Registration Dossier

Toxicological information

Toxicity to reproduction

Currently viewing:

Administrative data

Endpoint:
reproductive toxicity, other
Remarks:
Teratogenicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Remarks:
experimental data of read across substances
Justification for type of information:
Data for the target chemical is summarized based on the structurally similar read across chemicals

Data source

Referenceopen allclose all

Reference Type:
review article or handbook
Title:
Final Report on the Safety Assessment of Toluene=2,5Diamine, Toluene-2,5 -Diami ne Sulfate, and Toluene-3,4-Diamine
Author:
COSMETIC INGREDIENT REVIEW
Year:
1992
Bibliographic source:
Journal of the American College of Toxicology Volume 1 1, Number 4,1992
Reference Type:
secondary source
Title:
Opinion on: Toluene-2,5-diamine
Author:
European Commission (EC) - Scientific Committee on Consumer Products (SCCP)
Year:
2007
Bibliographic source:
the Scientific Committee on Consumer Products, SCCP/1084/07

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Reproductive and developmental toxicity study test chemical was performed on New Zealand White Rabbit
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
-IUPAC name:2-methyl-p-phenylenediamine sulphate- Name of test material : Toluene-2,5-diamine sulphate- Molecular formula : C7H12N2O4S- Molecular weight : 220.2478 g/mol- Substance type: Organic- Physical state: Off-white powderInChI:1S/C7H10N2.H2O4S/c1-5-4-6(8)2-3-7(5)9;1-5(2,3)4/h2-4H,8-9H2,1H3;(H2,1,2,3,4)Smiles:Cc1cc(ccc1N)N.OS(=O)(=O)O
Specific details on test material used for the study:
RA CAS no : 615-50-9Study reference: Title: Opinion on: Toluene-2,5-diamineFinal Report on the Safety Assessment of Toluene=2,5Diamine, Toluene-2,5 -Diami ne Sulfate, andToluene-3,4-DiamineAuthor: European Commission (EC) - Scientific Committee on Consumer Products (SCCP)COSMETIC INGREDIENT REVIEWBibliographic source: the Scientific Committee on Consumer Products, SCCP/1084/07Journal of the American College of ToxicologyVolume 1 1, Number 4,1992

Test animals

Species:
rabbit
Strain:
New Zealand White
Details on species / strain selection:
No data available
Sex:
female
Details on test animals and environmental conditions:
No data available

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
water
Remarks:
distilled water
Details on exposure:
Details on exposurePREPARATION OF DOSING SOLUTIONS: test material dissolved in distilled water DIET PREPARATION- Rate of preparation of diet (frequency):No data available- Mixing appropriate amounts with (Type of food )- Storage temperature of food: No data availableVEHICLE- Justification for use and choice of vehicle (if other than water): - Concentration in vehicle: 0, 10, 25, 50 mg/kg bw/d, - 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:No data available - Length of cohabitation: No data available - Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancyNo data available - 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): No data available - Any other deviations from standard protocol:The females were fertilised by natural mating. After coitus HCG was given i.v. to ensure ovulation.
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
12 days (from day 6 to 18 of gestation)
Frequency of treatment:
once daily
Details on study schedule:
No data available
Doses / concentrations
Remarks:
0, 10, 25, 50 mg/kg bw/d,
No. of animals per sex per dose:
Total:820 mg/kg bw/day:1610mg/kg bw/day:1625mg/kg bw/day:1650 mg/kg bw/day:16Positive control group:18
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Positive control:
No data available

Examinations

Parental animals: Observations and examinations:
Parental animals observation and examinationsCAGE SIDE OBSERVATIONS: yes DETAILED CLINICAL OBSERVATIONS: Yes Time schedule: daily BODY WEIGHT: YesTime schedule for examinations: The body weights were determined on days 0, 6, 18 and 28 of gestation.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 availableWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data Time schedule for examinations: OTHER:
Oestrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
No data available
Postmortem examinations (parental animals):
Postmortem examinations (Parent Animal)SACRIFICE :On day 28 of gestation the animals were sacrificed,Male animals: All surviving animals [describe when, e.g. as soon as possible after the last litters in each generation were produced.]: No dataMaternal animals: yes All surviving animals [describe when, e.g. after the last litter of each generation was weaned :GROSS NECROPSY: No data available HISTOPATHOLOGY / ORGAN WEIGHTSThe tissues indicated in Table [#] were prepared for microscopic examination and weighed, respectively.: macroscopic examination was performed
Postmortem examinations (offspring):
Postmortem examinations (offspring)SACRIFICE- The F1 offspring not selected as parental animals and all F2 offspring were sacrificed at [#?] days of age.- These animals were subjected to postmortem examinations (macroscopic and/or microscopic examination) as follows: the foetuses were dissected and examined for congenital abnormalities and macroscopic changes. The common section parameters were recorded. Half of the foetuses were examined for skeletal and the other half for visceral abnormalities.
Statistics:
No data available
Reproductive indices:
No data available
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 clinical signs were observed.
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, non-treatment-related
Description (incidence):
1 female at 10 and 1 female at 25 mg/kg bw/d died, at 50 mg/kg 3 females died presumably because of the intubation procedure.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weights of the females in the dose groups were similar to the controls.
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

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
clinical signs
mortality
body weight and weight gain
Remarks on result:
other: No effects on reproductive performance

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:
no mortality observed
Description (incidence and severity):
The number of the foetuses were not influenced by substance treatment
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The foetal body weights were not influenced by substance treatment
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):
The frequencies of external abnormalities, visceral malformations and variations as well as skeletal defects exhibited no substance-related changes.
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:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
viability
mortality
body weight and weight gain
gross pathology
Remarks on result:
other: no effects on overall developmental parameters

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 maternal toxicity and embryotoxicity was considered to be 50 mg/kg/day. When female New Zealand White Rabbit were treated with test chemical orally from day 6 to 18 of gestation.
Executive summary:

The reproductive and developmental toxicity study of test chemical was performed in female New Zealand White Rabbit. The test material dissolved in distilled water and administered in dose concentration 0, 10, 25, 50 mg/kg bw/d, by oral gavage route from day 6 to 18 of gestation while positive control Vitamin A in rape seed oil in dose concentration 6 mg/kg bw/d given by same route. The females were fertilised by natural mating. After coitus HCG was given i.v. to ensure ovulation. The animals were examined daily for mortality and clinical signs. The body weights were determined on days 0, 6, 18 and 28 of gestation. On day 28 of gestation the animals were sacrificed, the foetuses were dissected and examined for congenital abnormalities and macroscopic changes. The common section parameters were recorded. Half of the foetuses were examined for skeletal and the other half for visceral abnormalities. 1 female at 10 and 1 female at 25 mg/kg bw/d died, at 50 mg/kg 3 females died presumably because of the intubation procedure. No clinical signs were observed. Body weights of the females in the dose groups were similar to the controls. The changes in the incidences of intrauterine death observed were not dose-related. The number and sex of the foetuses as well as the foetal body weights were not influenced by substance treatment. The frequencies of external abnormalities, visceral malformations and variations as well as skeletal defects exhibited no substance-related changes. The positive control (Vitamin A) did not show teratogenicity and only slight embryotoxicity. Hence No Observed Adverse Effect Level (NOAEL) for maternal toxicity and embryotoxicity was considered to be 50 mg/kg/day. When female New Zealand White Rabbit were treated with test chemical orally from day 6 to 18 of gestation.