Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
22 January 1986 to 14 February 1986
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant, guideline study, available as unpublished report, no restrictions, fully adequate for assessment

Data source

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

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to
Guideline:
OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)
Deviations:
yes
Remarks:
occlusive dressing used
Qualifier:
according to
Guideline:
EPA OPP 82-2 (Repeated Dose Dermal Toxicity -21/28 Days)
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source of animals: H.A.R.E Inc., Hewitt, NJ, USA
- Age at study initiation: 106-113 days
- Weight at study initiation: males 2.86-3.65 kg; females 2.90-3.43 kg
- Fasting period before study: No
- Housing: Individually
- Diet: Certified Purina Rabbit Chow® #5322 ad libitum
- Water: Tap water ad libitum
- Acclimation period: Approximately 36 days

ENVIRONMENTAL CONDITIONS
- Temperature: 65±5°F
- Humidity: 50±20%
- Air changes (per hr): Not reported
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: 22 January 1986 To: 14 February 1986

Administration / exposure

Type of coverage:
occlusive
Vehicle:
water
Details on exposure:
TEST SITE
- Area of exposure: Approximately 120-240 cm2
- % coverage: Approximately 5-10% of total body surface
- Type of wrap if used: Gauze dressing secured with non-irritating adhesive tape.
- Time intervals for shavings or clippings: Prior to application and as necessary during the study

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Tap water followed by drying with paper towel
- Time after start of exposure: 6 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0 (purified water only), 1, 500, 1010 mg/kg/day
- For solids, paste formed: yes (purified water)

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes (Elizabethan collars)
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
22 consecutive days
Frequency of treatment:
Once daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 1, 500 and 1010 mg/kg/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily during pre-dose period, prior to and regularly after dosing on day 1; prior to dosing, within 30 mins of dosing and 30 mins after end of dosing period, prior to termination

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: Pre-dose, prior to dosing and approximately 30 mins after each application period

BODY WEIGHT: Yes
- Time schedule for examinations: Days -8, pre-dose on day 1, weekly thereafter and prior to necropsy

FOOD CONSUMPTION: Yes
- Time schedule for examinations: Pre-dose Days -8 to 1, weekly thereafter

FOOD EFFICIENCY: No

WATER CONSUMPTION: No

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Day -7 and Day 22
- Dose groups that were examined: All

PHYSICAL/AUDITORY EXAMINATIONS: Yes
- Time schedule for examinations: Day -14 and Day 20

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Days -7, -6 or -3, test days 21, 22, 23 or 24
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes (16-18 hours)
- How many animals: All
- Parameters examined: Haemoglobin, haematocrit, erythrocytes, leukocytes, differential leukocytes, platelets, prothrombin time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: Days -7, -6 or -3, test days 21, 22, 23 or 24
- Animals fasted: Yes (16-18 hours)
- How many animals: All
- Parameters examined: Urea nitrogen, creatinine, SGOT, SGPT, alkaline phosphatase, glucose, total protein, albumin, globulin, A/G ratio, total bilirubin, total cholesterol, inorganic phosphate, sodium, calcium, potassium, chloride

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (all animals) on day 22 or 23

ORGAN WEIGHTS: Yes (all animals)
- Organs weighed: adrenal glands, brain, heart, kidney, liver, ovary, pituitary, testis

HISTOPATHOLOGY: Yes (all animals)
- Organs/tissues examined: Liver, kidney, organs showing gross lesions or changes in size, skin (treated and untreated)
Statistics:
Body weight, food consumption, haematology, clinical chemistry and organ weight data were analysed for each sex separately. Tests for outliers and tests for homogeneity of variance were done. If the model assumptions were met, Dunnett's test was used. Otherwise appropriate ad-hoc analyses including data transforms, nonparametric tests and tests without assuming the homogeneity of group variance were performed. Nonparametric tests also used when parameters known not to be normally distributed.

Microscopic findings analysed separately for each sex by Fisher's Exact test and for both sexes by computing the convolved probabilities.

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):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
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
Details on results:
CLINICAL SIGNS AND MORTALITY: No mortalities. Clinical signs including inappetence, diarrhoea, soft faeces, and few or no faeces were observed in all groups including control groups. Since the incidence was low and no time or dose-relationships were established, the findings were considered not to be treatment-related.

BODY WEIGHT: Body weight development was comparable between all groups. The slight decrease in mean body weight of top dose males was due to one rabbit only (body weight loss of 260g, 8.1%).

CLINICAL CHEMISTRY: There was slightly decreased blood urea nitrogen in top dose males. In the absence of any meaningful correlation to other clinical chemistry parameters, this was considered to be of no toxicological relevance.

ORGAN WEIGHTS: There was a statistically significant decrease of the mean relative pituitary weights in low dose females, which in absence of any microscopic findings and dose-relationship was considered incidental.

Effect levels

Dose descriptor:
NOEL
Effect level:
1 010 other: mg/kg
Sex:
male/female
Basis for effect level:
other: No toxicologically significant treatment-related findings at highest dose tested

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Dermal administration of benoxacor at dose levels up to 1010 mg/kg revealed no significant treatment-related findings. Therefore, the NOEL for dermal administration in this study was 1010 mg/kg.
Executive summary:
Benoxacor was administered topically to intact skin under occlusive dressings, for 6 hours per day, to groups of rabbits at doses of 1, 500 or 1010 mg/kg/day for a minimum of 22 consecutive days. Standard parameters were investigated (clinical signs, dermal observations, body weights, food consumption, haematology, clinical chemistry, ophthalmoscopy, organ weights and gross pathological examinations). No treatment-related dermal effect, gross pathology changes or microscopic abnormalities were found. Benoxacor was found to be essentially non-toxic when administered topically at dose levels of up to 1010 mg/kg/day. The no observed effect level (NOEL) was considered to be 1010 mg/kg/day.