Registration Dossier

Administrative data

Endpoint:
chronic toxicity: dermal
Type of information:
migrated information: read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented publication which meets basic scientific principles. GLP. Supporting, READ-ACROSS information from struckturallly closely related glycol dimethacrlyate

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

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: liquid
Details on test material:
- 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 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

open allclose all
Dose descriptor:
NOAEL
Effect level:
5 other: %
Based on:
act. ingr.
Sex:
male
Basis for effect level:
other: local effects; skin irritation
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
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
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).

For EGDMA and its first metabolite HEMA there are two important pieces of information in this study: The progression of lesions over time does not exceed the additional safety factors applied for shorter, in this case subacute, studies. Secondly, dimethacrylate functionality does not indtroduce other toxicological alerts which are not covered by the existing studies.
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).

For EGDMA and its first metabolite HEMA there are two important pieces of information in this study: The progression of lesions over time does not exceed the additional safety factors applied for shorter, in this case subacute, studies. Secondly, dimethacrylate functionality does not indtroduce other toxicological alerts which are not covered by the existing studies.