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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Remarks:
(Prenatal Developmental Toxicity Study)
Type of information:
experimental study
Adequacy of study:
key study
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:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Principles of method if other than guideline:
A prenatal development toxicity study of p-methylaminophenol sulphate was performed in Sprague-Dawley rats.
GLP compliance:
not specified
Limit test:
no

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)

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
Analytical verification of doses or concentrations:
not specified
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
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
Duration of test:
20 days
Doses / concentrations
Remarks:
Doses/Concentrations: 0, 5, 25 or 125 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

Examinations

Maternal 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
Ovaries and uterine content:
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.
Fetal examinations:
Upon necropsy, the fetuses were subjected to external, soft tissue or skeletal examinations.
Statistics:
No data available
Indices:
No data available
Historical control data:
No data available

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

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

Maternal developmental toxicity

Number of abortions:
not specified
Pre- and post-implantation loss:
not specified
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
not specified
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
not specified
Other effects:
not specified

Effect levels (maternal animals)

Dose descriptor:
LOEL
Effect level:
25 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
body weight and weight gain

Maternal abnormalities

Abnormalities:
not specified

Results (fetuses)

Fetal body weight changes:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified
Reduction in number of live offspring:
not specified
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
no effects observed
Description (incidence and severity):
There were no treatment-related malformations or variations in any groups at external examination.
Skeletal malformations:
no effects observed
Description (incidence and severity):
There were no treatment-related malformations or variations in any groups at skeletal examinations.
Visceral malformations:
no effects observed
Description (incidence and severity):
There were no treatment-related malformations or variations in any groups at soft tissue examinations.
Other effects:
not specified

Effect levels (fetuses)

Dose descriptor:
NOAEL
Effect level:
125 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
external malformations
skeletal malformations
visceral malformations

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
no
Lowest effective dose / conc.:
125 mg/kg bw/day (nominal)
Treatment related:
not specified
Relation to maternal toxicity:
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.