Phenol, styrenated

Toxicity to reproduction

Administrative data

Endpoint:

two-generation reproductive toxicity

Remarks:

based on test type (migrated information)

Type of information:

migrated information: read-across based on grouping of substances (category approach)

Adequacy of study:

weight of evidence

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:

Effect of the test chemical with respect to pregnancy and lactation of animals

Author:

McFarlane, M et.al,

Year:

1997

Bibliographic source:

Fd.Chem.Tox.1997

Materials and methods

Test guideline

Qualifier:

no guideline available

Principles of method if other than guideline:

Two generation study in rats by administering the test chemical in diets for a period varying from 5 weeks to 22 months for P and F1.

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2,6-di-tert-butyl-p-cresol

EC Number:

204-881-4

EC Name:

2,6-di-tert-butyl-p-cresol

Cas Number:

128-37-0

Molecular formula:

C15H24O

IUPAC Name:

2,6-di-tert-butyl-4-methylphenol

Test material form:

other: Solid

Details on test material:

- Name of test material (as cited in study report):butylated hydroxytoluene(BHT)
-Synonyms-2,6-di-tert-butyl-p-cresol
- Molecular formula (if other than submission substance): C15H24O
- Molecular weight (if other than submission substance): 220.3536 g/mol
- Substance type: organic
- Physical state:solid
- Impurities (identity and concentrations):0.1%(impurities not specified)

Specific details on test material used for the study:

Molecular formula (if other than submission substance): C15H24O
- Molecular weight (if other than submission substance): 220.3536 g/mol
- Substance type: organic
- Physical state: solid
- Impurities (identity and concentrations): 0.1%(impurities not specified)

Test animals

Species:

rat

Strain:

Wistar

Details on species / strain selection:

No Data Available

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Bantin and Kingman (Hull, UK)
- Age at study initiation: (P) x wks; (F1) x wks
- Weight at study initiation: (P) Males: 200 g; Females: 60 g;
- Fasting period before study:Not available
- Housing: Polypropylene cages with sterilized sawdust as bedding male rats were housed singly, females in groups of seven or eight.
- Diet (e.g. ad libitum): ad libitum standard rodent breeding diet (CRM, Labsure)
- Water (e.g. ad libitum): ad libitum
- Acclimation period:2 wk

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 3°C
- Humidity (%):30-70%
- Photoperiod (hrs dark / hrs light): 12-hr light dark cycle

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: Test chemical contained in the diet

Details on exposure:

DIET PREPARATION:
- Rate of preparation of diet (frequency):twice a week
- Mixing appropriate amounts with (Type of food): standard rodent breeding diet
VEHICLE: Test chemical contained in the diet

Details on mating procedure:

- M/F ratio per cage:1/8
- Length of cohabitation:5 week after first offering the test chemical containing diet and continuing until sufficient pregnancies obtained.
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy Not available
- After … days of unsuccessful pairing replacement of first male by another male with proven fertility. Not available
- Further matings after two unsuccessful attempts: [no / yes (explain)] Not available
- After successful mating each pregnant female was caged (how): singly on sterilized wood chips
- Any other deviations from standard protocol:-Not available

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

No Data Available

Duration of treatment / exposure:

Exposure period: male: 5 weeks (F0)
4 weeks (F1) and 22 months (F1)
female: 8 weeks (F0)
Premating exposure period (males): 3 weeks
Premating exposure period (females): 3 weeks

Frequency of treatment:

Daily

Details on study schedule:

Animals were offered diets containing the test chemical ,concentration of the test chemical adjusted every 2 weeks. Male rats were allowed access to female rats at commencing 5 wk after first offering the test chemical containing diet and continuing until sufficient pregnancies were obtained and ensure number of pups of the F1, generation. Throughout pregnancy and lactation, dams continued to receive the dose of the test chemical.

