Registration Dossier

Administrative data

Description of key information

Repeated dose toxicity has been investigated in oral sub-chronic and chronic studies in rats, mice and dogs and in a sub-acute dermal toxicity study in rats. There was no evidence of specific target organ toxicity in any of the studies that would warrant classification or labelling for this end-point.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
20 March 1989 to 08 April 1991
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other: GLP compliant, guideline study, available as unpublished report, no restrictions, fully adequate for assessment
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
other: OECD Guideline 451 (Carcinogenicity Studies)
Deviations:
no
Qualifier:
according to
Guideline:
other: EPA OPP 83-5 (Combined Chronic Toxicity / Carcinogenicity)
Deviations:
no
Qualifier:
according to
Guideline:
other: Japan, 59 Nohsan No. 4200
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Tif: RAIf (SPF)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: approximately 5 weeks
- Weight at week -1: 74.85-115.4 g (males), 76.33-107.4 g (females)
- Housing: 5 per sex in macrolon type 4 cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 11 days

ENVIRONMENTAL CONDITIONS
- Temperature: 22±2°C
- Humidity: 55±10%
- Air changes: 16-20 per hr
- Photoperiod: 12 hrs dark / 12 hrs light

IN-LIFE DATES: From: 20 March 1989 To: 08 April 1991
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): every 4 weeks
- Mixing appropriate amounts with (Type of food): certified standard diet (Nafag No. 890 Tox)
- Storage temperature of food: room temperature

VEHICLE- Justification for use and choice of vehicle (if other than water): not applicable
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Pretest analyses confirmed stability of the diet preparations at room temperature over 35 days. The analysis of the first batch showed that food mixes were homogeneous (-9% to +7% of mean value). The analytically determined concentrations generally ranged from 84.8 to 104.6% of the nominal concentrations. The mean concentrations were 94.2%, 95.6 %, 93.0% and 93.2% of the nominal values in groups 2 to 5, respectively. The analytical data thus indicated that the mixing procedure was adequate and that the variance between nominal and actual dosage was generally acceptable.
Duration of treatment / exposure:
Two years
Frequency of treatment:
Continuous in diet
Remarks:
Doses / Concentrations:
10, 100, 1000 or 2000 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
80 per sex per group; 50 animals per sex/group for carcinogenicity evaluation; 10 animals for clinical chemistry, haematology and urinalysis; 10 additional animals for haematology only; 10 animals for interim sacrifice after 12 months
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: based on the results of previous acute and repeat dose studies
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily for signs of toxicity and mortality

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: at least weekly

BODY WEIGHT: Yes
- Time schedule for examinations: pretest and weekly during the first three months. Thereafter, the weight was recorded monthly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):- Food consumption for each animal determined and mean diet consumption calculated as g food/kg body weight/week: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
- Food consumption per cage were recorded pretest and weekly during the first three months. Thereafter, the weight was recorded monthly

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

WATER CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations: monthly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule/dose groups for examinations: eye examinations were conducted in control and high dose group animals pretest, after 26, 52, 78 weeks and at the end of the treatment period. Males and females from intermediate groups were examined prior to terminal sacrifice

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 13, 26, 52, 78 and 105 weeks
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes
- How many animals: 20/sex/group
- 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 13, 26, 52, 78 and 105 weeks
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes
- How many animals: 10/sex/group
- Parameters examined: glucose, urea, creatinine, total bilirubin, total protein, albumin, globulins, A/G ratio, cholesterol, sodium, potassium, calcium, chloride, inorganic phosphorus, aspartate aminotransferase, alanine aminotransferase, alkaline phosphatase, gamma-glutamyl transpeptidase

URINALYSIS: Yes
- Time schedule for collection of urine: pretest and after 13, 26, 52, 78 and 104 weeks
- Metabolism cages used for collection of urine: Yes -
Animals fasted: Yes (no access to food or water)
- Parameters examined: volume, colour, relative density, pH, protein, glucose, ketones, bilirubin, blood, urobilinogen, urine sediment

NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes (all animals)
- the following organs were weighed: brain, liver, kidneys, adrenals, gonads, spleen (after one year of treatment). At the end of the 2 year period, the thyroid and pituitary glands were also weighed

HISTOPATHOLOGY: Yes (all animals)
- the following tissues were examined microscopically: skin, mammary area, spleen, mesenteric lymph node, axillary 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
Other examinations:
At autopsy, fat samples were taken to investigate the accumulation of cloquintocet-mexyl after 12 and 24 months
Statistics:
Univariate standard methods were applied to the data. Each group was compared to controls by Lepage’s two sample test and tested for trends by Jonckheere’s test for ordered alternatives.
Clinical signs:
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):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
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:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
HISTOPATHOLOGY: NON-NEOPLASTIC
Histopathology did not reveal any inflammatory or degenerative changes which could be related to the test article. Lymphoid hyperplasia of the thymus was diagnosed in some males. The statistical trend analysis indicated a significant, treatment-related effect in the top dose group. There was no effect on thymic neoplastic lesions. Among the females, increased incidences of thyroid gland follicle hyperplasia were found. The changes were graded as slight in all cases with no dose-related trend in severity. Statistical analysis indicated a significant effect in the animals treated at 1000 ppm and above. Hyperplasia of the thyroid follicle epithelium is known to occur spontaneously in the rat strain used and the incidence in the 100 ppm dose group was comparable to the incidence usually found in control animals of this rat strain. In the absence of a dose relationship, the observation made in the 10 ppm group was considered to be an outlier and thus incidental. Furthermore there was no correlation between thyroid hyperplasia and proliferative lesions of the pituitary gland.
Dose descriptor:
NOAEL
Effect level:
100 ppm
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Hyperplastic changes in the thymus of males at 2000 ppm and of the thyroid gland (follicular epithelial hyperplasia) in females at 1000 and 2000 ppm
Dose descriptor:
NOAEL
Effect level:
3.77 mg/kg diet
Based on:
test mat.
Sex:
male
Dose descriptor:
NOAEL
Effect level:
4.33 mg/kg diet
Based on:
test mat.
Sex:
female
Critical effects observed:
not specified

Table 2: Test compound consumption: The average test article intake based on nominal and actual dietary concentrations

Dose of test material

Test article intake
(based on nominal concentrations)

Test article intake
(based on actual concentrations)

10 ppm

m: 0.387 mg/kg
f: 0.451 mg/kg

m: 0.365 mg/kg
f: 0.425 mg/kg

100 ppm

m: 3.947 mg/kg
f: 4.530 mg/kg

m: 3.773 mg/kg
f: 4.331 mg/kg

1000 ppm

m: 39.10 mg/kg
f: 44.35 mg/kg

m: 36.36 mg/kg
f: 41.25 mg/kg

2000 ppm

m: 78.56 mg/kg
f: 87.49 mg/kg

m: 73.40 mg/kg
f: 81.54 mg/kg

Table 3: Histopathological findings in the chronic rat study with cloquintocet-mexyl

0

10

100

1000

2000

Historic control values

Males

Thymus

- Lymphoid hyperplasia

- severity

 

0

 

0

 

1

1

 

2

1

 

5

2

- Lymphoma

0

2

0

1

0

Thyroid

- hyperplasia follicular epithelium

 

2

 

6

 

7

 

5

 

3

Females

Thymus

- Lymphoid hyperplasia

 

2

 

2

 

0

 

0

 

0

Thyroid

- hyperplasia follicular epithelium

- severity

 

0

0

 

8

1.4

 

5

1.6

 

10

1.5

 

11

1.4

 

0-4/76

Conclusions:
The effects of toxicological significance were hyperplastic changes in the thymus of males treated at 2000 ppm and of the thyroid gland in the females treated at 1000 and 2000 ppm. The NOAEL was 100 ppm, equivalent to a mean daily dose of 3.77 mg/kg bw/day in males and 4.33 mg/kg bw/day in females.
Executive summary:

Groups of 80 male and 80 female Tif:RAIf (SPF) rats were fed diet containing 0 (control), 10, 100, 1000 or 2000 ppm cloquintocet-mexyl. Mortality, clinical appearance and behaviour, bodyweights, bodyweight changes, food consumption, ophthalmology, haematology, blood and urine biochemistry, organ weights, gross pathology and histopathology were assessed. Ten animals per group per sex were killed after 52 weeks of treatment for interim examination.

