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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
Data is from peer-reviewed journal

Data source

Reference
Reference Type:
publication
Title:
Evaluation of the teratogenic potential of the Oxidative dyes 6-chloro-4-nitro-2-aminophenol And o-chloro-p-phenylenediamine
Author:
J. C. PICCIANO, W. E. MORRIS and B. A. WOLF
Year:
1984
Bibliographic source:
Fd. Chem. Toxic. Vol. 22, no. 2, pp. I47 149, 1984

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
The present study was conducted to determine the reproductive toxicity potential of 2-chloro-p-phenylenediamine (o-chloro-p-PD) (CAS No.- 615-66 -7) when administered orally to 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): o-chloro-p-phenylenediamine (o-chloro-p-PD)
- Molecular formula (if other than submission substance): C6H7N2Cl
- Molecular weight (if other than submission substance): 142.59 g/mole
- Substance type: Organic
- Physical state: Solid
- Impurities (identity and concentrations): No data available
Specific details on test material used for the study:
- Name of test material (as cited in study report): 2-chloro-p-phenylenediamine (o-chloro-p-PD)
- Molecular formula: C6H7N2Cl
- Molecular weight:142.59 g/mole
- Substance type: Organic
- Physical state: Solid
- Impurities (identity and concentrations):No data available

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
female
Details on test animals and environmental conditions:
- Source: Charles River Breeding Laboratories, Wilmington,MA
- Age at study initiation: (P) x wks; (F1) x wks : No data available
- Weight at study initiation: P - 225-250 g
- Fasting period before study: No data available
- Housing: Individually housed
- Diet (e.g. ad libitum): Purina Laboratory Rodent Chow, ad libitum
- Water (e.g. ad libitum):Water, ad libitum
- Acclimation period: 2 weeks

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

Administration / exposure

Route of administration:
oral: gavage
Type of inhalation exposure (if applicable):
not specified
Vehicle:
propylene glycol
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: o-chloro-p-phenylenediamine was dissolved in propylene glycol before administration.

DIET PREPARATION
- Rate of preparation of diet (frequency): No data available
- Mixing appropriate amounts with (Type of food): No data available
- Storage temperature of food: No data available

VEHICLE
- Justification for use and choice of vehicle (if other than water): Propylene glycol
- Concentration in vehicle: 0, 100, 200 and 400 mg/kg/day
- Amount of vehicle (if gavage): 10 ml/kg
- Lot/batch no. (if required): No data available
- Purity: No data available
Details on mating procedure:
- M/F ratio per cage:1 : 2 ratio
- Length of cohabitation:No data available
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: Sperm plug or the presence of sperm in a vaginal smear 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): Caged separately
- Any other deviations from standard protocol: No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
10 days
Frequency of treatment:
Daily
Details on study schedule:
Details on study schedule
- F1 parental animals not mated until [...] weeks after selected from the F1 litters: No data available
- Selection of parents from F1 generation when pups were [...] days of age. No data available
- Age at mating of the mated animals in the study: [...] weeks
(Explain how study was performed on perents and offspring separately whatever information we have): No data available
Doses / concentrations
Remarks:
Doses / Concentrations:
0,100, 200 and 400 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
Total : 53
10 ml/kg : 20 female
100 mg/kg/day : 11 female
200 mg/kg/day : 11 female
400 mg/kg/day : 11 female

Control animals:
yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:
Mortality , general health and condition and body weight were observed.
Oestrous cyclicity (parental animals):
Any irregularities in the estrous cycle were investigated.
Sperm parameters (parental animals):
No data available
Litter observations:
Litter was observed for survival rate, body weight, number of litter, sex ratio and general appearance were examined.
Postmortem examinations (parental animals):
Gross abnormalities were examined.

Number of implantation sites and number of resorptions were also examined.
Postmortem examinations (offspring):
Gross, visceral and skeletal anomalies in fetuses were observed.
Statistics:
Weight changes, the number of fetal implantations, fetal weights and the fetal sex ratio were analyzed by using Student's t test, The numbers of foetal resorptions and abnormal foetuses were compared by chi square analysis and vehicle control data were combined after an analysis of variance.
Reproductive indices:
Fertility index, gestation index, delivery index and implantation index were examined.

Offspring viability indices:
No data available

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
No abmormalities were observed in treated female rats.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
No mortality were observed in treated female rats.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Body weight and weight gain: Mean weight gain was decreased on 6-16 day in 200 mg/kg/day and on 6-20 day in 400 mg/kg/day treated female rats.
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
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
effects observed, treatment-related
Description (incidence and severity):
No effect were observed on reproductive performance of treated animals as compare to control.
No change were observed in fertility index, gestation index and implantation index of treated female rat as compare to control. Statistically significant increase in the number of resorptions were observed in 400 mg/kg/day treated rats.

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 effect on survival, clinical sign, body weight, Reproductive function and Reproductive performance

Target system / organ toxicity (P0)

Critical effects observed:
no

Results: P1 (second parental generation)

Effect levels (P1)

Remarks on result:
not measured/tested

Target system / organ toxicity (P1)

Critical effects observed:
not specified

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
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: Weight of both male and female fetuses were significantly decreased as compare to control
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:
effects observed, treatment-related
Description (incidence and severity):
No significant differences were observed in number of abnormal foetuses and the types of gross and skeletal anomalies as compare to contol.
Histopathological findings:
no effects observed
Description (incidence and severity):
No visceral anomalies were ovbserved in fetuses of treated female rats.
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Details on results (F1)

Reproductive performance:
No significant differences in the male:female sex ratio were observed as compare to control.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
200 mg/kg bw/day
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No effect on survival, body weight, Gross pathology and Histopathology

Target system / organ toxicity (F1)

Critical effects observed:
no

Results: F2 generation

Effect levels (F2)

Remarks on result:
not measured/tested

Target system / organ toxicity (F2)

Critical effects observed:
not specified

Overall reproductive toxicity

Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
NOAEL was considered to be 100 mg/kg/day for F0 generation and 200 mg/kg/day for F1 generation when female rat were exposed to 2-chloro-p -phenylenediamine (o-chloro-p-PD).
Executive summary:

In a reproductive toxicity study, female Sprague-Dawley rat were exposed 2-chloro-p-phenylenediamine (o-chloro-p-PD) orally in the concentration 0, 100, 200 and 400 mg/kg/day. In the parental generation, decreased in mean body weight were obsrved in 200 and 400 mg/kg/day treated rat as compared to control . In addition,significant increase in the number of resorptions were observed in female rat. Effect on fetal weight was observed when treated with 400 mg/kg/day. Therefore, NOAEL is considered to be 100 mg/kg/day for F0 generation and 200 mg/kg/day for F1 generation when rats are exposed to 2-chloro-p-phenylene diamine (o-chloro-p-PD) orally for 10 days.