Doses / concentrations

Remarks:

Doses / Concentrations:
F0-0,25,100 or 500 mg/kg bw day F1: 0, 25, 100 or 250 mg/kg bw/day
Basis:
nominal in diet

No. of animals per sex per dose:

Control: 7 males and 50 females
25 mg/kg bw/day:7 males and 50 females
100 or 500 mg/kg bw/day:7 males and 50 females

Control animals:

yes, concurrent no treatment

Details on study design:

Dose ranging study was done for dose selection

Positive control:

No Data Available

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS:
Time:Daily
BODY WEIGHT: Yes
- Time schedule for examinations:Weekly
ORGAN WEIGHT: Yes
Histopathological examinations:Yes
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
liver-biochemistry.: Yes

Oestrous cyclicity (parental animals):

No data

Sperm parameters (parental animals):

No data

Litter observations:

Examinations included:
number of foetuses/dams, number of pups per litter, number of pups found dead.

Postmortem examinations (parental animals):

GROSS NECROPSY: Liver, kidney, thyroid, lung, adrenal and body fat (with emphasis on the liver).

Postmortem examinations (offspring):

GROSS NECROPSY: Liver, kidney, thyroid, lung, adrenal and body fat (with emphasis on the liver)

Statistics:

Statistical analysis of data was performed using Student's t-test.

Reproductive indices:

Pregnancy proceeded normally in all groups of animals.There was no alteration in numbers of resorption sites. No statistically significant change was seen in the number of foetuses/dams.

Offspring viability indices:

The number of pups per litter did not differ between dose groups. There was a trend to an increase in the number of pups found dead or dying soon after birth with increase in dose but the actual number of deaths in affected litters was not influenced by treatment with the test chemical.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality:

not specified

Body weight and weight changes:

effects observed, non-treatment-related

Description (incidence and severity):

Dams given diets containing the test chemical at 750 or 1000 mg/kg body weight gained less weight than controls in the last week of pregnancy and did
not increase food consumption to the same extent during lactation, resulting in a fall in body weight. Dams treated with the test chemicals at nominal doses of 500 mg/kg body weight/day upwards showed a reduction in body weight gain during lactation.

Food consumption and compound intake (if feeding study):

effects observed, non-treatment-related

Description (incidence and severity):

Dams given diets containing the test chemical at 750 or 1000 mg/kg body weight id not increase food consumption to the same extent during lactation, resulting in a fall in body weight.

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:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

not specified

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

Details on results (P0)

Dams receiving 500 mg of the test chemical/kg body weight and day showed a significant increase in liver weight. There was no alteration in numbers of resorption sites. No statistically significant change was seen in the number of foetuses/dam.
There were no differences in food consumtion or body weight gain between female control rats and female rats fed with the test chemical-containing diet. Reduced body weight gain observed, in male rats treated with 500 mg/kg body weight with the test chemical.

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No effect on body weight and food consumption,no clinical signs of toxicity.

Target system / organ toxicity (P0)

Critical effects observed:

not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:

effects observed, treatment-related

Dermal irritation (if dermal study):

not specified

Mortality / viability:

no mortality observed

Body weight and weight changes:

not specified

Food consumption and compound intake (if feeding study):

not specified

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

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

Other effects:

not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):

not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:

not specified

Details on results (F1)

No significant effects on foetus development except pups belonging to 500 mg/kg bw/day failed to gain weight at the same rate as control pups.

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No differences in mating success or pregnancy were found. No alteration in numbers of resorption sites and no statistically significant change was seen in the number of fetuses per dam. The number of pups per litter did not differ

Target system / organ toxicity (F1)

Critical effects observed:

not specified

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The NOAEL for toxicity to reproduction was assessed to be 500 mg/kg body weight and day; the NOAEL for parental toxicity was assessed to be 100 mg/kg body weight and day.

Executive summary:

The results of this two-generation reproductive and developmental toxicity study on Wistar rats revealed no adverse effects on reproductive performance of the F0 (P) generation. The animals were fed with the test chemical at dietary levels of 0, 25, 100 or 500 mg/kg body weight. Maternal toxicity, indicated by a significant increase of the liver weight, was seen at 500 mg/kg body weight and day. No differences in mating success were found in treated dams and pregnancy proceeded normally in all groups. There was no alteration in numbers of resorption sites and no statistically significant change was seen in the number of fetuses per dam. The number of pups per litter did not differ. According to the findings of this study, no adverse effects on reproduction were found. The NOAEL for toxicity to reproduction was assessed to be 500 mg/kg body weight and day; the NOAEL for parental toxicity was assessed to be 100 mg/kg body weight and day.