Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP-compliant study, available as unpublished report, well-documented, no restrictions, adequate for assessment.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1981
Report Date:
1981

Materials and methods

Principles of method if other than guideline:
Method: other: International Research and Development Corp. method
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Substance type: High Boiling Liquid, Hydrocarbon
- Physical state: thick, pale yellow liquid

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Dutchland Laboratories, Denver, Pennsylvania
- Age at study initiation: young adult
- Weight at study initiation: mean of 2509 g (males) - 2495 g (females)
- Housing: individually housed
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 20 to 22 days prior to study initiation

ENVIRONMENTAL CONDITIONS
- Photoperiod (hrs dark / hrs light): 12 hour on/off cycle

IN-LIFE DATES: Study initiated on March 11, March 12 and March 13, 1980 and sacrificed on April 1, April 2 and April 3, 1980.

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: the back
- % coverage: approximately 30% of the body surface
- Type of wrap if used: Saran Wrapt and Elastoplast tape
- Time intervals for shavings or clipplings: The rabbits were shaved as needed during the study period to prevent the test or control articles from becoming matted in the hair and to facilitate accurate observations. Twice each week, immediately prior to test or control article administration, the dorsal skin of one-half of the rabbits in each sex group was abraded.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): the test site is washed with tepid IRDC tap water. Disposable paper towels were used to wash and dry the test site.
- Time after start of exposure: 6 hours

TEST MATERIAL
Individual doses were adjusted weekly based on the body weights obtained at the beginning of each study week.

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
21 days
Frequency of treatment:
6 hours/day, 5 days/week
Doses / concentrationsopen allclose all
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
Basis: nominal per unit body weight
Dose / conc.:
125 mg/kg bw/day (nominal)
Remarks:
Basis: nominal per unit body weight
Dose / conc.:
500 mg/kg bw/day (nominal)
Remarks:
Basis: nominal per unit body weight
Dose / conc.:
2 000 mg/kg bw/day (nominal)
Remarks:
Basis: nominal per unit body weight
No. of animals per sex per dose:
number of animals with abraded skin: 5M,5F/dose + Control article
number of animals with unabraded skin: 5M,5F/dose + Control article
Control animals:
yes

Examinations

Observations and examinations performed and frequency:
MORTALITY: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily

DERMAL IRRITATION : Yes
- Time schedule for examinations: once daily

BODY WEIGHT: Yes
- Time schedule for examinations: obtained and recorded during the pretest period and at weekly intervals during the study period.

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: Yes

WATER CONSUMPTION: No data

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Once during the pretest period and at 21 days of study
- Anaesthetic used for blood collection: No data
- Animals fasted: No
- How many animals: on 5 rabbits (intact and abraded) per sex per group
- Parameters checked in Table 1 were examined.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Once during the pretest period and at 21 days of study
- Animals fasted: No
- How many animals: on 5 rabbits (intact and abraded) per sex per group
- Parameters checked in Table 2 were examined.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (see Table 3)
Statistics:
Body weights (week 3), haematologic and biochemical parameters (Day 21) and absolute and relative organ weights (terminal sacrifices) were compared by analysis of variance (one-way classification), Bartlett’s test for homogeneity of variances and the appropriate t-test (for equal or unequal variances).

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):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY:
A number of incidental and spontaneous signs were noted for a few rabbits in the control and test groups; including: soft stool, mucoid diarrhea, brown stained anogenital region and emaciation. Female rabbit #7792, control group, exhibited signs of mucoid diarrhea, possible anorexia and emaciation prior to death. Male rabbit #7731, 2000 mg/kg, abraded skin, exhibited possible anorexia and no stool in pan prior to death. Possible anorexia was observed in an occasional animal in the control group and in the 500 and 2000 mg/kg test groups.
Two rabbits died during the course of the study period. Female rabbit #1792 (2 mI/kg, intact skin) was found dead on Day 14 and male rabbit #1131 (2000 mg/kg, abraded skin) was found dead on Day 7.

BODY WEIGHT AND WEIGHT GAIN:
No statistically significant differences were seen in group mean body weights.

DERMAL IRRITATION:
In the control group no dermal irritation was observed. At 125, 500 and 2000 mg/kg, the majority of rabbits exhibited very slight to moderate erythema, edema, atonia, desquamation and coriaceousness. Very slight to marked fissuring was also observed for some rabbits in the three test article groups. Several animals in all test groups exhibited marked desquamation during the latter part of the study. Blanching was observed infrequently in the 125 and 2000 mg/kg test article groups. An occasional animal in the 125 and 500 mg/kg test article groups also exhibited subcutaneous hemorrhaging. No eachar or exfoliation was observed in any group.

