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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well documented publication which meets basic scientific principles.

Data source

Reference
Reference Type:
publication
Title:
Acute and subchronic repeated cutaneous application of N-methyl diethanolamine in the Fischer 344 rat.
Author:
Werley, M.S. et al.
Year:
1997
Bibliographic source:
J. Toxicol. Cut. Ocular Toxicol., 16, 157-171

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): N-methyldiethanolamine
- Analytical purity: > 99.7%

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Kingston, NY
- Age at study initiation: 8 weeks
- Housing: stainless steel wire mesh cages
- Diet: Ground Purina Certified Rodent Chow #5002 (Ralston Purina Co., St. Louis, MO) and ground L26 Diet (PMI Feeds, Inc.), ad libitum
- Water: tap water ad libitum
- Acclimation period: 2 weeks


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 66-77°F
- Humidity (%): 40-70%
- Photoperiod: 12 hrs dark / 12 hrs light

Administration / exposure

Type of coverage:
occlusive
Vehicle:
water
Details on exposure:
TEST SITE
- Area of exposure: 2 x 2 inch
- Type of wrap if used: 12-ply NuGauze pad
- Time intervals for shavings or clipplings: A week before the first dose, prior to the first dose, and thereafter as necessary

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the application site was wiped with a damp cloth and then blotted dry.
- Time after start of exposure: 6 h
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hours/day; 5 days/week (total of 65 doses)
Doses / concentrations
Remarks:
Doses / Concentrations:
100, 250, 750 mg/kg bw/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: 4 weeks

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Inspection for clinical signs of toxic and/or pharmacologic effects was done daily.

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: daily

BODY WEIGHT: Yes
- Time schedule for examinations: before the first dose and weekly during the treatment and recovery period

FOOD CONSUMPTION: over weekly intervals

WATER CONSUMPTION: Yes
- Time schedule for examinations: over weekly intervals

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the study
- Anaesthetic used for blood collection: No data
- Animals fasted: No
- How many animals: 10/gender/dose
- Parameters examined: hemoglobin concentration, erythrocyte count, hematocrit, mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), total and differential leukocyte, platelet, and reticulocyte counts.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the study
- Animals fasted: yes
- How many animals: 10/gender/dose
- Parameters examined: urea nitrogen, creatinine, bilirubin (total, conjugated, and unconjugated), calcium, sodium, potassium, chloride, phosphorus, aspartate and alanine aminotransferases, creatine kinase, creatinine, creatinine clearance, a2u-globulin, and N-acetyl-ß-glucosaminidase, lactate dehydrogenase, y-glutamyl transferase, sorbitol dehydrogenase, alkaline phosphatase, and protein electrophoresis.

URINALYSIS: Yes
- Time schedule for collection of urine:
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No
- Parameters examined: total volume, color, microscopy, pH, osmolality, protein, glucose, ketones, bilirubin, urobilinogen, and blood.

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes. A complete necropsy was performed, and the following organs weighed: liver, kidneys, brain, heart, adrenal glands, spleen, ovaries, and testes.

HISTOPATHOLOGY: Yes. A large number of tissues and organs, including skin of the dosing area.
Statistics:
Data for quantitative continuous variables were intercompared for treatment versus control groups by Levene's test, for equality of variances, analysis of variance, and t-tests.

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
There were no deaths or signs indicating any systemic effect. Neither erythema nor edema was seen at any time in the mid- and low-dose groups, and no edema in the high-dose group. Erythema in the high-dose group, slight in severity, was seen at a few very limited time periods. More prominent effects seen for longer periods were desquamation, excoriation, ulceration, necrosis, and eschar. The incidence and severity of these findings were dosage-related. Low-dose findings were minimal.

BODY WEIGHT AND WEIGHT GAIN
There were no significant differences in absolute body weights over the study. There were no significant effects on female body weight gain. Decreases in body weight gain of males were small, transient, and variable, and generally limited to the first 7 weeks of the study.

FOOD CONSUMPTION
No treatment related differences in food consumption were evident for either gender.

WATER CONSUMPTION
No treatment related differences in water consumption were evident for either gender.

HAEMATOLOGY
There were no differences from the controls with respect to hematologic results.

CLINICAL CHEMISTRY
There were no differences from the controls with respect to clinical chemistry results.

URINALYSIS
There were no differences from the controls with respect to urinalysis results.

ORGAN WEIGHTS
There were no effects on organ weights, either absolute or relative to body weight.

GROSS PATHOLOGY
findings were limited to the area of treated skin in the MDEA animals. The most common lesions were acanthosis, hyperkeratosis, and parakeratosis. These features were most noticeable in the mid-dose females and high-dose males and females. Also present were minimal to marked dermal fibrosis, eschar, ulceration, and dermatitis. The lesions were dose-related and females were possibly more sensitive. Any lesions in the low-dose group were comparable to those of the controls, and probably a consequence of the wrapping procedure and scratching by the animals.

Effect levels

open allclose all
Dose descriptor:
other: local NOAEL
Effect level:
100 other: mg/kg bw/day (corresponding to 0.8 mg/cm2)
Sex:
male/female
Basis for effect level:
other: dose-related irritation in the mid and high dose groups; major histopathological features were acanthosis, hyperkeratosis, parakeratosis, dermatitis, dermal fibrosis, eschar, and ulceration
Dose descriptor:
other: systemic NOAEL
Effect level:
750 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: no systemic effects were reported

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Cutaneous treatment of rats with up to 750 mg/kg bw/day of MDEA for 65 doses over a 90 day interval produced moderate to severe irritation at the site of treatment but no systemic effects. The no observed effect level was 100 mg/kg bw/day.

Applicant's summary and conclusion