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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:
4 (not assignable)
Rationale for reliability incl. deficiencies:
secondary literature
Justification for type of information:
Data from secondary source

Data source

Reference
Reference Type:
secondary source
Title:
Opinion of the Scientific Committee on Consumer Products on p-methylaminophenol sulphate (A22)
Author:
EUROPEAN COMMISSION
Year:
2005
Bibliographic source:
the Scientific Committee on Consumer Products, SCCP/0963/05

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 p-methylaminophenol sulphate was performed in Sprague Dawley rats.
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: crystalline
Details on test material:
- Name of test material: p-Methylaminophenol sulfate
- IUPAC name: Bis(4-hydroxy-N-methylanilinium) sulphate
- Molecular formula: C14H20N2O6S
- Molecular weight: 344.386 g/mole
- Smiles:CNc1ccc(cc1)O.CNc1ccc(cc1)O.OS(=O)(=O)O
- Inchl: 1S/2C7H9NO.H2O4S/c2*1-8-6-2-4-7(9)5-3-6;1-5(2,3)4/h2*2-5,8-9H,1H3;(H2,1,2,3,4)
- Substance type: Organic
- Physical state: Solid crystalline (off white - white)
Specific details on test material used for the study:
- Name of test material: p-Methylaminophenol sulfate- IUPAC name: Bis(4-hydroxy-N-methylanilinium) sulphate- Molecular formula: C14H20N2O6S- Molecular weight: 344.386 g/mole- Smiles:CNc1ccc(cc1)O.CNc1ccc(cc1)O.OS(=O)(=O)O- Inchl: 1S/2C7H9NO.H2O4S/c2*1-8-6-2-4-7(9)5-3-6;1-5(2,3)4/h2*2-5,8-9H,1H3;(H2,1,2,3,4)- Substance type: Organic- Physical state: Solid crystalline (off white - white)

Test animals

Species:
rat
Strain:
Sprague-Dawley
Remarks:
Crl CD (SD) IGS BR
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:
CMC (carboxymethyl cellulose)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: p-methylaminophenol sulphate in a 0.5% suspension of carboxymethylcellulose was prepared prior to treatment.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 availableVEHICLE- Justification for use and choice of vehicle (if other than water): c
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 pregnancy: The day of positive proof for sperm in the vaginal smear or sperm plug was designated as day 0 post coitum (p.c.) or gestation day 0. - 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 data available - After successful mating each pregnant female was caged (how): No data available - Any other deviations from standard protocol: No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
14 days (from day 6 through day 19 post-coitum)
Frequency of treatment:
Daily from day 6 through day 19 post-coitum
Details on study schedule:
No data available
Doses / concentrations
Remarks:
Doses/Concentrations: 0, 5, 25 or125 mg/kg bw/day
No. of animals per sex per dose:
Total: 96 ratsControl :24 females5 mg/kg bw/day: 24 females25 mg/kg bw/day: 24 females125 mg/kg bw/day: 24 females
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Positive control:
No data available

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes - Time schedule: Daily- Cage side observations included: No data availableDETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: DailyBODY WEIGHT: Yes - Time schedule for examinations: On designated intervals during prenancyFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: On designated intervals during prenancy- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data availableWATER CONSUMPTION AND COMPOUND INTAKE(if drinking water study): No data availableOPHTHALMOSCOPIC EXAMINATION: No data availableHAEMATOLOGY: No data availableCLINICAL CHEMISTRY: No data availableURINALYSIS: No data availableNEUROBEHAVIOURAL EXAMINATION: No data availableOTHER: No data available
Estrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
No data available
Litter observations:
The following litter parameters were recorded: number of corpora lutea, implantation sites, early and late resorptions, dead and live fetuses, as well as the fetuses were weighed and sexed.
Postmortem examinations (parental animals):
On day 20 post-coitum, the dams were sacrificed and subjected to a macroscopic examination. The gravid uterus was weighed and the fetuses were removed by hysterectomy.
Postmortem examinations (offspring):
Upon necropsy, the fetuses were subjected to external, soft tissue or skeletal examinations.
Statistics:
No data available
Reproductive indices:
No data available
Offspring viability indices:
No data available

Results and discussion

Results: P0 (first parental animals)

General toxicity (P0)

Clinical signs:
no effects observed
Description (incidence and severity):
No treatment-related clinical signs were observed.
Dermal irritation (if dermal study):
not specified
Mortality:
no mortality observed
Description (incidence):
There were no premature deaths during the study.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Relevant maternal changes were only observed at 25 and 125 mg/kg/day where net body weight gain was slightly reduced when compared to 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
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Description (incidence and severity):
No relevant necropsy findings were recorded.
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P0)

Reproductive function: estrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed

Effect levels (P0)

Dose descriptor:
LOEL
Effect level:
25 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
body weight and weight gain
Remarks on result:
not determinable

Target system / organ toxicity (P0)

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

Results: P1 (second parental generation)

General toxicity (P1)

Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
not specified
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
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Reproductive function / performance (P1)

Reproductive function: estrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not specified

Effect levels (P1)

Dose descriptor:
other: not specified
Based on:
not specified
Sex:
not specified
Remarks on result:
other: not specified

Target system / organ toxicity (P1)

Critical effects observed:
not specified
System:
other: 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:
not specified
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:
not specified
Histopathological findings:
no effects observed
Description (incidence and severity):
There were no treatment-related malformations or variations in any groups at external, soft tissue or skeletal examinations.
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:
125 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
gross pathology
histopathology: non-neoplastic

Target system / organ toxicity (F1)

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

Overall reproductive toxicity

Reproductive effects observed:
no
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:
LOEL for maternal toxicity was considered to be 25 mg/kg/day while the dose-level of 125 mg/kg/day was considered to be the NOAEL for embryo-fetal toxicity when pregnant female Sprague Dawley rats were treated with p-Methylaminophenol sulphate orally.
Executive summary:

A reproductive and developmental toxicity study of p-Methylaminophenol sulphate was performed in female Sprague Dawley Crl CD (SD) IGS BR rats. The test material in a 0.5% suspension of carboxymethylcellulose were administered in dose concentration 0, 5, 25 or 125 mg/kg bw/day from day 6 through day 19 post-coitum by oral gavage. Animals were checked daily for clinical signs, and food consumption and body weight were recorded at designated intervals during pregnancy. On day 20 post-coitum, the dams were sacrificed and subjected to a macroscopic examination. The gravid uterus was weighed and the fetuses were removed by hysterectomy. The litter parameters like number of corpora lutea, implantation sites, early and late resorptions, dead and live foetuses were recorded. The fetuses were weighed, sexed and subjected to external, soft tissue or skeletal examinations. No treatment-related clinical signs and premature deaths were observed. Relevant maternal changes were only observed at 25 and 125 mg/kg/day where net body weight gain was slightly reduced when compared to controls. No relevant necropsy findings were noted. The litter parameters like number of corpora lutea, implantation sites, early and late resorptions, dead and live fetuses were not affected by treatment with the test item. Also, in fetuses there were no treatment-related malformations or variations in any groups at external, soft tissue or skeletal examinations. Therefore, LOEL for maternal toxicity was considered to be 25 mg/kg/day while the dose-level of 125 mg/kg/day was considered to be the NOAEL for embryo-fetal toxicity when pregnant female Sprague Dawley rats were treated with p-Methylaminophenol sulphate orally.