HAEMATOLOGY:
Changes in Segmented neutrophils, Lymphocytes and Erythrocytes at 2000 mg/kg were not considered to be related to Terphenyl, hydrogenated treatment.

CLINICAL CHEMISTRY:
Changes in Globulin, Total Protein and Glucose at 500 and 2000 mg/kg were not considered to he related to Terphenyl, hydrogenated treatment.

ORGAN WEIGHTS:
No toxicologically significant test article-related weight variations (absolute or relative) were observed among animals sacrificed at study termination.

GROSS PATHOLOGY:
1. Macroscopic
Toxicologically significant compound-related gross macroscopic lesions were observed in male and female rabbits receiving 125, 500 and 2000 mg/kg. The lesions commonly observed were thickening and crust formation.
2. Microscopic
Test article-related morphologic changes on the skin application sites were observed among all male and female rabbits at all dose levels; consisting of epithlial acanthosis, epidermal hyperkeratosis and inflammatory cell infiltrates among animals sacrificed at study termination. Microabscesses were present at the 2000 mg/kg dosage level. One male animal at 2000 mg/kg dosage level that died on the study, also showed similar type of changes on the skin application site mentioned above. The distribution and relative severity of the above skin changes were generally more pronounced among male and female rabbits at the 2000 mg/kg dosage level. The changes described in tissues other than the skin application sites were regarded as spontaneous in nature, not unusual for rabbits of this age and strain and unrelated to compound application.

Effect levels

Dose descriptor:
NOAEL
Remarks:
(Systemic toxicity)
Effect level:
2 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
clinical signs
mortality
dermal irritation
body weight and weight gain
haematology
clinical biochemistry
organ weights and organ / body weight ratios

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
There was no systemic toxicity up to 2.000 mg/kg bw/day. The NOAEL for systemic toxicity is therefore 2.000 mg/kg bw/day. Skin findings were observed at all dose groups, however more pronounced at the 2.000 mg/kg bw/day.
Executive summary:

Terphenyl, hydrogenated was administered by dermal application to three groups of 10 male and 10 female New Zealand White rabbits, one-half with intact skin and one-half with abraded skin, five days per week for three consecutive weeks at dosage levels of 0, 125, 500 and 2000 mg/kg. One rabbit at the high dosage level (2000 mg/kg) was found dead on study Day 7 and one control rabbit was found dead on study Day 14. A number of incidental and spontaneous pharmacotoxic signs were noted in the control and test groups. Possible anorexia was observed in an occasional animal in the control, 500 and 2000 mg/kg groups. No statistically significant differences were seen in group mean body weights. Very slight to moderate erythema, edema, atonia, desquamation, coriaceousness and very slight marked fissuring were observed for some rabbits in all test groups. Several animals in all test groups exhibited marked desquamation during the latter part of the study. Blanching (125 and 2000 mg/kg) and subcutaneous hemorrhaging (125 and 500 mg/kg) were observed. No relevant changes were observed for haematology and clinical chemistry. No toxicologically significant test article-related weight variations (absolute or relative) were observed among animals sacrificed at study termination. At macroscopic examination, commonly observed findings were thickening and crust formation of the skin were observed at all dose levels in both sexes. Test article-related histological changes on the skin application sites were observed among all male and female rabbits at all dose levels; consisting of epithelial acanthosis, epidermal hyperkeratosis and inflammatory cell infiltrates among animals sacrificed at study termination. Microabscesses were present at the 2000 mg/kg dosage level. One male animal at 2000 mg/kg dosage level that died on the study, also showed similar type of changes on the skin application site mentioned above. The distribution and relative severity of the above skin changes were generally more pronounced among male and female rabbits at the 2000 mg/kg dosage level. The changes described in tissues other than the skin application sites were regarded as spontaneous in nature, not unusual for rabbits of this age and strain and unrelated to compound application. In conclusion, daily administration of Terphenyl, hydrogenated to the skin of rabbits for 21-days produced gross and microscopic changes at the dosaqe levels of 125, 500 and 2000 mg/kg/day. There were however no major signs of systemic toxicity; the findings are considered to be related to the dermal application of Terphenyl, hydrogenated; the distribution and severity were generally more pronounced among male and female rabbits at the 2.000 mg/kg dose level.