Registration Dossier

Diss Factsheets

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Data is from study report

Data source

Reference
Reference Type:
other: study report
Title:
DERMAL, EYE, AWD ORAL TOXICOLOGICAL EVALUATIONS Phase Report-II
Author:
Indu A. Muni, Elliot B. Gordon, DABT Jane B. Goodband
Year:
1986
Bibliographic source:
NTRL- ADA 165408 1986, U.S. Army Medical Research And Development 21701-5012, page no 1-97

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: Repeated dose dermal toxicity study of Solvent yellow 33 in Albino Rabbits
Principles of method if other than guideline:
Repeated dose dermal toxicity study of Solvent yellow 33 in Albino Rabbits
GLP compliance:
no
Limit test:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
1,3-isobenzofurandione, reaction products with methylquinoline and quinoline
EC Number:
232-318-2
EC Name:
1,3-isobenzofurandione, reaction products with methylquinoline and quinoline
Cas Number:
8003-22-3
Molecular formula:
C18H11NO2
IUPAC Name:
1,3-isobenzofurandione, reaction products with methylquinoline and quinoline
Details on test material:
- Name of test material (as cited in study report): CI Solvent Yellow 33
- Molecular formula (if other than submission substance): C18H11NO2
- Molecular weight (if other than submission substance): 273.29 g/mole
- Substance type: Organic

- Physical state: Solid
- Impurities (identity and concentrations): 6.9 %

Test animals

Species:
rabbit
Strain:
other: Albino
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Pine Acres Rabbi try, West Brattleboro,
Vermont

- Age at study initiation: 17 weeks
- Housing: Animals were housed in individually stainless steel cages.
- Diet (e.g. ad libitum): Charles River Rabbit Formula (Agway), ad libitum
- Water (e.g. ad libitum):untreated municipal water via water bottle, ad libitum
- Acclimation period: They were quarantined for two weeks.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.44 to 22.22 °C
- Humidity (%): 35% to 65%
- Air changes (per hr): 12-16 air changes per hour
- Photoperiod (hrs dark / hrs light): 12-hour light cycle (1 AM to 7 PM).

IN-LIFE DATES: From: No data available

Administration / exposure

Type of coverage:
occlusive
Vehicle:
not specified
Details on exposure:
Details on dermal exposure
PREPARATION OF DOSING SOLUTIONS: No data available

TEST SITE
- Area of exposure: Back and sides
- % coverage: 6 in. x 6 in
- Type of wrap if used: plastic wrap & then stockinette
- Time intervals for shavings or clipplings: Prior to testing of animals
REMOVAL OF TEST SUBSTANCE
- Washing (if done): No data available
- Time after start of exposure: 6 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 50, 200 and 1000 mg/kg
- Concentration (if solution):
- Constant volume or concentration used: yes
- For solids, paste formed: yes
VEHICLE
- Justification for use and choice of vehicle (if other than water): No data available
- Amount(s) applied (volume or weight with unit): No data available
- Concentration (if solution): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available

Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
6 hours/ 5 days a week for 2 weeks
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:
1000, 200 and 50 mg/kg
Basis:
no data
No. of animals per sex per dose:
Total: 30
50 mg/kg: 5 male, 5 female
200 mg/kg: 5 male, 5 female
1000 mg/kg: 5 male, 5 female
Control animals:
yes
Details on study design:
No data available
Positive control:
No data available

Examinations

Observations and examinations performed and frequency:
Observations and examinations performed & frequency
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Once daily
- Cage side observations checked in table [No.?] were included: Mortality were observed

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

DERMAL IRRITATION (if dermal study): No data available
- Time schedule for examinations: No data available

BODY WEIGHT: Yes
- Time schedule for examinations: Twice 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 data available
- 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: No data available

WATER CONSUMPTION: No data available
- Time schedule for examinations: No data available

OPHTHALMOSCOPIC EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available

HAEMATOLOGY: No data available
- Time schedule for collection of blood: No data available
- Anaesthetic used for blood collection: No data available
- Animals fasted: No data available
- How many animals: No data available
- Parameters checked in table [No.?] were examined. No data available

CLINICAL CHEMISTRY: No data available
- Time schedule for collection of blood: No data available
- Animals fasted: No data available
- How many animals: No data available
- Parameters checked in table [No.?] were examined. No data available

URINALYSIS: No data available
- Time schedule for collection of urine: No data available
- Metabolism cages used for collection of urine: No data available
- Animals fasted: No data available
- Parameters checked in table [No.?] were examined. No data available

NEUROBEHAVIOURAL EXAMINATION: No data available
- Time schedule for examinations: No data available
- Dose groups that were examined: No data available
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data available
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

On all animals dying intercurrently as well as those surviving treatment and sacrificed on day 14.

HISTOPATHOLOGY: Yes, Histopathologic examination on multiple skin sections of treated and untreated skin.

