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Toxicological information

Repeated dose toxicity: dermal

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Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23 Oct 1985 - 08 Oct 1986
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1986
Report Date:
1986
Reference Type:
publication
Title:
Hemolytic activity of ethylene glycol phenyl ether (EGPE) in rabbits
Author:
Breslin, W.J. et al.
Year:
1991
Bibliographic source:
Fund Appl Toxicol 17:466-481

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
Deviations:
yes
Remarks:
minor deviations regarding weight at study initiation
Principles of method if other than guideline:
No guideline mentioned in the report.
However, study is equivalent or similar to OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study) with minor deviations regarding weight at study initiation:
Males: about 3250 g; Females: about 3380 g
GLP compliance:
yes
Remarks:
according to FDA and EPA GLP Practice regulation
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Specific details on test material used for the study:
- Name of test material (as cited in study report): Ethylene glycol phenyl ether
- Physical state: colorless liquid
- Analytical purity: 99.9%
- Lot/batch No.: 53 (C44172)

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton-Dutchland, Inc. Denver, Pennsylvania
- Age at study initiation: approx. 5-6 months
- Weight at study initiation: Males: about 3250 g; Females: about 3380 g
- Fasting period before study: none
- Housing: single
- Diet (e.g. ad libitum): 4 oz./day/animal (Certified Laboratory Rabbit Chow #5322, Ralston Purina Co., St. Louis, Missouri)
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 21 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): approx. 20
- Humidity (%): approx. 50
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: 10 x 15 cm on the back of each test animal.
- Type of wrap if used: Occlusive bandage of absorbent gauze and nonabsorbent cotton held in place using a Lycra/spandex jacket.
- Time intervals for shavings or clipplings: clipping periodically as required during the course of the study.

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): Dosing volume was approximately 0.05 to 0.50 ml/kg bw/day and was adjusted weekly based on body weight. Control rabbits received 0.5 ml/kg bw/day distilled water
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
6 hours per day, 5 days/week for 13 consecutive weeks
Doses / concentrationsopen allclose all
Dose / conc.:
50 mg/kg bw/day (nominal)
Dose / conc.:
150 mg/kg bw/day (nominal)
Dose / conc.:
500 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: Results from previous studies

Examinations

Observations and examinations performed and frequency:
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: The animals were examined daily for general state of health and clinical symptoms of toxicity.

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: The condition of the skin was assessed and recorded prior to each daily dose for the first two weeks and approx. weekly thereafter using a modified Draize scoring system (see attached background material).

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: Yes, periodically (data were not presented in the report)

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: At end of study. In-situ examination of the eyes by a glass slide technique with fluorescent illumination
- Dose groups that were examined: All animals

HAEMATOLOGY: Yes
- Time schedule for collection of blood: 1 week prior to exposure (pre-exposure), 4 week interim, and at test termination.
- Anaesthetic used for blood collection: No
- Animals fasted: No
- How many animals: All animals
- Parameters checked in table were examined.

CLINICAL CHEMISTRY: Yes / No / No data
- Time schedule for collection of blood: 1 week prior to exposure (pre-exposure), 4 week interim, and at test termination
- Animals fasted: No
- How many animals: All animals
- Parameters checked in table were examined.

URINALYSIS: No
Sacrifice and pathology:
GROSS PATHOLOGY: A complete set of organs was collected from each animal and was preserved in neutral phosphate-buffered 10% formalin. The lungs were infused with formalin to their approximate normal inspiratory volume whereas the nasal cavity was flushed with formalin via the pharyngeal duct to ensure rapid fixation of the tissues.

HISTOPATHOLOGY: A complete histopathological examination of tissues was conducted for the rabbits of the control and the high dose groups. For this purpose, tissues were prepared by conventional techniques, stained with Hematoxylin/Eosin and were evaluated by means of light microscopy.
Statistics:
Body and organ weights, as well as hematological and clinical-chemical data were analyzed using Bartlett's test for equality of variances. Based on the outcome, a parametric or nonparametric analysis of variance was conducted, followed by Dunnett's test or the Wilcoxon rank-sum test with Bonferroni's correction. The critical level of significance was p < 0.05. Statistical outliers were identified by a sequential outlier test but were not excluded from analysis except for body weight.
Level of significance: see attached background material

