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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
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 is from peer reviewed publication

Data source

Reference
Reference Type:
publication
Title:
Teratology and percutaneous toxicity studies on hair dyes
Author:
C. Burnett , E. I. Goldenthal , S. B. Harris , F. X. Wazeter , J. Strausburg , R. Kapp & R. Voelker
Year:
1976
Bibliographic source:
Journal of Toxicology and Environmental Health,1, 1027-1040, 1976

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: Refer below principle
Principles of method if other than guideline:
A repeated dose dermal toxicity study was performed to determine the toxic nature of N-methyl-p-aminophenol sulfate using Charles River CD female 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 : N-methyl-p-aminophenol sulfate- Molecular formula : C7H9NO.1/2H2O4S- Molecular weight : 344.386 g/mol- Substance type: Organic- Physical state: No data- Impurities (identity and concentrations): No data

Test animals

Species:
rat
Strain:
other: Charles River CD
Details on species / strain selection:
No data available
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS- Source: No data available- Age at study initiation: No data available- Weight at study initiation: No data available- Fasting period before study: No data available- Housing: The mated female animals were housed individually in temperature- and humidity-controlled rooms.- Diet (e.g. ad libitum): Ralston Purina Laboratory Chow, ad libitum- Water (e.g. ad libitum): Water, ad libitum- Acclimatization period: No data availableENVIRONMENTAL CONDITIONS- Temperature (°C): No data available- Humidity (%): No data available- Air changes (per hr): No data available- Photoperiod (hrs dark / hrs light): No data available

Administration / exposure

Type of coverage:
not specified
Vehicle:
other: water and 6% hydrogen peroxide
Details on exposure:
TEST SITE- Area of exposure: The dorso-scapular area- % coverage: No data available- Type of wrap if used: No data available- Time intervals for shavings or clipplings: The hair at the site of application on the dorso-scapular area was shaved closely the day prior to application.REMOVAL OF TEST SUBSTANCE- Washing (if done): No data available- Time after start of exposure: No data availableTEST MATERIAL- Amount(s) applied (volume or weight with unit): 2 ml/kg of the 7404 and P-26 dye formulation- Concentration (if solution): 0, 0.05% (0.5735 mg/kg: Formulation P-26) or 1% (11.47 mg/kg: Formulation 7404)- Constant volume or concentration used: No data available- For solids, paste formed: No data availableVEHICLE- Justification for use and choice of vehicle (if other than water): No data available- Amount(s) applied (volume or weight with unit): No data available- Concentration (if solution): No data available- Lot/batch no. (if required): No data available- Purity: No data availableUSE OF RESTRAINERS FOR PREVENTING INGESTION: No data available
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data available
Duration of treatment / exposure:
20 days
Frequency of treatment:
Once on days 1, 4, 7, 10, 13, 16 and 19 of gestation
Doses / concentrations
Remarks:
Doses/Concentrations: 0, 0.05% (0.5735 mg/kg: Formulation P-26) or 1% (11.47 mg/kg: Formulation 7404)
No. of animals per sex per dose:
Total: 120 ratsControl: 60 femalesPositive control: 20 females0.5735 mg/kg : 20 females11.47 mg/kg: 20 females
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Positive control:
Acetylsalicylic acid

