Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
19 October 1987 to 16 November 1987
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other: GLP compliant, guideline study, available as unpublished report, no restrictions, fully adequate for assessment
Cross-reference
Reason / purpose:
reference to same study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1988
Report Date:
1988

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:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): CGA185072 (company code)
- Analytical purity: 91.6%
- Physical state: solid
- Date of reanalysis: November 1990
- Storage condition of test material: room temperature

Test animals

Species:
rat
Strain:
other: Tif: RAIf rat, Sprague-Dawley derived
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source of animals: Ciba-Geigy Ltd., Animal Production, Sisseln, Switzerland
- Age at study initiation: 8 weeks
- Weight at study initiation (week -1): 261-323 g (males), 225-286 g (females)
- Fasting period before study: no
- Housing: individually in macrolon type 3 cages
- Diet: Nafag No. 890 Tox diet ad libitum
- Water: ad libitum
- Acclimation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22±3°C
- Humidity: 55±15%
- Air changes (per hr): approximately 15/hr
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From:19.10.1987 To: 16.11.1987

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on exposure:
TEST SITE
- Area of exposure: shaved dorsum
- % coverage: 10% body surface
- Type of wrap if used: gauze pad backed with aluminium foil secured around trunk with adhesive tape
- Time intervals for shavings or clipplings: clipped 24 h prior to administration and at weekly intervals during the test

REMOVAL OF TEST SUBSTANCE
- Washing (if done): cleaned with lukewarm water
- Time after start of exposure: exposure was for 6h per day for 5 days per week for 4 weeks

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0, 50, 200 or 1000 mg/kg bw/day
- Concentration (if solution): test material applied as supplied
- test site and gauze pad moistened with distilled water immediately before application


Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
6 hours per day
Frequency of treatment:
5 days per week for 4 consecutive weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 50, 200 and 1000 mg/kg bw/day
Basis:
nominal per unit body weight
No. of animals per sex per dose:
5
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale: based on the findings of previous studies

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily for mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

DERMAL IRRITATION (if dermal study): Yes
- Time schedule for examinations: daily, approximately 17 hours after removal of the dressing

BODY WEIGHT: Yes
- Time schedule for examinations: pre-test and subsequently at weekly intervals

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

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

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 4 weeks of treatment
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes, overnight
- How many animals: all survivors
- Parameters examined: erythrocyte count, haemoglobin, haematocrit, mean corpuscular volume, mean corpuscular haemoglobin, leucocyte count, differential leucocyte count, thrombocyte count, prothrombin time, red cell morphology

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: after 4 weeks of treatment
- Animals fasted: Yes, overnight
- How many animals: all survivors
- Parameters examined: glucose, urea, total protein, albumin, globulins, A/G ratio, sodium, potassium, calcium, inorganic phosphorus, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (all animals)
- the following organs were weighed: brain, heart, liver, kidneys, adrenals, thymus, ovaries/testes, spleen .

HISTOPATHOLOGY: Yes (all animals)
- the following tissues were examined microscopically: skin (treated and untreated area), mammary area, spleen, mesenteric lymph node, axillary lymph node, popliteal lymph node, sternum with bone marrow, femur with joint, skeletal muscle, trachea, lung, heart, aorta, submandibular salivary gland, liver, pancreas, oesophagus, stomach, small intestine, large intestine, kidneys, urinary bladder, prostate, seminal vesicle, testis, epididymis, uterus, ovary, pituitary gland, adrenal gland, thyroid with parathyroid gland, thymus, peripheral nerve, brain, spinal cord, eye with optic nerve, extraorbital lacrimal gland, any tissue with gross lesions
Statistics:
Univariate standard methods were applied

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
Food efficiency:
no effects observed
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:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: No systemic or local effects at highest dose tested.

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
Dermal administration of cloquintocet-mexyl was tolerated without any local or systemic effects at a limit dose of 1000 mg/kg bw/day. The NOAEL for systemic and local effects was 1000 mg/kg bw/day in this study
Executive summary:

Five male and 5 female Tif:RAIf (SPF) rats were subject to topical application of cloquintocet-mexyl at dose levels of 0 (control), 50, 200 or 1000 mg/kg bw/day for 6 hours per day, five days per week for four consecutive weeks. Mortality, clinical appearance and behaviour, signs of skin irritation, bodyweights, bodyweight changes, food consumption, haematology, blood biochemistry, organ weights, gross pathology and histopathology were assessed.

Dermal administration of cloquintocet-mexyl was tolerated without any local or systemic effects at a limit dose of 1000 mg/kg bw/day. The NOAEL for systemic and local effects was 1000 mg/kg bw/day.