Cloquintocet-mexyl was well tolerated at dietary concentrations up to 2000 ppm (73.4/81.5 mg/kg bwt/day in males and females respectively). The effects of toxicological significance were hyperplasic changes in the thymus of males at 2000 ppm and of the thyroid gland in females at 1000 and 2000 ppm.

Based on the histopathological findings of the thyroid follicular epithelial hyperplasia at 1000 ppm in females the NOAEL was 100 ppm, equivalent to a mean daily dose of 3.77/4.33 mg/kg bwt/day in males and females respectively.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
4.33 mg/kg bw/day
Study duration:
chronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
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
Reason / purpose:
reference to same study
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
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
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
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
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
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
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.
Critical effects observed:
not specified
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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat

Repeated dose toxicity: dermal - local effects

Link to relevant study records
Reference
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
Reason / purpose:
reference to same study
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
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
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
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
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
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
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.
Critical effects observed:
not specified
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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Repeated dose toxicity has been evaluated in key subchronic and chronic dietary toxicity studies in the rat, mouse and dog. Based on the intended use as a plant protection product exposure of humans is most likely to arise from residues in food and hence this is the most relevant route of exposure for mammalian toxicity studies.

In the rat the key study addressing subchronic exposures (90 day dietary exposure; Fankhauser, 1989) showed increased water consumption, pathological effects in the bladder and kidney and associated clinical chemistry findings at high doses (1000 ppm and above). The NOAEL was 150 ppm, equivalent to a mean daily intake of 9.66 mg/kg in males and 10.2 mg/kg in females.

Following chronic dietary exposure (2 year study; Fankhauser, 1992) toxicologically significant effects were hyperplastic changes in the thymus of males at 2000 ppm (approximately 73 mg/kg/day in males; 81 mg/kg/day in females) and of the thyroid gland (follicular epithelial hyperplasia) in females at 2000 ppm and 1000 ppm (approximately 36 mg/kg/day in males; 41 mg/kg/day in females). No treatment-related effects were seen at 100 ppm (3.77 or 4.33 mg/kg/day in males and females, respectively).

Dermal administration to rats was tolerated without any local or systemic effects at a limit dose of 1000 mg/kg/day (6 hrs/day, 5 days/week for 4 weeks) (Schneider, 1988).

In the mouse subchronic and chronic toxicity studies treatment-related findings were limited to increased water consumption and chronic inflammatory changes in the urinary bladder at 18 months. The subchronic NOAEL was 2400 ppm, equivalent to 357 and 470 mg/kg/day in males and females, respectively (Fankhauser, 1989) and the chronic NOAEL was 1000 ppm (111 or 102 mg/kg/day in males and females).

Diets containing concentrations of cloquintocet-mexyl of 15000 ppm and greater were unpalatable to dogs leading to significant body weight loss and a number of effects considered to result from general stress and emaciation. In the subchronic toxicity study, liver cell necrosis in one female and thymic atrophy in one male at 1000 ppm (30.2 mg/kg/day) were both considered to be treatment-related (Allen, 1989). However, 1500 ppm (approximately 44 mg/kg/day) administered for 52 weeks was without effect (Corney, 1991).


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
The combined chronic toxicity/carcinogenicity study in the rat has been selected. It is considered as the most relevant repeated dose toxicity study.

Justification for classification or non-classification

No evidence of significant target organ toxicity was seen in repeat dose oral studies in rats, mice and dogs of up to 1 year duration or in a rabbit repeat dose dermal toxicity study at dose levels below regulatory thresholds. No classification is necessary in relation to repeated dose toxicity:

- under Directive 67/548/EEC, as amended for the 28th time in Directive 2001/59/EC.

- under Regulation (EC) 1272/2008.