1-methyltrimethylene dimethacrylate

Repeated dose toxicity: dermal

Administrative data

Endpoint:

chronic toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

GLP.

Justification for type of information:

Read across to the methacrylic metabolite:

According to RAAF 2019, the analogue read-across approach, Scenario 1: “read-across based on (bio)transformation to common compound(s)” has been identified as appropriate in order to fulfill the data gap.

Thus, the information requirement (according to REACH Regulation Annex IX) is covered with read across to the methacrylic metabolites.

For detailed information and justification please refer to the attached Read across Justification Document: “Read across assessment according to ECHA’s Read Across Assessment Framework (RAAF)”.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2003

Materials and methods

Principles of method if other than guideline:

Carcinogenesis study according EPA Dermal Bioassay Workshops (April 28-29, 1987 and May 18-19, 1988)

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2,2'-ethylenedioxydiethyl dimethacrylate

EC Number:

203-652-6

EC Name:

2,2'-ethylenedioxydiethyl dimethacrylate

Cas Number:

109-16-0

Molecular formula:

C14H22O6

IUPAC Name:

ethane-1,2-diylbis(oxyethane-2,1-diyl) bis(2-methylacrylate)

Test material form:

liquid

Specific details on test material used for the study:

- Name of test material (as cited in study report): triethylene glycol dimethacrylate

Test animals

Species:

mouse

Strain:

other: C3H/HeNHsd

Sex:

male

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Harlan Sprague-Dawley (Indianapolis, IN)
- Housing: individually
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 2-3 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°F): 65-77
- Humidity (%): 40-70%
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:

open

Vehicle:

acetone

Details on exposure:

TEST SITE
applied to the clipped interscapular region of the back
- Type of wrap if used: no wrap
- Time intervals for shavings or clipplings: during the week prior to the first dose and as needed during the dosing period, the fur was clipped from the dorsal area of the trunk

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 50 µL
- Concentration (if solution): 5, 25, 50%

USE OF RESTRAINERS FOR PREVENTING INGESTION: no

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

78 weeks

Frequency of treatment:

5 d/week

Doses / concentrations

Remarks:

Doses / Concentrations:
5, 25, 50%
Basis:
other: applied in 50 µL per animal

No. of animals per sex per dose:

70 males/group

Control animals:

yes, concurrent no treatment

yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: mortality and overt signs of toxicity twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

DERMAL IRRITATION (if dermal study): No

BODY WEIGHT: Yes
- Time schedule for examinations: weekly for the first 13 weeks and every 4 weeks thereafter.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: week 52 and 79
- How many animals: 10/group

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: week 52 and 79
- How many animals: 10/ group

OTHER: Cutaneous cell proliferation assay using the bromodeoxyuridine (BrdU) procedure was
performed on 4 or 5 mice/group at 4, 13, 52, and 78 weeks

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (high dose group; Iungs, liver, kidneys, spleen, stomach, and gross lesions in all dose groups)

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

increase in mortality in the 50% group; however, clinical or histological effects were noted to which the increased mortality could be attributed, and it was uncertain whether substance-related toxicity was directly responsible

Dermal irritation:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Description (incidence):

increase in mortality in the 50% group; however, clinical or histological effects were noted to which the increased mortality could be attributed, and it was uncertain whether substance-related toxicity was directly responsible

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:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

increase in kidney weight; however, there were no correlating microscopic findings

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Description (incidence and severity):

no other than dermal effects

Histopathological findings: neoplastic:

no effects observed

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

5 other: %

Based on:

act. ingr.

Sex:

male

Basis for effect level:

other: local effects; skin irritation

2

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day

Based on:

act. ingr.

Sex:

male

Basis for effect level:

other: local effects; skin irritation

3

Dose descriptor:

NOAEL

Effect level:

25 other: %

Based on:

act. ingr.

Sex:

male

Basis for effect level:

other: systemic; increased mortality and effects in the kidneys in the high dose group

4

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day

Based on:

act. ingr.

Sex:

male

Basis for effect level:

other: systemic; increased mortality and effects in the kidneys in the high dose group

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

The NOAEL for local effects was 5% (approx. 100 mg/kg bw/d). Taking into account the increased mortality and effects in the kidneys in the high dose group the systemic NOAEL is 25% (approx. 500 mg/kg bw/d).

Executive summary:

In a 78 weeks dermal carcinogenicity study, TREGDMA (91% a.i.) was applied to the clipped interscapular region of the back of 70 maleC3H/HeNHsd mice/dose at dose levels of 5, 25 and 50% TREGDMA in acetone, corresponding to approx. 100, 500 and 1000 mg/kg bw/d. Untreated and acetone-treated control groups were used as controls.The doses were applied in 50 µL/animal/day 5 days per week.

Cutaneous treatment of male mice with TREGDMA did not result in any treatment-related changes in hematology, clinical chemistry, body weights or weight gain. There was a significant increase in mortality in the 50% TREGDMA dose group compared to the control groups.However, there were no clinical or histological effects to which the increased mortality could be attributed, and it was uncertain whether test substance related toxicity was directly responsible.

A dose-related increase in kidney weight was observed in the 25 and 50% dose groups at the terminal sacrifice. However, there were no correlating microscopic findings in the kidneys and the biological significance of the increase in weight was uncertain.

Clinical signs of irritation, consisting primarily of exfoliation were observed in all dose groups. The time of onset, incidence, and severity of exfoliation were related to dose.

The mean measured rate of epidermal basal cell proliferation of the mid and high dose groups was consistently increased compared to both control groups at each measurement. There was no relationship between chronic inflammation of the skin and cell proliferation and the induction of skin tumors in normal mouse skin after 78 weeks of treatment although there was evidence of irritation and cell proliferation throughout the treatment period.There was no indication of carcinogenicity at any dose level.

The NOAEL for local effects was 5% (approx. 100 mg/kg bw/d). Taking into account the increased mortality and effects in the kidneys in the high dose group the systemic NOAEL is 25% (approx. 500 mg/kg bw/d).