2-tert-butylhydroquinone

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from a publication.

Data source

Reference

Reference Type:

publication

Title:

Evaluation of the Teratogenic Potential of Tertiary Butylhydroquinone (TBHQ) in the Rat

Author:

Walter J. Krasavage

Year:

1977

Bibliographic source:

TERATOLOGY Volume 16, Issue 1, pages 31–33, August 1977.

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other:

Principles of method if other than guideline:

The experimental diets containing 0, 0.125, 0.25 or 0.50% test chemical were fed from day 6 to day 16 of gestation to Sprague-Dawley rats. On day 20 of gestation, the teratologic effects were examined.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-tert-butylhydroquinone

EC Number:

217-752-2

EC Name:

2-tert-butylhydroquinone

Cas Number:

1948-33-0

Molecular formula:

C10-H14-O2

IUPAC Name:

2-tert-butylbenzene-1,4-diol

Details on test material:

- Name of test material (as cited in study report):2-tert-butylhydroquinone (TBHQ)
- Molecular formula (if other than submission substance):C10H14O2
- Molecular weight (if other than submission substance):166.22 g/mol
- Substance type:Organic
- Physical state:solid

Specific details on test material used for the study:

- Molecular weight (if other than submission substance):166.22 g/mol
- Substance type:Organic
- Physical state:solid

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: Sexually mature Sprague-Dawley rats were used
- Diet (e.g. ad libitum): PURINA Laboratory Chow supplemented with 5.0% Mazola brand corn oil, ad libitum
- Water (e.g. ad libitum): Ad libitum

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: PURINA Laboratory Chow supple-mented with 5.0% Mazola brand corn oil

Details on exposure:

DIET PREPARATION
- Mixing appropriate amounts with (Type of food): Test chemical was added to ground PURINA Laboratory Chow supplemented with 5.0% Mazola brand corn oil in concentrations of 0, 0.125, 0.25 or 0.5%

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No Data Available

Details on mating procedure:

- Impregnation procedure: cohoused
- M/F ratio per cage: 1:2
- Proof of pregnancy: Inseminations were verified by daily vaginal smears
- After successful mating each pregnant female was housed individually

Duration of treatment / exposure:

Day 6 to 16 of gestation period

Frequency of treatment:

daily

Duration of test:

Upto day 20 of gestation

Doses / concentrations

Remarks:

Doses / Concentrations:
0, About 125, 250 or 500 mg/kg
Basis:
nominal in diet
0, 0.125, 0.25 or 0.50%

No. of animals per sex per dose:

Control: 20 females
125 mg/kg: 20 females
250 mg/kg: 20 females
500 mg/kg: 20 females

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: The selected doses were 62.5, 125 and 250 times the approved use level for humans
- Rationale for animal assignment: Inseminated females were randomly assigned to one of four groups (20 rats/group)

Examinations

Maternal examinations:

Individual body weights were recorded on the day of insemination and daily throughout the period of gestation. Food consumption was monitored from day 0 to 20 of gestation. The mean body weight of the fetuses was calculated by averaging the body weight per litter within each group and calculating the mean of these values to obtain the group mean.

Ovaries and uterine content:

On day 20 of gestation, the females were killed by ether inhalation and the uteri were exposed by laparotomy. Total implantation sites were counted and categorized as consisting of live fetuses, dead fetuses or resorptions.
The ovaries of all females were removed and the total number of corpora lutea was recorded

Fetal examinations:

The fetuses were removed from the placentae, blotted dry, carefully examined for gross anomalies, sexed and weighed. Half of the fetuses were fixed in Bouin's fixative and examined for internal soft tissue anomalies according to the free-hand razor blade technique. The other half were fixed in 95% ethanol, eviscerated, macerated in KOH and stained with alizarin red for skeletal examination.

Statistics:

No Data Available

Historical control data:

No Data Available

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Details on results:

No Data Available

Maternal developmental toxicity

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in pregnancy duration:

not specified

Changes in number of pregnant:

not specified

Other effects:

not specified

Details on maternal toxic effects:

Maternal toxic effects:no effects
Details on maternal toxic effects:
No effect on the mean body weight gain or food consumption of the dams
Average number of corpora lutea, implantation sites, viable fetuses, resorptions and body weight of the fetuses per litter, fetal mortality and sex ratio were unaffected at 125, 250 or 500 mg/kg levels of treatment.

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

body weight and weight gain

dead fetuses

early or late resorptions

food consumption and compound intake

gross pathology

histopathology: non-neoplastic

maternal abnormalities

number of abortions

pre and post implantation loss

total litter losses by resorption

Remarks on result:

other: teratogenicity was measured

Maternal abnormalities

Abnormalities:

not specified

Results (fetuses)

Fetal body weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

Some sporadic cases were observed wherein the animals in 500 mg/kg were found to be of lesser weight whn compared to control.

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

no effects observed

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

no effects observed

Other effects:

not specified

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects
Details on embryotoxic / teratogenic effects:
A significant number of rudimentary ribs were seen in all groups. However, the incidence of this variation was two times greater in the control group than in any treatment group (125, 250 or 500 mg/kg)
The ingestion of test chemical did not cause any gross external or internal tissue anomalies.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The NOAEL value for the test chemical to Sprague-Dawley rats was determined to be about 500 mg/kg bw in diet. The substance did not produce any teratogenic effects at this dose level.

Executive summary:

The test chemical is an approved antioxidant used alone or in combination with other antioxidants in food. The teratogenic potential of test chemical is examined in this study. Test chemical was administered via the diet to pregnant Sprague-Dawley rats at concentrations of 0,0.125, 0.25or0.50% (about 0,125, 250 or 500 mg/kg bw) during the sensitive period of gestation. The experimental diets were fed from day 6 to day 16 of gestation. On day 20 of gestation, the females were killed by ether inhalation and examined for teratologic effects. The results of the present study revealled, the mean body weight and feed consumption of the dams were unaffected. The average number of corpora lutea, implantation sites, viable fetuses, resorptions and fetal body weights and mortality did not differ between the control and treated groups. Skeletal examinations revealed a significant number of fetuses with rudimentary ribs; however, the control group showed twice as many animals with this anomaly. Test chemical also did not result in any gross external or internal tissue anomalies in the fetuses. Therefore, it is concluded that test chemical fed to pregnant rats at doses up to 250 times the approved use level for humans caused no abnormalities in rat fetuses. The substance was considered to be non-teratogenic at all dose levels and the NOAEL is determined to be about 500 mg/kg bw in diet.