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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report Date:
2016

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Qualifier:
according to
Guideline:
EU Method B.31 (Prenatal Developmental Toxicity Study)
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
Eighty-eight mated female New Zealand White rabbits were assigned to four dose groups. The test item was administered once daily by oral gavage from Days 6 to 28 post-coitum at doses of 50, 150 and 450 mg/kg/day (Groups 2, 3 and 4, respectively). The rabbits of the control group received the vehicle, water, alone. Females were checked daily for the presence of clinical signs. Food consumption and body weight were determined at periodic intervals.

All animals surviving to Day 29 post-coitum were subjected to an examination post-mortem and external, thoracic and abdominal macroscopic findings were recorded. A laparohysterectomy was performed on each surviving female of the groups. The uteri, placentae and ovaries were examined, and the numbers of fetuses, early and late resorptions, total implantations and corpora lutea were recorded. Gravid uterine weights were recorded, and corrected body weights (changes) were calculated. The fetuses were weighed, sexed and examined for external, visceral and skeletal malformations and developmental variations. All live fetuses were euthanized. One half of the fetuses were decapitated and the heads were fixed in Bouin’s fixative, all fetuses were dissected and examined for visceral anomalies and subsequently fixed in 96% aqueous ethanol and stained with Alizarin Red S for skeletal examinations.
GLP compliance:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: flakes
Details on test material:
Identification Trimethylolpropane
Appearance White flakes
Purity/Composition 99.6%
Test substance storage At room temperature, desiccated
Purity/composition correction factor No correction factor required
Stability at higher temperatures Yes, maximum temperature: 120°C, maximum duration: 24h/N2
Chemical name (IUPAC), synonym 2-Ethyl-2-(hydroxymethyl)-1,3-Propanediol
or trade name
CAS Number 77-99-6
Molecular formula C6H14O3
Molecular weight 134.2
Volatile No
pH 5-6 at concentration of 50% in water

Test animals

Species:
rabbit
Strain:
New Zealand White

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
Mating procedures:
One female was placed on a one-to-one-basis in the cage of a male rabbit. The time of mating was established by visual observation of mating. This day was designated Day 0 post-coitum.
Duration of treatment / exposure:
From Days 6 to 28 post-coitum, inclusive.
Frequency of treatment:
Once daily for 7 days per week.
Duration of test:
28 days
No. of animals per sex per dose:
22 female rabbits per dose
Control animals:
yes, concurrent vehicle

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
>= 450 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Dose descriptor:
NOAEL
Effect level:
>= 450 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

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
450 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Remarks on result:
other: 450 mg/kg/day was the highest applied dose

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

Maternal findings

A dose-related effect on food consumption and body weight gain was seen at 150 and 450 mg/kg/day. When compared to the control group, reduced mean values for food intake and body weight gain were seen during the first 10 days of treatment (i.e. from Days 6-16 post-coitum). Changes were relatively slight and did not always reach statistical significance. Furthermore, as recovery towards control values was seen during the remainder of the treatment period, the decreases in food intake and body weight gain were not considered to be adverse. Terminal body weights corrected for (gravid) uterine weight were unaffected by treatment.

No effects on food consumption and body weight were seen after treatment at 50 mg/kg/day.

Remaining maternal parameters (i.e. mortality, clinical signs, macroscopic appearance at necropsy and maternal pregnancy data) were unaffected in the 50, 150 and 450 mg/kg/day groups.

Developmental findings

No developmental toxicity was observed after treatment up to 450 mg/kg/day.

The trend towards slightly lower male and female fetal body weights noted at 150 and 450 mg/kg/day was most likely secondary to the lower body weight gains observed in maternal animals from Days 6-16 post-coitum. As changes were only slight (not reaching statistical significance) and all values remained within normal limits, it was not considered to be toxicologically relevant.

Litter size and sex ratio were unaffected by treatment up to 450 mg/kg/day.

There were no treatment-related external, visceral and skeletal variations or malformations.

Applicant's summary and conclusion

Executive summary:

Principles of method:

Eighty-eight mated female New Zealand White rabbits were assigned to four dose groups. The test item was administered once daily by oral gavage from Days 6 to 28 post-coitum at doses of 50, 150 and 450 mg/kg/day (Groups 2, 3 and 4, respectively). The rabbits of the control group received the vehicle, water, alone. Females were checked daily for the presence of clinical signs. Food consumption and body weight were determined at periodic intervals.

All animals surviving to Day 29 post-coitum were subjected to an examination post-mortem and external, thoracic and abdominal macroscopic findings were recorded. A laparohysterectomy was performed on each surviving female of the groups. The uteri, placentae and ovaries were examined, and the numbers of fetuses, early and late resorptions, total implantations and corpora lutea were recorded. Gravid uterine weights were recorded, and corrected body weights (changes) were calculated. The fetuses were weighed, sexed and examined for external, visceral and skeletal malformations and developmental variations. All live fetuses were euthanized. One half of the fetuses were decapitated and the heads were fixed in Bouin’s fixative, all fetuses were dissected and examined for visceral anomalies and subsequently fixed in 96% aqueous ethanol and stained with Alizarin Red S for skeletal examinations.

Maternal findings

A dose-related effect on food consumption and body weight gain was seen at 150 and 450 mg/kg/day. When compared to the control group, reduced mean values for food intake and body weight gain were seen during the first 10 days of treatment (i.e. from Days 6-16 post-coitum). Changes were relatively slight and did not always reach statistical significance. Furthermore, as recovery towards control values was seen during the remainder of the treatment period, the decreases in food intake and body weight gain were not considered to be adverse. Terminal body weights corrected for (gravid) uterine weight were unaffected by treatment.

No effects on food consumption and body weight were seen after treatment at 50 mg/kg/day.

Remaining maternal parameters (i.e. mortality, clinical signs, macroscopic appearance at necropsy and maternal pregnancy data) were unaffected in the 50, 150 and 450 mg/kg/day groups.

Developmental findings

No developmental toxicity was observed after treatment up to 450 mg/kg/day.

The trend towards slightly lower male and female fetal body weights noted at 150 and 450 mg/kg/day was most likely secondary to the lower body weight gains observed in maternal animals from Days 6-16 post-coitum. As changes were only slight (not reaching statistical significance) and all values remained within normal limits, it was not considered to be toxicologically relevant.

Litter size and sex ratio were unaffected by treatment up to 450 mg/kg/day.

There were no treatment-related external, visceral and skeletal variations or malformations.

In conclusion, based on the results in this prenatal developmental toxicity study the maternal and developmental No Observed Adverse Effect Level (NOAEL) for Trimethylolpropan was established as being 450 mg/kg/day, the highest dose tested.