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Description of key information

Guideline GLP acute toxicity studies are available for cloquintocet-mexyl technical (purity 91.6 or 96.7%) for the oral, inhalation and dermal routes of exposure. Data indicate that acute toxicity is expected to be low. Cloquintocet-mexyl  does not pose an acute hazard following oral (oral LD50 > 5000 mg/kg), skin contact (dermal LD50 > 2000 mg/kg) or acute inhalation (4 hour LC50 > 935 mg/m3) exposures and does not warrant classification for acute toxicity.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
09.02.1987 to 03.03.1987
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other: GLP compliant, guideline study, available as unpublished report, no restrictions, fully adequate for assessment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 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Tif RAIf (SPF), Sprague-Dawley derived
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Ciba-Geigy Ltd, Animal Production, Sisseln, Switzerland
- Age at study initiation: 7 - 8 weeks
- Weight at study initiation: 162-212g
- Fasting period before study: Not specified
- Housing: conventional laboratory cages
- Diet (e.g. ad libitum): Not specified
- Water (e.g. ad libitum): Not specified
- Acclimation period: 5 days


IN-LIFE DATES: From: 09.02.1987 To: 03.03.1987
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Details on oral exposure:
The test material was admixed to distilled water containing 0.5% CMC and 0.1% polysorbate 80.
The dosing solution was prepared immediately before administration. The stability was therefore not checked. 10 ml of the solution per kg body weight were applied by gastric intubation. The highest dose group received 20 ml/kg body weight due to the poor solubility of the test material.
Doses:
2000 or 5000 mg/kg bw
No. of animals per sex per dose:
Five per sex per group
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: obsrved hourly for 5 h on day of dosing and twice daily subsequently. Bodyweights recorded pre-test and at weekly intervals
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
Not applicable - median lethal dose exceeded Guideline limit dose of 2000 mg/kg bw
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 - ca. 5 000 mg/kg bw
Remarks on result:
other: None of the rats dosed at 2000 mg/kg bw died. One of four males dosed at 5000 mg/kg bw died and two of five females.
Mortality:
None of the rats dosed at 2000 mg/kg bw died. One of four males dosed at 5000 mg/kg bw died and two of five females at the higher dose level.
Clinical signs:
Dyspnea, exophthalmus, ruffled fur and curved body positions were observed in all animals. Recovery was evident by day 13.
Body weight:
No information
Gross pathology:
No macroscopic abnormalities noted among rats dosed at 2000 mg/kg bw
Haemorrhagic lungs and stomachs for one male and two females dosed at 5000 mg/kg bw. Intestinal dilation noted for one female
Other findings:
None

One male dosed at 5000 mg/kg bw died on day 2, the two females decedents died on days 1 and 3.

Dose

Mortality

Day of death

2000 mg/kg
5000 mg/kg

0/ 5
1 / 4


day 2

2000 mg/kg
5000 mg/kg

0 / 5
2 / 5


day 1, 3

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
LD50 greater than 5000 mg/kg bw
Executive summary:

Groups of Tif RAIf (SPF), Sprague-Dawley derived rats were dosed with CGA185072 technical, purity 91.6% at doses of 2000 or 5000 mg/kg test material in 0.5% aqueous CMC and 0.1% polysorbate 80.The animals were assessed daily for the following 14 days for any signs of systemic toxicity and their bodyweights recorded at intervals throughout the study.After 14 days surviving rats were sacrificed and subjected to gross necropsy as were those rats which died spontaneously. Dyspnea, exophthalmus, ruffled fur and curved body positions were observed in all animals. At 5000 mg/kg bw one male and two females died. Surviving animals recovered within 13 days. At necropsy, no macroscopic abnormalities were found at 2000 mg/kg. At 5000 mg/kg one male and 2 females showed hemorrhagic lungs and a hemorrhagic stomach. The small intestine of one female was dilated.

The acute oral LD50 of CGA185072 tech. is greater than 5000 mg/kg in male and female rats.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
12 March 1987 to 26 May 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 403 (Acute Inhalation Toxicity)
Deviations:
yes
Remarks:
Using the available equipment it was not possible to generate an atmosphere with a concentration of greater than 935 ug/m3
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation: 6-8 weeks
- Weight at study initiation: circa 200 g
- Fasting period before study: None specified
- Housing: Conventional laboratory cages
- Diet (e.g. ad libitum): not specified
- Water (e.g. ad libitum): Not specified
- Acclimation period: 5 days

IN-LIFE DATES: From: 12.03.1987 To: 26.05.1987
Route of administration:
inhalation: dust
Type of inhalation exposure:
nose only
Vehicle:
other: unchanged (no vehicle)
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: aerosol generated using Wright dust generator
- Exposure chamber volume: not specified
- Method of holding animals in test chamber: nose-only exposure restraint tubes
- Source and rate of air: flow rate for air supply was 25 L/min
- Method of conditioning air: not specified
- System of generating particulates/aerosols: Wright dust generator
- Method of particle size determination: two samples taken duriing exposure using Cascade impactor
- Treatment of exhaust air: not specified
- Temperature, humidity, pressure in air chamber: temperature - 22.0 +/- 0.1C; Humidity 42+/-2% RH

TEST ATMOSPHERE
- Samples taken from breathing zone: yes

VEHICLE
- Composition of vehicle (if applicable): air
- Concentration of test material in vehicle (if applicable): Nominal concentration = 935 mg/m3 and gravimetrically determined concentration = 935+/-482 mg/m3

TEST ATMOSPHERE (if not tabulated)
- Particle size distribution: see tabulated results



Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
ca. 4 h
Concentrations:
The maximum possible concentration that could be achieved for this test material under the conditions of the test was 935 mg/m3. From gravimetric analysis it was determined that in excess of 70% of the dust generated was respirable.
No. of animals per sex per dose:
5
Control animals:
yes
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: observed twice daily for 14 days. Bodyweights recorded pre-test and at weekly intervals subsequently
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, food consumption
Statistics:
No statistical analysis as the median lethal dose concentration exceeded the maximum atmosphere concentration that could be generated.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 935 mg/m³ air
Based on:
other: nominal concentration
Exp. duration:
4 h
Remarks on result:
other: One male only (of five males and five females) died.
Mortality:
One male died immediately after removal from the exposure chamber
Clinical signs:
other: Dyspnoea, lethargy and brown stains around the snout were observed in most treated animals
Body weight:
All animals gained weight during the study
Gross pathology:
The stomach of the rat which died was distended with gas. There were no other macroscopic abnormalities observed
Other findings:
None

Sex

Dose

Mortality

Male

Control group

935 mg/m3

0 / 5

1 / 5

Female

Control group

935 mg/m3

0 / 5

0 / 5

 

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The inhalation LC50 in rats was greater than 935 mg/m3 (the maximum practical atmosphere concentration that could be generated).
Executive summary:

CGA185072 technical, purity 91.6%, batch P. 607001/002, was administered by inhalation exposure to Wistar rats 6 -8 weeks old at study initiation. There were 5 males and 5 females in the treated group and a further group of controls. An atmosphere was generated by a Wright dust generator, which scraped the test material from the surface of a compressed powder in a stream of air (flow rate 25 l/min). The maximum concentration which could be generated was 935 mg/m3. The animals were exposed for 4 hours in a nose-only chamber. Animals were observed twice daily for 14 days. Body weights and food consumption were recorded pretest and weekly thereafter. After 14 days surviving animals were sacrificed and subjected to gross necropsy. Lung weights were recorded. One male died immediately following completion of the exposure period. The remaining nine rats survived. Clinical observations included dyspnoea, lethargy and brown stains around the snout. All rats gained weight and no necropsy abnormalities were seen. The inhalation LC50 was greater than 935 mg/m3.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LC50
Value:
935 mg/m³

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
17 March 1987 to 31 March 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 402 (Acute Dermal Toxicity)
Deviations:
no
Principles of method if other than guideline:
Not applicable
GLP compliance:
yes (incl. certificate)
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Tif RAIf rats
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: not specified
- Age at study initiation:7 - 8 weeks
- Weight at study initiation: 210 - 254 g
- Fasting period before study: not applicable
- Housing: not specified
- Acclimation period: not specified

IN-LIFE DATES: From: 17.03.1987 To: 31.03.1987
Type of coverage:
semiocclusive
Vehicle:
other: 0.5% carboxymethylcellulose and 0.1% polysorbate 80 in distilled water
Details on dermal exposure:
The application site was covered with gauze pad which was held in place for 24 hours with a tape
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: animals weighed at weekly intervals
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, and dermal reactions
Statistics:
No statistical analysis needed. LD50 estimated from limit dose administration
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No effects at limit dose level
Mortality:
No deaths occurred following topical administration of a dose of 2000 mg/kg bw
Clinical signs:
Slight dyspnoea, curved body position and slight sedation were reported. Complete recovery was reported within 12 days after treatment
Body weight:
Bodyweights not reported
Gross pathology:
No macroscopic abnormalities noted during necropsy
Other findings:
Not applicable

The dermal LD50 was found to exceed the limit dose of 2000 mg/kg bw administered in this study.

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The dermal LD50 for rats determined for both sexes, was greater than 2000 mg/kg bw
Executive summary:

Test material: CGA185072 technical, purity 91.6%, batch P. 607001/002. Cloquintocet-mexyl was administered as a suspension in 0.5% carboxymethylcellulose and 0.1% polysorbate 80 in distilled water, applied to the shaved dorsum of five male and five female Tif RAIf rats at a single dose level of 2000 mg/kg body weight. The application site was covered with gauze pad which was held in place for 24 hours with a tape. The animals were observed for symptoms of toxicity and mortality for 14 days and then subjected to necropsy procedures. No mortality occurred. Clinical signs of reaction to treatment were limited to commonly observed effects including dyspnoea, curved body position and slight sedation. Recovery was complete within 12 days. At necropsy there were no deviations from normal morphology. The dermal LC50 was greater than 2000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

Non-human information

Acute oral toxicity data for cloquintocet-mexyl indicate an oral LD50 value in rats of > 5000 mg/kg (Hartmann HR, 1987). The acute oral toxicity in mice is > 2000 mg/kg (Hartmann HR, 1991). A four hour acute inhalation toxicity study in rats showed no acute inhalation toxicity showed at the highest achievable concentration of 935 mg/m3 (Jackson GC, 1987). An acute dermal toxicity study gave an acute dermal LD50 value in rabbits of > 2000 mg/kg (Hartmann HR, 1987).  

Human information

There are no studies on the oral, inhalation or dermal toxicity in humans for cloquintocet-mexyl.


Justification for selection of acute toxicity – oral endpoint
The acute toxicity study in the rat study has been selected, the study in the mouse also did not show adverse effects at the corresponding limit dose (i.e. 2000 mg/kg bw)

Justification for selection of acute toxicity – inhalation endpoint
Only one study available

Justification for selection of acute toxicity – dermal endpoint
Only one study available

Justification for classification or non-classification

There are sufficient data on cloquintocet-mexyl to indicate that the substance is of low acute toxicity by the oral, dermal and inhalation routes and does not warrant classification for acute toxicity:

- under Directive 67/548/EEC, as amended for the 28th time in Directive 2001/59/EC, Annex VI, 3.2.

- under Regulation (EC) 1272/2008, Annex I, Part 3, 3.1.2.