Registration Dossier

Administrative data

Description of key information

No clinical signs or adverse histological changes were observed in male mice treated with after 80-weeks dermal exposure.
No carcinogenic effect of trimethylolpropane trimethacrylate was observed in male mice after 80-week dermal exposure in this study.

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Qualifier:
no guideline followed
Principles of method if other than guideline:
The purpose of this investigation was to assess the carcinogenic potentialof substances in the classical mouse skin bioassay. In addition, the study also provided information about the chronic dermal toxicity of substance.
GLP compliance:
yes
Species:
mouse
Strain:
C3H
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Jackson Laboratory, Bar Harbor, Maine
- Age at study initiation: 6-8 weeks old
- Weight at study initiation: no data
- Fasting period before study: no data
- Housing: 5 animals in stainless steel suspended cages.
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2 weeks
Mice manifesting any signs of morbidity during the quarantine period were not included in the experiment.

ENVIRONMENTAL CONDITIONS: no data
Route of administration:
dermal
Vehicle:
unchanged (no vehicle)
Details on exposure:
Before starting treatments, mice were weighed and their backs shaved with electric clippers. Their backs were also shaved biweekly.
The materials were applied to the interscapular region of the shaven backs on the surface of the skin grew to 1 mm3.
Duration of treatment / exposure:
80 weeks
Frequency of treatment:
twice per week
Remarks:
Doses / Concentrations:
25 mg/mice
Basis:
nominal conc.
No. of animals per sex per dose:
50 mice/dose
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Before initiating the long-term bioassay, a pilot study was conducted to find a suitable dose and solvent.
In the acute pilot study, five mice were exposed to 50 mg of undiluted test substance. No clinical signs or mortalities were observed after treatment (3-days of observation).
In the first dilution study, three mice were exposed to 50 mg twice week to 10% test substance in acetone during two weeks. A very sightly epilated was observed.
In the second dilution study, three mice were exposed to 25 mg twice week to undiluted test substance during 4 weeks. No toxic signs were observed.


- Rationale for animal assignment : random
- Rationale for selecting satellite groups: no satellite group

Positive control:
yes: 0.05% benzo(a)pyrene in mineral oil. 50 mg twice week.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS and DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

DERMAL IRRITATION (if dermal study): Yes

BODY WEIGHT: Yes
- Time schedule for examinations: before first treatment, and weekly during the first month, thereafter every two weeks.

FOOD CONSUMPTION: no data
WATER CONSUMPTION: no data
OPHTHALMOSCOPIC EXAMINATION: no data
HAEMATOLOGY: no data
CLINICAL CHEMISTRY: no data
URINALYSIS: no data
NEUROBEHAVIOURAL EXAMINATION: no data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Complete histological examinations was performed on 10% of the treated mice, and 100% of untreated mice.
At autopsy, all skin neoplasms were measured and recorded on a necropsy sheet. The interscapular area was dissected as one rectangular piece of skin. This section included all neoplasms and suspicions lesions. After removal, this section od skin was spread on a piece of filter paper and submerged in neutral formalin. The subcutaneous lymph nodes from the neck, axillary and groin areas were dissected out, placed in ambedding bags, and immersed in fixative. The abdominal, chest and cranial cavities were examined. All organs were removed and any abnormalities were recorded. Tissue from each organ was preserved in neutral formalin for possible microscopic examination.
On animals that died or those sacrified because of moribond condition, a complete post mortem examination was performed.
Other examinations:
no
Statistics:
no
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
not specified
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:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
MORTALITY:
Five mice died during the study on days 10, 39, 55, 57 and 65. Tissues of these mice were not saved.
Four mice were sacrified before the end of the study on days 39, 59, 68 and 71 ; the cause of the sacrifice was not detailed. All the other mice were sacrified between days 78 and 84.

CLINICAL SIGNS:no data

BODY WEIGHT AND WEIGHT GAIN: At the beginning of the study, mice weighed approximately 25 g
A slight decrease of body weight was observed in the two first days after first application. Thereafter the bodyweight inscreased to attain 29-30g at week 35. A decrease of body weight was observed at the end of the study (after the week 75).

GROSS PATHOLOGY
No gross observation of skin was observed in the treated and control animals.
The skin non-neoplasic lesions observed in the treated animals: ulcer (1/46 mice), acanthosis (46/46 mice), fibrosis (24/46), and hyperkeratosis (2/46).
Acanthosis and fibrosis were chemically and/or mechanically induced. Both lesions were observed in non-treated animals (acanthosis: 43/48, fibrosis:31/48). Ulcer (7/48), abscess (1/48), dysplasia (1/48) were observed in non-treated mice.

HISTOPATHOLOGY: NON-NEOPLASTIC
Pathologic lesions observed in the treated animals: lung (pneumonia, 1/4 mice), liver (carcinoma, 1/4 ; necrosis, 1/4; but not the same animal), lymphadentitis (2/4).