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
In fact, a statistically significant decrease in AST activity was reported for the females of the 150 mg/kg/d dose group after 4 weeks of treatment, whereas the males of the 50 mg/kg bw /d showed an increased ALT activity at study termination. However, these effects neither showed a dose-response relationship nor were they seen at the other sampling time points. Therefore, these effects were not considered to be treatment-related.
Urinalysis findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
No toxicologically significant changes were observed in terminal body weights or absolute and relative organ weights. A statistical decrease in absolute liver weight was identified in female rabbits administered 50 mg/kg bw/day of test substance, but there was no dose-response relationship. Therefore, the statistically identified difference in liver weight was not considered to be treatment-related.
Gross pathological findings:
no effects observed
Description (incidence and severity):
There were no treatment-related gross pathological changes observed in either male or female rabbits. The few observations in these animals at necropsy were considered spontaneous changes typical of those expected in New Zealand White rabbits of this age. Likewise, there were no treatment-related lesions observed.
Description (incidence and severity):
The only potentially treatment-related effects were the sporadic occurrence of erythema (4 males) and the very slight to slight scaling of the skin at the application site (8 males and 9 females at week 7) in animals exposed to 500 mg/kg bw/day. Exfoliation was resolved in all but 2 females during weeks 9-13. As these observations were not associated with any gross or histological changes in the skin, they were not considered to be of toxicological significance.
Details on results:
CLINICAL SIGNS AND MORTALITY
No overt signs of systemic toxicity
no mortalities at any dose

BODY WEIGHT AND WEIGHT GAIN
The mean body weights of male and female rabbits were not affected by treatment with 2-phenoxyethanol during the course of the study.

FOOD CONSUMPTION
Results on food consumption were not reported.

OPHTHALMOSCOPIC EXAMINATION
No findings were reported.

HAEMATOLOGY
No treatment-related effects could be evidenced.

CLINICAL CHEMISTRY
No treatment-related effects could be evidenced.
In fact, a statistically significant decrease in AST activity was reported for the females of the 150 mg/kg/d dose group after 4 weeks of treatment, whereas the males of the 50 mg/kg bw /d showed an increased ALT activity at study termination. However, these effects neither showed a dose-response relationship nor were they seen at the other sampling time points. Therefore, these effects were not considered to be treatment-related.

URINALYSIS
Not examined

ORGAN WEIGHTS
No toxicologically significant changes were observed in terminal body weights or absolute and relative organ weights. A statistical decrease in absolute liver weight was identified in female rabbits administered 50 mg/kg bw/day of test substance, but there was no dose-response relationship. Therefore, the statistically identified difference in liver weight was not considered to be treatment-related.

GROSS PATHOLOGY
There were no treatment-related gross pathological changes observed in either male or female rabbits. The few observations in these animals at necropsy were considered spontaneous changes typical of those expected in New Zealand White rabbits of this age. Likewise, there were no treatment-related lesions observed.

HISTOPATHOLOGY: NON-NEOPLASTIC
See attached background material

OTHER FINDINGS
The only potentially treatment-related effects were the sporadic occurrence of erythema (4 males) and the very slight to slight scaling of the skin at the application site (8 males and 9 females at week 7) in animals exposed to 500 mg/kg bw/day. Exfoliation was resolved in all but 2 females during weeks 9-13. As these observations were not associated with any gross or histological changes in the skin, they were not considered to be of toxicological significance.

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
500 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: overall effects
Dose descriptor:
LOAEL
Effect level:
> 500 mg/kg bw/day (nominal)
Sex:
male/female
Basis for effect level:
other: overall effects

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

No overt signs of toxicity were noted in the animals. There were no deaths. There was no significant effect of treatment on body or organ weights, clinical chemistries, hematologic variables, or pathology. The only potentially treatment-related effects was the sporadic observation of erythema (4 males) and very slight to slight scaling of the skin at the site of test material application (8 males and 9 females at week 7) in animals exposed to 500 mg/kg bw/day.
Exfoliation was resolved in all but 2 females during weeks 9-13. As these observations were not associated with any gross or histological changes in the skin, they were not considered to be of toxicologic significance.

For tables of results refer to attached background material

Applicant's summary and conclusion