up to 10000 ppm.

There were signs of toxicity in parents and offspring receiving 10000 ppmα,α,α',α'-tetramethyl-m-xylene-α,α'-diol, seen as reduced bodyweight.

The NOAEL was 2500 mg/kg diet, equivalent to 168.0 mg/kg bw/d for males, 253.9 mg/kg bw/d for females.

Applicant's summary and conclusion

Conclusions:
NOAEL 200 mg/kg bw for parent animals and developmental effects.
Executive summary:

Abstract from study report :

The objective of this study was to provide data on the possible effects on pregnant female rats and development of the embryo and fetus consequent to daily administration bygavageof the test substance from gestation day (GD) 6-15.

Females were treated with 40, 200 and 1000mg/kg bw. The control group was treated with corn oil. At Caesarean section females and fetuses of all groups were macroscopically examined. Fetuses and reproductive organs were weighed. Fetuses were further processed for visceral and skeletal examination examination.

No mortality was seen. Clinical signs of toxicity, including myasthenia of limbs, side position and activity decreased were observed in eight pregnant females of high-dose group in 20 minute after gavage during GD 6-15.Clinical signs were disappeared 6 hours after exposure.Daily clinical obserbations during the gestation period did not reveal any remarkable findings in animal’s appearance, general condition or behaviour among the low-dose, mid-dose and control groups.

Body weight was statistically significantly decreased in high-dose relative to control groups at GD 6, 9 and 12. No effect was seen on the mean maternal body weight in the mid-dose and low-dose groups during pregnancy.

In each group, 25 females were mated of which 22, 20, 23 and 21 females of the control and low-, mid- and high-dose groups, respectively, appeared to be pregnant and had live fetuses at Caesarean section. No statistically significant differences were observed in the females fecundity index among the groups. Dead fetuses and pre-implatation loss was significantly increased in high-dose relative to control group. No differences were observed in the number of corpora lutea, the number of implantation sites, and post-implatation loss, live fetuses and sex ratio between the groups.

No effect was seen on the weight of gravid uterus and empty uterus. Macroscopic findings at necropsy did not reveal any remarkable or treatment related findings.

No dose-relationship was established for external abnormity.

No visceral anomalies were observed among the dosing and control groups.

No statistically significant differences in the incidences of skeletal malformations were observed among the groups.

In conclusion, no observed effect level in maternal effect after gavage during GD 6-15 were 200 mg/kg bw. No observed effect level in developmental effect after gavage with during GD 6-15 were 200 mg/kg bw.