Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
From January 22 1990 to 16 July 1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not affect the quality of the relevant results.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1990
Report Date:
1990

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
Qualifier:
according to
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
- Name of test material: XRD-498
- Molecular formula: C12H9F2N5O2S
- Molecular weight: 325.3

- Physical state: white powder
- Analytical purity: 99.8%

- Lot/batch No.: AGR 240043

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Hazleton Research Products
- Age at study initiation: at least 9 weeks

- Fasting period before study : no
- Housing: one/cage
- Diet (e.g. ad libitum): Purina Certified Chow #5322, ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 9 weeks, all rabbits were acclimated to an elastic jacket used to hold the test material dressing in contact with the skin for at least four days prior to the first application


Administration / exposure

Type of coverage:
occlusive
Vehicle:
water
Details on exposure:
TEST SITE
- Area of exposure: an area approximately 10x 15 cm on the back of each rabbit was clipped free of fur prior to study inititation and as necessary thereafter
- % coverage:
- Type of wrap if used: absorbant gauze and non-absorbant cotton, held in place with elastic jacket
- Time intervals for shavings or clipplings: as needed

REMOVAL OF TEST SUBSTANCE
- Washing (if done): test site was wiped with water-dampened disposable towel to remove any residual test material
- Time after start of exposure: six hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10 x 15 cm
- Concentration (if solution): 100, 500, or 1000 mg/kg body weight/day
- Constant volume or concentration used: yes


USE OF RESTRAINERS FOR PREVENTING INGESTION: yes - elastic jacket
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No information
Duration of treatment / exposure:
6 hours per application
Frequency of treatment:
15 applications during a 21 day interval
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
control
Basis:
nominal per unit body weight
Remarks:
Doses / Concentrations:
100 mg/kg body weight/day
Basis:
nominal per unit body weight
Remarks:
Doses / Concentrations:
500 mg/kg body weight/day
Basis:
nominal per unit body weight
Remarks:
Doses / Concentrations:
1000 mg/kg body weight/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
5 per sex per dose
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: The 1000 mg/kg/day dose level represents a limit test as outlined by EPA testing guidelines, and is the maximum amount of material that can be practically maintained at the application site. The lower two doses were selected to evaluate any potential effects over a 10-fold dose range.
- Rationale for animal assignment (if not random): random
Positive control:
No information

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: At the end of each dosing week

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

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: No data

WATER CONSUMPTION: Yes
- Time schedule for examinations: daily

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

HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to day of necropsy
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: all
- Parameters checked : hematocrit, hemoglobin concentration, erythrocyte count, total leukocyte count, platelet counts, blood smears, and erythrocyte, leukocyte and platelet morphology

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to day of necropsy
- Animals fasted: No data
- How many animals: all
- Parameters checked : alkaline phosphatase activity, alanine aminotransferase activity, aspartate aminotransferase activity, total protein, albumin, globulin, total bilirubin, glucose, urea nitrogen, creatinine, phosphorus, calcium, sodium, potassium, chloride.

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

NEUROBEHAVIOURAL EXAMINATION: No data
- 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 - eyes (cornea, lens, other internal components), weights of liver, kidney, testes recorded, lungs were distended, nasal cavity was flushed
HISTOPATHOLOGY: Yes - tissues prepared for light microscopic evaluation - untreated and treated skin, liver, kidneys, and any grossly visible lesions, epidermal hyperplasia, inflammation, number of cell from the basal layer to the statum corneum of the epidermis were counted to grade the degree of epidermal hyperplasia
Statistics:
Body weights, organ weights, clinical chemistry data, and appropriate hematology data were evaluated by Bartlett's test for equality of variances. In-life body weight were analyzed by three-way repeated measures ANOVA for time-sex-dose interaction. Hematologic and clinical chemistry parameters, terminal body weights, and organ weights were evaluated using 2-way ANOVA. Results for absolute and relative testes weights were analyzed using a one-way ANOVA.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Dermal irritation:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not specified
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not specified
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:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
Dermal administration of XRD-498 resulted in local cutaneous irritative effects in some rabbits given 100, 500, or 1000 mg/kg body weight/day, 5 days/week for 21 days. Epidermal hyperplasia of more extensive (diffuse) distribution than the multifocal hyperplasia of control rabbits, was observed in 3 of 10 low dose, 7 or 10 intermediate dose and 7 of 10 high dose rabbits. Detailed examination of the kidneys and liver revealed no evidence of systemic toxicity in male and female rabbits given up to 1000 mg/kg body weight/day.

Effect levels

Dose descriptor:
NOEL
Effect level:
> 1 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects clinical signs; mortality; body weight; food consumption; ophthalmoscopic examination; haematology; clinical chemistry;; gross pathology; organ weights; histopathology;

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Based on the results of this study, the no-observed-effect-level for systemic toxicity was greater than 1000 mg XRD-498/kg/day (highest dose administered) following dermal administration.
Executive summary:

The potential toxicity of XRD-498 when administered via the dermal route was examined in rabbits. XRD-498 was applied to the clipped backs of groups of New Zealand white rabbits (5/sex/dose) at dose levels of 0 (control), 100, 500, or 1000 mg/kg body weight/day, 5 days/week for 21 days. No evidence of systemic toxicity or skin irritation was observed during the in-life phase of the study. There were no treatment-related gross pathologic alterations at necropsy. Histopathologic examination revealed local cutaneous irritative effects in several animals from all treatment groups. Irritative effects were characterized as very slight epidermal hyperplasia, which was occasionally accompanied by dermal inflammation or parakeratosis. Six of 10 control rabbits had multifocal epidermal hyperplasia that was attributed to irritation caused by repeated contact with the dressings used to hold the control vehicle (water) on the dermal test site. Treatment-related epidermal hyperplasia, of more extensive (diffuse) distribution than the multifocal epidermal hyperplasia of control rabbits, was observed in 3 of 10 low dose, 7 of 10 intermediate dose, and 7 of 10 high dose rabbits. Detailed examination of the liver and kidneys revealed no evidence of systemic toxicity in males or females of any dose level. Under conditions of this study, the no-observed-effect-level for systemic toxicity was greater than 1000 mg XRD-498/kg/day (highest dose administered) for male and female New Zealand white rabbits following dermal administration.