Registration Dossier

Toxicological information

Repeated dose toxicity: dermal

Currently viewing:

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
1978
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study well documented, meets generally accepted scientific standards and described in sufficient details
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
reference to same study
Reason / purpose for cross-reference:
reference to other study

Data source

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

Materials and methods

Principles of method if other than guideline:
TMPTA (500 mg/kg bw) was applied to the backs of New Zealand White albino rabbits (5/sex/dose) once daily, 5 days/week for 2 weeks. Six animals per group were sacrificed after 15 days and remaining 4 animals after 30 days. Animals were monitored for the clinical signs and mortality, body weight gains, dermal reactions, gross pathology and histopathology.
GLP compliance:
not specified
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
2-ethyl-2-[[(1-oxoallyl)oxy]methyl]-1,3-propanediyl diacrylate
EC Number:
239-701-3
EC Name:
2-ethyl-2-[[(1-oxoallyl)oxy]methyl]-1,3-propanediyl diacrylate
Cas Number:
15625-89-5
Molecular formula:
C15H20O6
IUPAC Name:
2,2-bis[(prop-2-enoyloxy)methyl]butyl prop-2-enoate
Constituent 2
Reference substance name:
Trimethylolpropane Triacrylate (TMPTA)
IUPAC Name:
Trimethylolpropane Triacrylate (TMPTA)
Details on test material:
- Name of test material (as cited in study report): Trimethylolpropane Triacrylate (TMPTA)
- Physical state: Clear liquid
- Lot/batch No.: 4-78
- Storage condition of test material: Stored at room temperature

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Marland Breeding Farms, Inc. Hewitt, New Jersey
- Weight at study initiation: Male-2.5 (2.3 - 3.0) kg; Female-2.5 (2.2 - 2.9) kg
- Housing: Individually housed in suspended stainless steel cage
- Diet: Purina rabbit chow, ad libitum
- Water: Ad libitum
- Acclimation period: At least one week

ENVIRONMENTAL CONDITIONS
- Photoperiod: 12 h light/ 12 h dark

Administration / exposure

Type of coverage:
open
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: Back
- Time intervals for shavings or clippings: Clipping was repeated as necessary throughout the study

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 500 mg/kg bw
- Constant volume or concentration used: Yes

USE OF RESTRAINERS FOR PREVENTING INGESTION: Yes
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Not applicable
Duration of treatment / exposure:
Two weeks
Frequency of treatment:
Daily, five days/week for two weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
500 mg/kg bw/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
Five
Control animals:
yes, concurrent no treatment
Details on study design:
- Rationale for animal assignment: Random
Positive control:
None

Examinations

Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: Daily

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


Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Other examinations:
None
Statistics:
None

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Dermal irritation:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
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:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY:
- Decreased motor activity and nasal discharge during the study
- The ears of some animals came in contact with the test material and subsequently exhibited edema and scab formation

BODY WEIGHT AND WEIGHT GAIN: Four animals (2 males and 2 females) exhibited slight weight losses

DERMAL IRRITATION:
- Animals exhibited severe erythema with desquamation, necrotic skin and eschar formation
- Exfoliation (sloughing of the eschar tissue) occurred during the second week of the post-dose period
- Fissuring of the skin and slight to moderate edema and atonia were also noted in most animals during the 2 week treatment period; these signs decreased in incidence and severity during the post-dose period

HISTOPATHOLOGY:
Observation in animals sacrificed after two weeks:
- No evidence of a systemic effect
- Severe necrosis of the epithelium and upper dermis

Observation in animals sacrificed after four weeks:
- No evidence of a systemic effect
- Epithelial and subepithelial dermal necrosis persisted two weeks after termination of treatment



Effect levels

Dose descriptor:
NOAEL
Remarks:
sytemic
Effect level:
> 500 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: mortality; body weight; dermal reactions; gross pathology and histopathology

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

None

Applicant's summary and conclusion

Conclusions:
A systemic NOAEL for trimethylolpropane triacrylate (TMPTA) was considered to be 500 mg/kg bw. A LOAEL of 500 mg/kg bw/day can be set for local effects.
Executive summary:

A repeated dermal toxicity study was performed to assess the dermal irritation caused by trimethylolpropane triacrylate (TMPTA) in New Zealand White rabbits.

 

Groups of New Zealand White rabbits (5/sex/dose) received topical application of TMPTA (500 mg/kg bw) to the back, once daily, 5 days/week for 2 weeks. Six animals per group were sacrificed after 15 days and remaining 4 animals per group after 30 days.

 

Signs of severe dermal irritation observed in rabbits treated with TMPTA. Animals exhibited severe erythema with necrotic skin and eschar formation, edema, atonia, fissuring of the skin, desquamation and exfoliation of eschar tissue. Signs of severe irritation persisted in most animals throughout the post-treatment period. Motor activity decreased and nasal discharge occurred in several animals in the treated group, few animals exhibited slight body weight losses.

 

Microscopic examination of selected tissues revealed no evidence of systemic toxicity resulting from administration of TMPTA. Evaluation of treated skin revealed severe necrosis of the epithelium and upper dermis (after 15 days) and epithelial and subepithelial dermal necrosis (after 30 days).

 

In conclusion, as no systemic substance related effects were observed the systemic NOAEL of trimethylolpropane triacrylate (TMPTA) was considered to be > 500 mg/kg bw.