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data availableDETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: No data availableDERMAL IRRITATION (if dermal study): Yes- Time schedule for examinations: No data availableBODY WEIGHT: Yes- Time schedule for examinations: On days 1, 4, 7, 10, 13, 16 and 19 day of gestationFOOD CONSUMPTION: Yes- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: YesFOOD EFFICIENCY: No data available WATER CONSUMPTION: No data availableOPHTHALMOSCOPIC EXAMINATION: No data availableHAEMATOLOGY: No data availableCLINICAL CHEMISTRY: No data availableURINALYSIS: No data availableNEUROBEHAVIOURAL EXAMINATION: No data availableOTHER: No data available
Sacrifice and pathology:
GROSS PATHOLOGY: YesTwenty pregnant rats from each group were sacrificed on day 20 of gestation by chloroform anesthesia, and Cesarean sections were performed. The uteri were examined, corpora lutea of pregnancy counted, and the number, distribution, and location of live, dead, and resorbed fetuses recorded. All fetuses were examined for gross anomalies, sexed, and weighed.HISTOPATHOLOGY: YesApproximately one-third the fetuses from each litter were fixed and subsequently examined for visceral anomalies by razor blade sectioning. The remaining fetuses in each litter were fixed, eviscerated, cleared, stained´with KOH-alizarin red S, and examined for skeletal anomalies.
Other examinations:
No data available
Statistics:
All statistical analyses compared the treatment groups with the control groups. The number of females exhibiting resorption sites, number of females exhibiting two or more resorptions, number of dead or resorbed fetuses, and the number of fetuses with soft-tissue or skeletal anomalies and accessory ribs was compared using chi-square test criterion with Yates' correction on 2 X 2 contingency tables or Fisher's exact probability test as appropriate to judge the significance of difference. The mean number of corpora lutea, implantation sites, live fetuses, and resorption sites was compared by analysis of variance (one-way classification) using Dunnett's multiple comparison tables to judge the significance of differences. The live fetal weights were compared by analysis of variance (hierarchal classification) using Dunnett's multiple comparison tables to judge the significance of differences.Statistically significant differences between groups were judged valid only when there were significant differences between any one of the dye treated groups and each of the three untreated control groups.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No signs of toxicity were seen throughout the study in the treated rats.
Dermal irritation:
no effects observed
Description (incidence and severity):
Except for the changes in the color of the skin and hair at the site of dye application, no irritation or other changes in appearance were seen.
Mortality:
not specified
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Changes in female body weights were similar for rats in the untreated controls and all dye-treated groups.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Mean food consumption for all groups throughout gestation was similar in the treated and control group rats.
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:
no effects observed
Description (incidence and severity):
No significant changes were observed regarding soft-tissue anomalies between the dye-treated groups and the untreated control groups. Normally occurring skeletal variations were present in all groups; the most frequent variation noted was accessory ribs.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
no effects observed
Description (incidence and severity):
The dye formulations produced no significant differences in the mean number of corpora lutea, implantation sites and live fetuses, and the sex ratio when compared with the untreated control groups. No differences between groups were seen regarding the number of females exhibiting resorption sites or mean resorptions per pregnancy.

Effect levels

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Dose descriptor:
NOAEL
Remarks:
Formulation 7404
Effect level:
11.47 other: mg/kg
Based on:
test mat.
Sex:
female
Basis for effect level:
clinical signs
mortality
dermal irritation
body weight and weight gain
food consumption and compound intake
gross pathology
Dose descriptor:
NOAEL
Remarks:
Formulation P26
Effect level:
0.574 other: mg/kg
Based on:
test mat.
Sex:
female
Basis for effect level:
clinical signs
mortality
dermal irritation
body weight and weight gain
food consumption and compound intake
gross pathology

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL for N-methyl-p-aminophenol in female Charles River CD rats is considered to be 11.47 mg/kg for Formulation 7404 and 0.5735 mg/kg for formulation P26, where both formulations contain the target compound.
Executive summary:

A repeated dose dermal toxicity study was performed to determine the dermal toxic nature of N-methyl-p-aminophenol sulfate. The study was performed on female Charles River CD rats, where 2 ml/kg dye formulation 7404 or P-26 containing 1% and 0.05% N-methyl-p-aminophenol sulfate, respectively, was applied to the dorso-scapular area. These dye formulations contained other active ingredients in an aqueous solution and were mixed with an equal volume of 6% hydrogen peroxide prior to application. The application was made during the gestation days 1, 4, 7, 10, 13, 16 and 19. The animals were observed for clinical signs, body weight changes, dermal irritation if any and food consumption. No dye formulation related toxicity was noted. Changes in female body weights and food consumption were similar for rats in the untreated controls and all dye-treated groups. No irritation or other changes in appearance were noted except for changes in skin and hair color at the site of topical application of the dye formulation. Based on the observations made, NOAEL for N-methyl-p-aminophenol sulfate in female Charles River CD rats was considered to be 11.47 mg/kg for formulation 7404 and 0.5735 mg/kg for formulation P26, where both formulations contain the target compound.