Registration Dossier

Toxicological information

Repeated dose toxicity: dermal

Currently viewing:

Administrative data

Endpoint:
sub-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

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
2003

Materials and methods

Principles of method if other than guideline:
subchronic study according to EPA Dermal Bioassay Workshops (April 28-29, 1987 and May 18-19, 1988).
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
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:
2-(2-{2-[(2-methylprop-2-enoyl)oxy]ethoxy}ethoxy)ethyl 2-methylprop-2-enoate
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, 100%

USE OF RESTRAINERS FOR PREVENTING INGESTION: no
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
5 d/week
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day
Remarks:
= 5 %

Dose / conc.:
500 mg/kg bw/day
Remarks:
= 25 %
Dose / conc.:
1 000 mg/kg bw/day
Remarks:
= 50 %
Dose / conc.:
2 000 mg/kg bw/day
Remarks:
= 100 %
No. of animals per sex per dose:
10 males
Control animals:
yes, concurrent no treatment
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: weekly starting 1 week before dosing

BODY WEIGHT: Yes
- Time schedule for examinations: weekly starting 1 week before dosing

HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to sacrifice
- How many animals: 5/group

NECROPSY: YES


ORGAN WEIGHTS: YES
-liver, kidneys, spleen, brain and testes were weighed.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to sacrifice
- How many animals: 5/group

NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: weekly starting 1 week before dosing
- Dose groups that were examined: all groups
- Battery of functions tested: observation in an open arena and the following endpoints were evaluated: stereotypy, arousal, approach response, startle response, tail pinch, salivation, Iacrimation, mouthbreathing, piloerection, gait, muscle tone, air righting reflex, convulsions, tremors, and diarrhea

OTHER: cutaneous cell proliferation evaluations using the PCNA procedure in 5/test group and 10/control group
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (high dose group; Iungs, liver, kidneys, spleen, stomach, and gross lesions in all dose groups)
Other examinations:
Proliferating cell nuclear antigen (PCNA) immunohistochemical analysis

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:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
inreased liver weights in 50 and 100% groups, but no clinical or histopathological evidence of liver toxicity
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:
not examined

Effect levels

open allclose all
Dose descriptor:
NOAEL
Remarks:
local
Effect level:
100 mg/kg bw/day
Based on:
act. ingr.
Sex:
male
Basis for effect level:
other: acanthosis, hyperkeratosis
Remarks on result:
other: = 5%
Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
2 000 mg/kg bw/day
Based on:
act. ingr.
Sex:
male
Remarks on result:
other: = 100%; no relevant systemic effects observed

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

For TREGDMA-treated animals, exfoliation/desquamation was observed in all animals of the 25, 50 and 100% dose groups at some time during the study. Ulceration and excoriation also were seen in a few animals from these groups that resolved by day 35. No findings were recorded in the 5% dose group.

Hyperkeratosis was observed in all animals from the 25, 50, and 100% dose groups and acanthosis was observed in 80 or 100% of the animals from these groups. A single animal was diagnosed with dermatitis from the 100% group. Grading of these lesions generally correlated with dose. No microscopic changes of the skin were noted for the 5% dosage.

Skin basal cell proliferation (PCNA assay) was increased in the 25, 50, and 100% groups, but statistically significant only in the 100% group.

Applicant's summary and conclusion

Conclusions:
The 13 week-NOAEL of TREGDMA in mice for local effects (acanthosis, hyperkeratosis) was 5% in acetone (approx. 100 mg/kg bw/d). The 13 week-NOAEL for systemic effects was 100% (approx. 2000 mg/kg bw/d).
Executive summary:

In a 13 weeks dermal toxicity study, TREGDMA (91% a.i.) was applied to the clipped interscapular region of the back of 10 maleC3H/HeNHsd mice/dose at dose levels of 0 (control), 5, 25, 50 and 100% TREGDMA in acetone, corresponding to approx. 100, 500, 1000 and 2000 mg/kg bw/d. The doses were applied in 50 µL/animal/day 5 days per week.

During the treatment phase of the study, no effects were observed except for skin lesions at the site of treatment. Exfoliation and desquamation was observed in all animals of the 25, 50 and 100% dose groups at some time during the study. Ulceration and excoriation also were seen in a few animals from these groups that resolved by day 35. No findings were recorded in the 5% dose group.

The only treatment-related finding at necropsy, other than for treated skin, was an increase in liver weight of approx. 7 and 10% compared with the control group in the 50 and 100% groups, respectively. There was no clinical or histopathological evidence of liver toxicity, thus the etiology and biological significance of the increased weight was uncertain.

Hyperkeratosis was observed in all animals from the 25, 50, and 100% dose groups and acanthosis was observed in 80 or 100% of the animals from these groups. A single animal of the 100% group was diagnosed with dermatitis. No microscopic changes of the skin were noted for the 5% dosage.

Skin basal cell proliferation (PCNA assay) was increased in the 25, 50, and 100% groups, but was statistically significant only in the 100% group.

In this study, the 13 week-NOAEL of TREGDMA for local effects (acanthosis, hyperkeratosis) was 5% (approx. 100 mg/kg bw/d). The 13 week-NOAEL for systemic effects was 100% (approx. 2000 mg/kg bw/d).