HISTOPATHOLOGY: NEOPLASTIC
No skin tumors were present in mice treated with trimethylolpropane trimethacrylate. One mouse in the "no treatment" group had a squamous cell carcinoma.
Relevance of carcinogenic effects / potential:
No carcinogenic effect of trimethylolpropane trimethacrylate was observed in male mice after 80-week dermal exposure in this study.
Dose descriptor:
NOAEL
Remarks:
(systemic toxicity)
Effect level:
25 other: mg/mice
Sex:
male
Basis for effect level:
other: No clinical signs or adverse histological changes. Mean bw of mice (ECHA guide R8) = 30g -> 25 mg/mice corresponding to 833 mg/kg/d
Dose descriptor:
NOAEL
Remarks:
(carcinogenicity)
Effect level:
25 other: mg/mice
Sex:
male
Basis for effect level:
other: No tumor

Description of pathologic lesions of the skin:

-Acanthosis: A thickening of the epidermis caused by an increase in the number of cells of the stratum granulosum.

-Fibrosis: A thinckening of the dermis caused by an increase of collagenous fibrous tissue.

-Hyperkeratosis: A piling up of the stratum corneum epidermidis.

-Ulcer: A defect in the epidermis and part of dermis. Inflammatory infiltration by lymphocytes and macrophages is present in the dermal tissue. Granulation tissue may cover the base of the deflect.

Conclusions:
No clinical signs or adverse histological changes were observed in male mice treated with after 80-weeks dermal exposure.
Executive summary:

The purpose of this investigation was to assess the carcinogenic potentialof substances in the classical mouse skin bioassay. In addition, the study also provided information about the chronic dermal toxicity of substance.

Group of 25 mice were exposed to 25 mg of TMPTMA by animal by day, corresponding to 833 mg/kg bw/d, twice weekly during 80 weeks. A control group of 25 mice were not treated. Nine mice died or was sacrified during the study. There were no data on clinical signs. A slight decrease of body weight was observed in the two first days after first application. Thereafter the bodyweight inscreased to attain 29-30g at week 35. A decrease of body weight was observed at the end of the study (after the week 75).

No gross observation of skin was observed in the treated and control animals. The skin non-neoplasic lesions observed in the treated animals were ulcer (1/46 mice), acanthosis (46/46 mice), fibrosis (24/46), and hyperkeratosis (2/46). Acanthosis and fibrosis were chemically and/or mechanically induced. Both lesions were observed in non-treated animals (acanthosis: 43/48, fibrosis:31/48). Ulcer (7/48), abscess (1/48), dysplasia (1/48) were also observed in non-treated mice.

Pathologic lesions were observed in the treated animals: on lung (pneumonia, 1/4 mice), liver (carcinoma, 1/4 ; necrosis, 1/4; but not the same animal) and lymphadentitis (2/4). No skin tumors were present in mice treated with trimethylolpropane trimethacrylate. One mouse in the "no treatment" group had a squamous cell carcinoma.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
833 mg/kg bw/day
Study duration:
chronic
Species:
mouse
Quality of whole database:
Barkley's study was considered to be reliable.

Additional information

80 -week carcinogenicity study on mouse by dermal route (Barkley 1982):

The purpose of this investigation was to assess the carcinogenic potential of substances in the classical mouse skin bioassay. In addition, the study also provided information about the chronic dermal toxicity of substance.

Group of 25 mice were exposed to 25 mg of TMPTMA by animal by day, corresponding to 833 mg/kg bw/d, twice weekly during 80 weeks. A control group of 25 mice were not treated. Nine mice died or was sacrified during the study. There were no data on clinical signs. A slight decrease of body weight was observed in the two first days after first application. Thereafter the bodyweight inscreased to attain 29-30g at week 35. A decrease of body weight was observed at the end of the study (after the week 75).

No gross observation of skin was observed in the treated and control animals. The skin non-neoplasic lesions observed in the treated animals were ulcer (1/46 mice), acanthosis (46/46 mice), fibrosis (24/46), and hyperkeratosis (2/46). Acanthosis and fibrosis were chemically and/or mechanically induced. Both lesions were observed in non-treated animals (acanthosis: 43/48, fibrosis:31/48). Ulcer (7/48), abscess (1/48), dysplasia (1/48) were also observed in non-treated mice.

Pathologic lesions were observed in the treated animals: on lung (pneumonia, 1/4 mice), liver (carcinoma, 1/4 ; necrosis, 1/4; but not the same animal) and lymphadentitis (2/4). No skin tumors were present in mice treated with trimethylolpropane trimethacrylate. One mouse in the "no treatment" group had a squamous cell carcinoma.

Justification for classification or non-classification

Based on the results of the dermal carcinogenicity study, no classification is required for TMPTMA according to the CLP Regulation (EC) N° 1272-2008.