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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data is from peer reviewed journal

Data source

Reference
Reference Type:
publication
Title:
Evaluation of the Teratogenic and Mutagenic Potential of the Oxidative Dyes, 4 -Chlororesorcino1, M-Phenylenediamine, and Pyrogallol
Author:
J.C. PICCIANO, W.E. MORRIS, S. KWAN, and B.A. WOLF
Year:
1983
Bibliographic source:
JOURNAL OF THE AMERICAN COLLEGE OF TOXICOLOGY , Volume 2, Number 4, 1983

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other:
Principles of method if other than guideline:
In reprotox studies, the dye 4-chlororesorcinol was administered by gavage to Sprague-Dawley rats on days 6 through 15 of gestation at the following dose levels: at 50, 100, and 200 mg/kg and the effects were noted.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
4-chlororesorcinol
EC Number:
202-462-0
EC Name:
4-chlororesorcinol
Cas Number:
95-88-5
Molecular formula:
C6H5ClO2
IUPAC Name:
4-chlorobenzene-1,3-diol
Test material form:
solid: particulate/powder
Remarks:
migrated information: powder
Details on test material:
- Name of test material (as cited in study report): 4-Chlororesorcinol
- Molecular formula (if other than submission substance): C6H5O2Cl
- Molecular weight (if other than submission substance): 144.56 g/mol
- Substance type: Organic
- Physical state: Beige-brown powder
- Impurities (identity and concentrations): No data available

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals or test system and environmental conditions:
- Source: Charles River Breeding Laboratories, Wilmington, Mass.
- Age at study initiation: (P) x wks; mature (F1) x wks : No data available
- Weight at study initiation: 225 and 250 grams
- Fasting period before study: No data available
- Housing: No data available
- Diet (e.g. ad libitum): Purina Laboratory Rodent Chow .ad libitum

- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): Constant
- Humidity (%): Constant
- Air changes (per hr): No data available
- Photoperiod (hrs dark / hrs light): No data available

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The solutions were prepared fresh daily and administered at a rate of 10 ml/kg.

DIET PREPARATION - Not applicable
- Rate of preparation of diet (frequency):
- Mixing appropriate amounts with (Type of food):
- Storage temperature of food:

VEHICLE
- Justification for use and choice of vehicle (if other than water): No data available
- Concentration in vehicle: to get a dose of 0, 50, 100 and 200 mg/kg body weight/day
- Amount of vehicle (if gavage): 10 ml/kg
- Lot/batch no. (if required):
- Purity:
Details on mating procedure:
- M/F ratio per cage: 1:2 ratio
- Length of cohabitation: No data available
- Proof of pregnancy: Sperm in vaginal smear is referred to as day 0 of pregnancy
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.: No data available
- Further matings after two unsuccessful attempts: [no / yes (explain)]: No data available
- After successful mating each pregnant female was caged (how): Once mating was determined, each female was separated, housed, and identified
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
10 days (gestation day 6-15)
Frequency of treatment:
Daily
Details on study schedule:
no details available
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 100, and 200 mg/kg body weight/day
Basis:
nominal conc.
No. of animals per sex per dose:
0 mg/kg bw/day: 22 female
50 mg/kg bw /day: 7 female
100 mg/kg bw /day: 7 female
200 mg/kg bw/day: 8 female
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The dose levels for the dyes were determined by previous range finding studies to estimate the maximum tolerated dosages. The dose levels were as follows: 50, 100, and 200 mg/kg for 4-chlororesorcinol.
- Rationale for animal assignment (if not random): Mature male and female Sprague-Dawley rats were chosen for the study. Pregnant females were assigned on a random basis to a high, medium, or low dosage group for 4-chlororesorcinol.
- Other:
On day 20 of gestation, estimated as 24 hours preparturition, the dams were sacrificed by carbon dioxide inhalation. The viability of each foetus was determined. The metrial glands were counted, identifying original implantation sites. An implantation site not occupied by a foetus was designated a resorption site. Each fetus was sexed and weighed to the nearest 0.1 gram. Any fetal external malformations were recorded after gross examination of the head, trunk and limbs.
Positive control:
Positive controls were included in the study. Vitamin A (Aquasol A Drops, USV Laboratories, N.Y.) was.dosed at a rate of 100,000 I.U. per animal on day 9 of gestation only. Aspirin (Fisher Scientific Company, N.J.) was dosed at a rate of 350 mg/kg on days 6-15 of gestation.

Examinations

Parental animals: Observations and examinations:
Survival, clinical sign and body weight were examined.
Oestrous cyclicity (parental animals):
Any irregularities in the estrous cycle were investigated
Sperm parameters (parental animals):
No data available
Litter observations:
Survival, sex ratio, Number of Litters, No. Abnormal Fetuses and body weight of fetus were examined.
Postmortem examinations (parental animals):
Gross abnormalities and histopathology were examined.
Number of implantation sites and resorption site was examined.
Postmortem examinations (offspring):
Gross abnormalities, visceral anomalies and skeletal anomalies/ variations were examined.
Statistics:
Statistical analysis was performed by using Student’s T-test for comparison of maternal weight changes, the number of fetal implantations, fetal weight and fetal sex ratio. Chi square analysis were used to compared the number of fetal resorptions and abnormal fetuses. A “naive” model trend analysis was conducted according to Johnson and Siskin. For all statistical analyses, a level of probability of p = 0.05 was used for significance. When lower levels of probability were observed, these were noted.
Reproductive indices:
Fertility index, gestation index and implantation index were examined.
Offspring viability indices:
Yes, viability of each fetus was determined

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
All dams appeared normal upon gross observation throughout the studies
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
when treated with 200 mg/kg bw/day, on day 6-16 significant decrease in weight gains were observed in females as compared to control.
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
when treated with 200 mg/kg bw/day, on day 6-16 significant decrease in weight gains were observed in females as compared to control.
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
not specified
Other effects:
not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Description (incidence and severity):
No effect were observed on reproductive function of treeated rat as compared to control.
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed
Description (incidence and severity):
No effect were observed on reproductive performance of treated rat as compared to control.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No adverse effect on survival, clinical sign, body weight , Gross abnormalities, histopathology and reproductive performance.

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Mortality / viability:
not specified
Body weight and weight changes:
not examined
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
When treated with 200 mg/kg bw/day, open eye, Gastromegaly and Wavy Rib were observed in fetaus of treated rat. Although abnormalities were observed but they are not statistically significant as compared to control.
Histopathological findings:
not specified

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
100 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effect on survival and gross pathology of foetus

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Exposure to the positive control agents, Vitamin A and aspirin,resulted in a statistically significant increase in abnormal fetuses with a broad spectrum of gross visceral and skeletal anomalies ranging from a frequency of 18-60%.

Applicant's summary and conclusion

Conclusions:
NOAEL of 4-Chlororesorcinol in female Sprague-Dawley rats was considered to be 100 mg/kg body weight /day for F0 and F1 generation.
Executive summary:

In a reproductive toxicity study, Sprague-Dawley female rat were exposed to 4-Chlororesorcinol in the concentration of 0, 50, 100 and 200 mg/kg body weight /day on day 6 -15 of gestation.

A significant reduction in mean maternal weight gain and significant decrease in total resorpton of 200 mg/kg body weight /day treated rat were observed as compared to control.

On fetal evaluation open eye, gastromegaly and wavy rib were observed but the effect is not statistically significant as compared to contol.

Therefore NOAEL was considered to be 100 mg/kg body weight/day for F0 and F1 genearation when rats are exposed to 4-Chlororesorcinol orally for 10 days.