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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
one-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data from peer reviewed journal

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Final Report on the Safety Assessment of Amino Nitrophenols as Used in Hair Dyes
Author:
Christina L. Burnett et.al
Year:
2009
Bibliographic source:
International Journal of Toxicology ,2009
Reference Type:
publication
Title:
Chronic Toxicity, Teratologic, and Reproduction Studies with Hair Dyes
Author:
THEODORE WBRNICK et.al
Year:
1975
Bibliographic source:
TOXICOLOGY AND APPLIED PHARMACOLOGY ,1975

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Reproductive toxicity study of test material was performed on CFE-S rats
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report):2-Amino-4 nitrophenol
- Molecular formula : C6H6N2O3
- Molecular weight : 154.12g/mole
- Substance type:Organic

Test animals

Species:
rat
Strain:
other: CFE-S
Details on species / strain selection:
No data available
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 15 week old

Administration / exposure

Route of administration:
oral: feed
Vehicle:
not specified
Details on exposure:
Details on exposure
PREPARATION OF DOSING SOLUTIONS:
Test material mixed with feed .
DIET PREPARATION
- Rate of preparation of diet (frequency):No data available
- Mixing appropriate amounts with (Type of food )
- Storage temperature of food: No data available
VEHICLE
- Justification for use and choice of vehicle (if other than water):
- Concentration in vehicle: 0,97.5,616 mg/kg bw/day (0,1950,7800 ppm)
- Amount of vehicle (if gavage): No data available

- Lot/batch no. (if required): No data available
- Purity: No data available
Details on mating procedure:
- M/F ratio per cage:1:1
- Length of cohabitation: No data available
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy:The presence of sperm during daily vaginal inspections (day 0 of pregnancy). .
- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: [no / yes (explain)]No data available
- After successful mating each pregnant female was caged (how): individual
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
9 days ( from day 6 through day 15 of gestation )
Frequency of treatment:
Daily
Details on study schedule:
No data available
Doses / concentrations
Remarks:
0, 97.5,616 mg/kg bw/day (0,1950,7800ppm)
No. of animals per sex per dose:
Total:120
0 mg/kg bw/day:20male and 20 female
97.5mg/kg bw/day:20male and 20 female
616mg/kg bw/day:20male and 20 female
Control animals:
yes
Details on study design:
No data available
Positive control:
No data available

Examinations

Parental animals: Observations and examinations:
Parental animals observation and examinations
CAGE SIDE OBSERVATIONS: yes

DETAILED CLINICAL OBSERVATIONS: Yes

Time schedule:


BODY WEIGHT: Yes
Time schedule for examinations: biweekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):

Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data: No data available
Oestrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
Each fetus was weighed, measured, and examined for gross abnormalities
Postmortem examinations (parental animals):
Postmortem examinations (Parent Animal)
SACRIFICE : All females were killed by chloroform inhalation on the 19th day of pregnancy and the fetuses delivered by Caesarian section.

Male animals: All surviving animals [describe when, e.g. as soon as possible after the last litters in each generation were produced.]: No data
Maternal animals: yes

GROSS NECROPSY: The number and distribution of fetuses, and the number of corpora lutea, live and
stillboin fetuses, and early and late resorptions were recorded
HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.:
macroscopic examination was performed
Postmortem examinations (offspring):
Each fetus was weighed, measured, and examined for gross abnormalities. One-third of each litter was examined for visceral abnormalities by employing the slicing method of Wilson (1965). The remaining two-thirds were cleared and the bone structure stained with alizarin red S in order to define any skeletal abnormalities
Statistics:
Statistical analysis using the 95% confidence level. The methods used included chi square test, analysis of variance and t test, and the Fisher exact probability test (Snedecor, 1962)
Reproductive indices:
No data available
Offspring viability indices:
No data available

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
The 616 mg/kg /day dose group excreted blue-brown colored urine
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
no effects observed
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:
no effects observed
Description (incidence and severity):
No dose related significant deference were observed in the average number of implantation sites, live pups, or early and late resorptions per litter, or in the number of females with one or more resorption sites.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
616 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
reproductive performance
Remarks on result:
other: overall no toxic effects on reproductive parameters

Target system / organ toxicity (P0)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
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:
no effects observed
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
Description (incidence and severity):
No grossly abnormal pups were noted in the 97.5 mg/kg /day dose group (244 pups); there was one in control group (244 pups). One grossly abnormal pup was noted out of the 262 examined in the 616 mg/kg /day dose group.
Histopathological findings:
not specified
Other effects:
not specified

Developmental neurotoxicity (F1)

Behaviour (functional findings):
not specified

Developmental immunotoxicity (F1)

Developmental immunotoxicity:
not specified

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
616 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
gross pathology
other: overall no developmental toxic effects observed
Remarks on result:
other: overall no developmental toxic effects observed

Target system / organ toxicity (F1)

Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Overall reproductive toxicity

Reproductive effects observed:
not specified
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
No Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 616 mg/kg/day (7800ppm. When male and female CFE-S rats were treated with test material orally.
Executive summary:

Reproductive and developmental toxicity study of test material was performed on male and female CFE-Srats .20 male and 20 female rats /dose group were used.One male was mated with one female until copulation was confirmed by the presence of sperm during daily vaginal inspections (day 0 of pregnancy).The females then were weighed, transferred into individual cages.The test materialmixed with feed were administers in dose concentration 0, 97.5,616 mg/kg bw/day (0, 1950,7800 ppm)from day from day 6 through day 15. Pregnancy was further confirmed by biweekly weighing of the females. All females were killed by chloroform inhalation on the 19th day of pregnancy and the fetuses delivered by Caesarian section. The number and distribution of fetuses, and the number of corpora lutea, live and stillboin fetuses, and early and late resorptions were recorded. Each fetus was weighed, measured, and examined for gross abnormalities. One-third of each litter was examined for visceral abnormalities by employing the slicing method of Wilson (1965). The remaining two-thirds were cleared and the bone structure stained with alizarin red S in order to define any skeletal abnormalities (Murphy, 1965)

 

No dose-related significant differences were observed in the parameters examined. The 616mg/kg /day (7800 ppm) dose group excreted blue-brown colour urine.No grossly abnormal pups were noted in the 97.5 mg/kg /day dose group (244 pups); there was one in control group (244 pups). One grossly abnormal pup was noted out of the 262 examined in the 616 mg/kg /day dose group.however, the average numbers of implantation sites, live pups, and early or late resorptions were not significantly different among the groups. HenceNo Observed Adverse Effect Level (NOAEL) for reproductive and developmental toxicity was considered to be 616 mg/kg/day (7800ppm.When male and femaleCFE-Srats were treated with test material orally.