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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
two-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
disregarded due to major methodological deficiencies
Study period:
1988
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
significant methodological deficiencies
Remarks:
Poor study design (poor test substance, details of negative control group is not stated and a viral infection resulted in poor reproductive performance in all groups

Data source

Reference
Reference Type:
publication
Title:
Multigeneration Reproduction and Carcinogenicity Studies In Sprague-Dawley Rats Exposed Topically to Oxidative Hair-Colouring Formulations Containing p-Phenylenediamine and Other Aromatic Amines
Author:
Burnett, C. M., and Goldenthal, E. I
Year:
1988
Bibliographic source:
Food and Chemical Toxicology 26,467-474

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
- Principle of test: the solution was applied topically twice weekly throughout the growth, mating, gestation and foetal viability indices and body weights were evauated and these were compared with the values for the three concurrent control groups.
- Short description of test conditions: The generation F0 was exposed until they were 100 days old and after they were mated. The generation F1a were used in a carcainogenicity study. The generation F0 was re-mated and 20 mals and 20 female of the generation F1b were exposed untiil they were 100 days old and after ther were mated to produce the F2a and F2b generation. the F2b generation, after a selection, were mated to produce F3 generation.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid
Details on test material:
No data
Specific details on test material used for the study:
SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: haur dye formulation n°7043
- Expiration date of the lot/batch: No data
- Purity test date: No data
- Purity : 0.5%
- other consituents : toluenediamine sulphate (6%), m-aminophenol (0.7%),p-aminophenol (1%), 4-nitro-p-phenylenediamine (0.25%), oleic acid (15%), isopropanol (10%), glycerine (4.5%), proylene glycol (9%), sodium sulphit (0.2%), ammonia 29% (9%), water (ad 100%).

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: No data
- Stability under test conditions: No data
- Solubility and stability of the test substance in the solvent/vehicle: No data
- Reactivity of the test substance with the solvent/vehicle of the cell culture medium: No data

TREATMENT OF TEST MATERIAL PRIOR TO TESTING
- Treatment of test material prior to testing: No
- Preliminary purification step (if any): No

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Wilmington, MA
- Females (if applicable) nulliparous and non-pregnant: No data
- Age at study initiation: 6-8 weeks old
- Weight at study initiation: 100-00 g
- Fasting period before study: No data
- Housing: individual
- Diet : ad libitum (Purina Laboratroy Chow)
- Water: ad libitum
- Acclimation period: No data

DETAILS OF FOOD AND WATER QUALITY: No data

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

Administration / exposure

Route of administration:
dermal
Vehicle:
other: Hydrogen peroxid (6%)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
- 0.5 ml of the test formulation mixing with an equal volume of 6% hydrogen peroxide
- Prepared fresh for each application

VEHICLE
- Justification for use and choice of vehicle (if other than water): No data
- Concentration in vehicle: 0.25%
- Lot/batch no. (if required): obtained from commercial suppliers
- Purity: No data
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: 15 days
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
- If unsuccessful pairing : No data
- After successful mating each pregnant female was caged individualy and were allowed to deliver naturally
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
F0 :until they were 100 days old
F1 : until they were 100 days old
Frequency of treatment:
Twice weekly
Details on study schedule:
- F1 parental animals not mated until 11 weeks after selected from the F1 litters.
- Selection of parents from F1 generation when pups were 21 days of age.
- Age at mating of the mated animals in the study:: 100 days

Doses / concentrations
Dose / conc.:
0.5 other: %
No. of animals per sex per dose:
40 per sex per dose
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: commercial product
- Other: the rats of each sex were randomly assigned to nine groups of 40 animals of each in such a way as to achieve comparable mean group body weight.

Positive control:
No

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: No data

FOOD CONSUMPTION : Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data

Oestrous cyclicity (parental animals):
No
Sperm parameters (parental animals):
No
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: Yes
- If yes, maximum of 10 pups/litter; excess pups were killed and discarded.

PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 ] offspring: number and sex of pups, pharmacological effects, llive births, postnatal mortality, weight

GROSS EXAMINATION OF DEAD PUPS: No

ASSESSMENT OF DEVELOPMENTAL NEUROTOXICITY: No

ASSESSMENT OF DEVELOPMENTAL IMMUNOTOXICITY: No
Postmortem examinations (parental animals):
No data
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at 21 days of age.
- These animals were subjected to postmortem examinations : Yes for 5 males and 5 females.

GROSS NECROPSY No data

HISTOPATHOLOGY / ORGAN WEIGTHS
These tissues were prepared for microscopic examination : adrenals, colon, heart, ileum, jejunum, kidneys, liver, lungs, ovaries, uterus and skin.
Statistics:
Yes (each treatment group with each of the three separate control groups by sex)

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
not examined
Dermal irritation (if dermal study):
effects observed, treatment-related
Description (incidence and severity):
Consisted of mild dermatitis seen intermittently throughout the treatment period.
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
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 examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed
Description (incidence and severity):
Fertility, gestation, survival and live birth indices and the mean numbers weaned and mean weaning weights for each litter in each generation were comparable amonth the test and control group.

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
not examined
Dermal irritation (if dermal study):
effects observed, treatment-related
Description (incidence and severity):
Consisted of mild dermatitis seen intermittently throughout the treatment period.
Mortality:
not examined
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
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:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not specified

Reproductive function / performance (P1)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not examined
Description (incidence and severity):
Fertility, gestation, survival and live birth indices and the mean numbers weaned and mean weaning weights for each litter in each generation were comparable amonth the test and control group.

Results: F1 generation

General toxicity (F1)

Clinical signs:
not examined
Dermal irritation (if dermal study):
effects observed, treatment-related
Description (incidence and severity):
Consisted of mild dermatitis seen intermittently throughout the treatment period.
Mortality / viability:
not examined
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
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:
not specified
Histopathological findings:
not specified
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Results: F2 generation

General toxicity (F2)

Clinical signs:
not examined
Dermal irritation (if dermal study):
effects observed, treatment-related
Description (incidence and severity):
Consisted of mild dermatitis seen intermittently throughout the treatment period.
Mortality / viability:
not examined
Body weight and weight changes:
not examined
Food consumption and compound intake (if feeding study):
not examined
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:
not specified
Histopathological findings:
not examined
Other effects:
not examined

Developmental neurotoxicity (F2)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F2)

Developmental immunotoxicity:
not examined

Applicant's summary and conclusion

Conclusions:
A multi-generation reproduction toxicity study was carried out by using a formulation containing 0.5% 1-Naphthol. Because of the poor study design (poor test substance, details of negative control group is not stated and a viral infection resulted in poor reproductive performance in all groups) the study it was considered to be of limited value only
Executive summary:

A multi-generation reproduction toxicity study was carried out by using a formulation containing 0.5% 1-Naphthol. Because of the poor study design (poor test substance, details of negative control group is not stated and a viral infection resulted in poor reproductive performance in all groups) the study it was considered to be of limited value only