Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Dec 16, 1985 – May 7, 1986
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP conform study according to OECD guideline.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1986
Report Date:
1986

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material: Naphthalene
- Substance type: Aromatic hydrocarbon
- Physical state: Clear flake solid
- Analytical purity: 99.98%
- Impurities: 0.005% tetralin, 0.009% 2-methyl-naphthalene
- Composition of test material, percentage of components: See above
- Purity test date: April 29, 1986
- Lot/batch No.: #5601-56-1
- Expiration date of the lot/batch: Not provided
- Stability under test conditions: Stable
- Storage condition of test material: Room temperature

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
SOURCE:
- Age at study initiation: 7 weeks
- Weight at study initiation: Males 219.8 – 277.4g; females 152.7 – 197.2g
- Fasting period before study: None
- Housing: Singly in stainless steel cages with solid sides and wire mesh floors
- Diet: ad linitum, ground Purina Certified Rodent Chow #5002
- Water: ad libitum
- Acclimation period: 3 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 + 3 °C
- Humidity (%): 30 – 70%
- Air changes (per hr): 20 – 30/hr
- Photoperiod (hrs dark / hrs light): 12 light/12 dark

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: 2x2 inches (1 inch = 2.54 cm)
- % coverage: approximately 10% of body surface
- Type of wrap if used: Coban Action Wrap secured with Scotchrap Veterninary Elastic Tape
- Time intervals for shavings or clipplings: Not specified

REMOVAL OF TEST SUBSTANCE
- Washing (if done): No, wiped clean
- Time after start of exposure: 6 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): applied neat ranging from 100 – 1000 mg/kg body weight
- Concentration (if solution): not applicable
- Constant volume or concentration used: not applicable
- For solids, paste formed: no

VEHICLE
- Justification for use and choice of vehicle (if other than water): not applicable

USE OF RESTRAINERS FOR PREVENTING INGESTION: No
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Verification of starting purity. Was applied neat.
Duration of treatment / exposure:
13 weeks
Frequency of treatment:
5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 100, 300, 1000 mg/kg
Basis:
no data
No. of animals per sex per dose:
10/sex/dose with a satellite group of an additional 10/sex for the control and high dose
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: Tested to limit dose
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: random
- Post-exposure recovery period in satellite groups: 4 weeks
Positive control:
None

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily for mortality and general clinical signs
- Cage side observations checked in table were included.

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly

DERMAL IRRITATION (if dermal study): No, other than gross observations
- Time schedule for examinations:

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Pre-dose and post-dosing
- Dose groups that were examined: all

HAEMATOLOGY: Yes
- Time schedule for collection of blood: pre-dose, 4 weeks and 13 weeks
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes
- How many animals: 10/sex/group pre-dose and 5/sex/group during dosing periods
- Parameters checked in table were examined: Leukocyte and erythrocyte count, hemoglobin, hematocrit, MCV, MCH, MCHC, platelet count, differential leukocyte count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: pre-dose, 4 weeks and 13 weeks
- Animals fasted: Yes
- How many animals: 10/sex/group pre-dose and 5/sex/group during dosing periods
- Parameters checked in table were examined: Fasted glucose, urea nitrogen, creatinine, AST, ALT, total protein, albumin, total bilirubin, direct bilirubin, calcium, phosphorus, sodium, potassium, chloride

URINALYSIS: Yes
- Time schedule for collection of urine: Pre-dose, week 4 and week 13
- Metabolism cages used for collection of urine: Yes
- Animals fasted: Yes
- Parameters checked in table were examined: pH, protein, glucose, ketone, color, volume, bilirubin, blood, urobilinogen, specific gravity, turbidity

NEUROBEHAVIOURAL EXAMINATION: No
- Time schedule for examinations:
- Dose groups that were examined:
- Battery of functions tested: sensory activity / grip strength / motor activity / other:
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Yes. Food consumption, body and organ weight were intercompared for the dose groups and control group by Levene’s test for homogeneity of variances, analysis of variance and individual t-tests (if significance in the analysis of variance).

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
Excortiated skin and papules in treatment area of high dose male and female animals. This effect was also observed in the control animals and would appear to have been exacerbated by treatment but not caused by treatment.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed

Effect levels

open allclose all
Dose descriptor:
NOEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Excoriated skin and papules at 1000 mg/kg.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Naphthalene has no effect on toxicity in rats when applied dermally for 13 weeks.
Executive summary:

Male and female Sprague-Dawley CD® rats were exposed to naphthalene via the dermal route at 0, 100, 300, and 1000 mg/kg body weight/day. The test material was applied under occlusion for 6 hours per day, 5 days per week for 13 weeks. Following the exposure period, animals from each of the control and high dose groups were followed for 4 weeks during a recovery phase. No treatment-related effects on the incidence of clinical observations, ophthalmological changes, gross anatomic alterations, or histopathologic changes were observed. Cutaneous exposure to naphthalene did not affect food consumption, body weight, or clinical measurements conducted for clinical chemistry, haematology, and urinalysis parameters. Testes weights in the high dose group were slightly reduced at the 13-week sacrifice. However, this change was not noted at the 17-week recovery sacrifice. No other organ weight changes were observed. The decreased testes weight was considered to be of negligible biological significance based on the small magnitude of the change and the absence of any corroborating evidence of tissue alteration upon histologic examination. Based on the results of this study, cutaneous exposure of rats to crystalline naphthalene at or below 1000 mg/kg body weight/day is not considered to result in any biologically significant responses. The no observable effect level (NOEL) is considered to be at least 300 mg/kg body weight/day.