Organ examined.
Treated skin, one section of untreated skin, all gross lesions, heart, liver and kidney for all animals were examined.
Other examinations:
No data available
Statistics:
No data available

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Mortality- All the animals survived throughout the entire study. Clinical signs: Mild diarrhea and nasal discharge were observed in treated rabbits. When treated with 200 mg/kg, Scattered mild nasal discharge and mild to moderate diarrhea during the study in treated rabbits. When treated with 50 mg/kg, One male rabbit displayed mild diarrhea on day 14.
Dermal irritation:
effects observed, treatment-related
Description (incidence and severity):
Dermal irritation score were recorded daily based on draize method. There was no erythema & edema observed at 50, 200 and 1000 mg/kg treated sites of rabbits during the 14 day observation period.
Mortality:
mortality observed, treatment-related
Description (incidence):
Mortality- All the animals survived throughout the entire study. Clinical signs: Mild diarrhea and nasal discharge were observed in treated rabbits. When treated with 200 mg/kg, Scattered mild nasal discharge and mild to moderate diarrhea during the study in treated rabbits. When treated with 50 mg/kg, One male rabbit displayed mild diarrhea on day 14.
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
When treated with 50 mg/kg, significantly decreased in food intake of two rabbit and one female rabbits were observed.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Hyperkeratosis, acanthosis and adnexal hyperplasia were observed.
Histopathological findings: neoplastic:
not specified
Details on results:
Body weight and weight gain:
When treated with 1000 mg/kg, Two female rabbits decreased in weight between days 0 and 3.
Female rabbit increased in weight on day 7 and maintained or gained weight during the remainder of the study.
The body weight of female rabbit remained constant between days 3 and 7, increased by day 10, and decreased again on day 14.
Male rabbit decreased in weight between days 7 and 10 and maintained weight between days 10 and 14.
Male rabbit decreased in weight between days 7 and 10 but regained the weight by day 14.
All other rabbits either maintained or gained weight during the study.
When treated with 200 mg/kg, Four male and three female rabbits maintained or increased body weight during the 14 day study. One male and one female rabbit decreased in weight between days 0 and 3 but increased in weight by day 7.
The other female rabbit decreased in weight between days 7 and 10 but increased in weight by day 14.
When treated with 50 mg/kg, significantly decreased in body weight between days 3 and 7, and days 1 and death (day 10) were observed.
One male and one female rabbit lost weight between days 0 and 3. Three male and four female rabbits maintained or gained weight between days 0 and 3. By day 7, these two rabbits increased in weight.
The body weight of female rabbit decreased between days 7 and 10 but increased again by day 14. Only one male rabbit decreased in weight between days 10 and 14.

Gross pathology:
One male rabbit was observed to have scattered 1 mm X 1 mm white lesions on the lobes of the liver. Petechial hemorrhages were observed on both kidneys of the remaining female rabbit when treated with 1000 mg/kg.
The medial liver lobe of one male rabbit displayed a circular pattern with 2 mm X 2 mm white circular lesions. The colon of another male rabbit was gaseous, and the large intestine of the remaining male rabbit was gaseous and contained watery diarrhea when treated with 200 mg/kg.
Both kidneys of two female rabbits displayed scattered beige areas, and both kidneys of one of these rabbits displayed petechial hemorrhages. The colon of one male rabbi t appeared gaseous, arid the lobes of the 1iver of one female rabbit displayed scattered white circular lesions, 1 mm X1 mm in size when treated with 50 mg/kg.

Details on results:
Pathologic changes are graded on a four-point scale: mild, moderate, marked, severe. No definitive dose related increase in severity of these skin lesions.
The test material caused skin changes after repeated contact. These changes were confined to thickening of the epidermal prickle cell layer, the outer horny layer and accessory cells of the denims. Systemic toxicity was not evident.

Effect levels

Dose descriptor:
NOEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Dermal irritation parameters and other observations based on body weights .

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The no-adverse-effect-level (NOEL) was considered to be 1000 mg/kg when albino male and female rabbits treated with CI Solvent Yellow 33.
Executive summary:

In a subacute repeated dose dermal toxicity study, albino male and female rabbits treated with CI Solvent Yellow 33 in the concentration of 50, 200 and 1000 mg/kg for 6 hours/ 5 days a week. Results shows that CI Solvent Yellow 33 was not toxic dermaly. No effect was observed on survival of treated rabbits. There was no erythema & edema observed at 50, 200 and 1000 mg/kg treated sites of rabbits during the 14 day observation period. Changes in body weight and food consumption were observed in treated rabbits but the changes are not constant. In addition, mild to moderate degrees of one or more of hyperkeratosis, acanthosis and adnexal hyperplasia were observed. The treated skin sections were compared with untreated skin sections from the same rabbit. There was no definitive increase in severity of skin lesions with increasing dose levels. All other lesions found on organs were of an incidental nature and it could not be determined whether or not these changes were related to the absorption and toxicity of CI Solvent Yellow 33. Therefore, NOEL was considered to be 1000 mg/kg when albino male and female rabbits treated with CI Solvent Yellow 33 by dermal application for 2 weeks.