Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
June 1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented ; it is a range-finding study of the 90-week dermal carcinogenicity study.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1979
Report Date:
1979

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
A dermal toxicity study was performed to assess dermal irritation caused by TMPTMA. Albino rabbits (5/sex/dose) were treated one daily, five days per week for two weeks for a total of 10 treatments. After 15 days, six/animals/group (3 abraded and 3 non-adraded, regardless sex) were sacrified and 30 days after the onset of treatment (two weeks after the last treatment) the remaining animals (4/group) were sacrified.
GLP compliance:
no
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: clear liquid
Details on test material:
- Name of test material (as cited in study report): Trimethylolpropane trimethacrylate (TMPTMA)
-Storage: at room temperature

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Maland Breeding Farms, Inc. Hewitt, New jersey
- Age at study initiation: no data
- Weight at study initiation: males : mean 2.5 kg (2.3-3.0), females mean = 2.5 kg (2.2-2.9)
- Fasting period before study:no data
- Housing: Individually housed in suspended stain-less steel caging.
- Diet (e.g. ad libitum): Purina Rabbit chow, ad libitum
- Water (e.g. ad libitum): tap water, ad libitum
- Acclimation period: at least one week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%):no data
- Air changes (per hr):no data
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on exposure:
On the day prior to the first treatment, the hair was clipped from the back of each rabbit, over an area large enough to accomodate the dose volume. Clipping was repeated at necessary throughout the study. The skin of half the animals (3M and 2F or 2M and 3F) was abraded over the area of exposure using an inverted clipper head prior to the first treatment and twice weekly thereafter. The abrasions were deep enough to penetrate the stratum corneum, but no to disturb the dermis.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
2 weeks
Frequency of treatment:
daily, 5/week
Doses / concentrations
Dose / conc.:
300 mg/kg bw/day
No. of animals per sex per dose:
5 rabbits/ sex
Control animals:
yes
Details on study design:
Treatment was accomplished by dispensing the dose volume from a disposable syringe onto the animal's back and spreading it evenly over the area of exposure. Doses volumes were based on the most recent weekly body weights. Each animal was fitted with a plastic collar, designed to prevent ingestion of the test material, which was worn throughout the study. No dressings was applied to the teatment site.
Positive control:
no

Examinations

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

DERMAL IRRITATION : yes
- Time schedule for examinations: daily

BODY WEIGHT: Yes
- Time schedule for examinations: pretest, weekly during treatment and terminally

FOOD CONSUMPTION: no

WATER CONSUMPTION: no

OPHTHALMOSCOPIC EXAMINATION: no

HAEMATOLOGY: no

CLINICAL CHEMISTRY: no

URINALYSIS: no

NEUROBEHAVIOURAL EXAMINATION: no
Sacrifice and pathology:
Complete postmortem examination for animals dying spontaneoulsy or killed in a moribund conditions.
Other examinations:
no
Statistics:
no

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Irritation only
Histopathological findings: neoplastic:
not examined
Details on results:
Control group : In this non-treated control group, half the animals were abraded and all wore callars and were clipped as needed throughout the study. Slight or very slight erythema and desquamation were observed in some animals on single occasions (Days 5 and 6 or 7 only). No unusual in-life signs were noted. All animals exhibited weight gains over the study period.

Treated group (TMPTMA): Slight erythema occurred in some or all animals during the two-week treatment period. Some animals (one to four) also exhibited slight edema during the first ten days of study but not subsequently. Desquamation, generally slight, occurred in the majority of animals during the second week noted in a few animals on single occasions during the treatment period. None of the rabbits treated with TMPTMA exhibited necrotic skin or eschar formation. No consistent patterns of unusual in-life signs occurred. One female exhibited a very slight weight loss.
Microscopic examination of selected tissues obtained from animals treated for two weeks with the test material revealed no evidence of a systemic effect of any of the materials administered. However, minimal to mild irritation was present in skin samples from rabbits treated with TMPTMA.

Examination of tissues from rabbits heald for two weeks after treament revealed no evidence of a systemic effect pf the test material. Only minimal epithelial hyperplasia and hyperkeratosis was present in rabbits which received TMPTMA.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks:
(systemic effects)
Effect level:
300 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects observed at this dose.
Dose descriptor:
LOAEL
Remarks:
(local effects)
Effect level:
300 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Skin irritation was observed in rabbits.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Executive summary:

TMPTMA was applied to the backs of albino rabbits (5/sex/group). Rabbits were treated daily, five days per week, for two weeks (for a total of 10 treatments). Six treated animals were sacrified after two weeks and the remaining four animals were held for an additional two weeks during which no treatment was performed prior sacrifice.

Animals treated with TMPTMA (300 mg/kg/d) exhhibited signs of slight dermal irritation with no eschar formation or necrotic skin. No consistent pattern of unusual in-life signs occurred. One female exhibited a very slight weight loss.

Microscopic examination of selected tissues obtained from animals treated for two weeks with the test material revealed no evidence of a systemic effect of any of the materials administered. However, minimal to mild irritation was present in skin samples from rabbits treated with TMPTMA. Examination of tissues from rabbits heald for two weeks after treament revealed no evidence of a systemic effect pf the test material. Only minimal epithelial hyperplasia and hyperkeratosis was present in rabbits which received TMPTMA.