Acetic acid, 2-[(5-chloro-8-quinolinyl)oxy]-, 1-methylhexyl ester

Repeated dose toxicity: dermal

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other: GLP compliant, guideline study, available as unpublished report, no restrictions, fully adequate for assessment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 for cross-reference:

reference to same study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1988

Report date:

1988

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

Deviations:

yes

Remarks:

occlusive dressing used

Test guideline 2

Qualifier:

according to guideline

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

Test material information

Constituent 1

Reference substance name:

heptan-2-yl [(5-chloroquinolin-8-yl)oxy]acetate

EC Number:

619-447-3

Cas Number:

99607-70-2

Molecular formula:

C18H22ClNO3

IUPAC Name:

heptan-2-yl [(5-chloroquinolin-8-yl)oxy]acetate

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 or test system 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.