Registration Dossier

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
publication
Title:
Effects of butylated hydroxyanisole on the development and functions of reproductive system in rats
Author:
Sang-Hee Jeong, Byung-Yong Kim, Hwan-Goo Kang,Hyun-Ok Ku, Joon-Hyoung Cho∗
Year:
2005
Bibliographic source:
Toxicology 208 (2005) 49–62

Materials and methods

Principles of method if other than guideline:
The above experiment was performed to assess and evaluate reproductive & developmental effects of the test chemical on Sprague–Dawley rats.
GLP compliance:
not specified

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): tert-butyl-4-methoxyphenol(BHA)
- Molecular formula (if other than submission substance): C11H16O2
- Molecular weight (if other than submission substance): 180.11 Da
- Substance type: organic
- Physical state: Solid

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: (P) x wks; (F1) x wks: 7 weeks old
- Diet (e.g. ad libitum):Purina Laboratory Rat Chow ad libitum
- Water (e.g. ad libitum):UV-sterilized tap water, ad libitum
- Acclimation period:1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C):23–25 ◦C
-humidity: 40–60%
- Photoperiod (hrs dark / hrs light):12-h light/dark

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on mating procedure:
- Proof of pregnancy: [ sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No Data Available
Duration of treatment / exposure:
Males: for a total of 7 weeks
Females: for a total of 10 weeks
Frequency of treatment:
Once daily
Details on study schedule:
Parental generation:
Male rats were treated for total 7 weeks including further 3 weeks of post breeding and F0 female rats were treated for maximum 10 weeks including further 3 weeks of gestation and 3 weeks of lactation period. F0 rats were examined for clinical signs of toxicity, body weight changes and feed and water consumption throughout the dosing period. F0 male rats were sacrificed for the measurement of organ weights, analysis of hormones and cholesterol in serum and examination of sperm motility and morphology and necropsy findings. F0 female rats were sacrificed for the evaluation of necropsy finding, organ weights and hormones and cholesterol contents in serum after weaning.

F1 generation:
Following delivery of the entire litter (postnatal day 0, PND 0), all male and female pups were counted differentially, and examined for clinical signs of toxicity and mortality. During the lactation period, pups were examined for body weight gain and gross morphological abnormalities. Twelve offspring from each sex, litter and treatment group (by selection of 1–2 pups/sex/litter) were treated with each dose of the test chemical from PND 21 until 13 weeks old and another 12 offspring from each sex, litter and treatment group were sacrificed for the evaluation of anogenital distance, necropsy finding or organ weights on PND 21.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 10, 100 or 500 mg/kg
Basis:

No. of animals per sex per dose:
Control: 12 males; 12 females
10 mg/kg/day: 12 males; 12 females
100 mg/kg/day: 12 males; 12 females
500 mg/kg/day: 12 males; 12 females
Control animals:
yes, concurrent vehicle
Details on study design:
No Data Available

Examinations

Parental animals: Observations and examinations:
No Data Available
Oestrous cyclicity (parental animals):
The estrous cycles were decided under microscope (×200) according to the component ratio of leucocytes, nucleated epithelia and cornified epithelia
Sperm parameters (parental animals):
Testes and epididymis were excised and weighed
from each animal. The right cauda epididymis was used for sperm count and left one for sperm motility and sperm head morphology analysis.
-Sperm number was counted using distal cauda of right epididymis, Sperms were immobilized in ice bath for 5 min and then counted under inverted microscope (×100) using hemocytometer
Litter observations:
No Data Available
Postmortem examinations (parental animals):
On necropsy time, thyroid gland and other organs such as adrenal gland, liver, testes, ovary and etc.were taken out for examination
Postmortem examinations (offspring):
Thyroid follicular epithelial cells of F1 female and male rats exposed to BHA 100 and 500 mg/kg/day were enlarged in cell height, vacuolated and exfoliated and follicles were decreased in size with sparse colloidal fluid. Any significant histopathological findings were not observed in other organs as liver, testes, ovary and adrenal gland of F1 female and male rats
Statistics:
Data are expressed as mean±S.D. Statistical significance of differences was determined using Statistical software (version 5.5) by performing oneway analysis of variance with post hoc comparisons between the vehicle control group and each treatment group
Reproductive indices:
Different parameters like Body weight,organ weights, Hormonal changes were analysed
Offspring viability indices:
Body weight of F1 pups between control andtreatment groups were examined in both male and female pups on PND 21,
organ weights (liver,Spleens,Testes,adernal )were also examined in ofsprings .

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weights in treated rats were not different significantly from vehicle control group.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Body weights in treated rats were not different significantly from vehicle control group.
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:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Description (incidence and severity):
Motility, number and head morphology of sperm were not impaired by the test chemical.
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
The ratio of copulation per cohabited pairs was decreased and cohabitation day for copulation took approximately 2 times longer than that of control by the test chemical 500 mg/kg,

Effect levels (P0)

open allclose all
Dose descriptor:
LOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Changes in body and organ weights and in hormonal levels
Dose descriptor:
NOEL
Effect level:
10 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effects were observed.

Results: F1 generation

General toxicity (F1)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
No change in Sperm motility was observed. But, length of sperm head affected by higher doses.
Dermal irritation (if dermal study):
not specified
Mortality / viability:
not specified
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight of F1 pups on PND 0 was not different between control and treatment groups but decreased in both male and female pups on PND 21 by the test chemical in 500 mg/kg/day dose group.
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:
effects observed, treatment-related
Description (incidence and severity):
Changes were observed in higher dose groups of 100 and 500 mg/kg dose groups.
Gross pathological findings:
not specified
Histopathological findings:
effects observed, treatment-related
Description (incidence and severity):
Changes in thyriod follicular cells at 500 mg/kg dose group.
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Effect levels (F1)

Dose descriptor:
LOAEL
Generation:
F1
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: effects were observed

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The low observed adversed effect level (LOAEL) of the test chemical was found at a dose level of 100 mg/kg bw/day and NOEL value was observed at dose level of 10 mg/kg bw/day in Sprague-Dawley Rats.
Executive summary:

In a one-generation study, the effect of the test chemical on reproduction and development was investigated in male and female Sprague-Dawley rats. The rats were exposed daily to 0, 10, 100 or 500 mg/kg/day of the test chemical by oral administration. At dose 100 mg/kg/day changes in testosterone level in serum were observed, the weights of sex organs such as vagina, testes and ventral prostate were decreased while the weights of liver, adrenal gland and thyroid gland increased by 100 mg/kg/day of the test chemical. Organ weights of liver, adrenal gland and thyroid gland of F0 rats were increased by 500 mg/kg/day of the test chemical, body weight of F1 offspring was significantly decreased with change in relative weight of liver and brain also. Therefore, LOAEL was considered to be 100 mg/kg/day when male and female Sprague-Dawley rats were exposed to the test chemical at different concentrations.