Registration Dossier
Registration Dossier
Diss Factsheets
Use of this information is subject to copyright laws and may require the permission of the owner of the information, as described in the ECHA Legal Notice.
EC number: 619-447-3 | CAS number: 99607-70-2
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data

Repeated dose toxicity: oral
Administrative data
- Endpoint:
- chronic 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:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 1 992
- Report date:
- 1992
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- other: OECD Guideline 451 (Carcinogenicity Studies)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: EPA OPP 83-5 (Combined Chronic Toxicity / Carcinogenicity)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- other: Japan, 59 Nohsan No. 4200
- Deviations:
- no
- Principles of method if other than guideline:
- Not applicable
- GLP compliance:
- yes
- Limit test:
- no
Test material
- 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 technical
- Analytical purity: 91.6%
- Physical state: solid
- Storage condition of test material: room temperature
Constituent 1
Test animals
- Species:
- rat
- Strain:
- other: Tif: RAIf (SPF)
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source of animals: Ciba-Geigy Limited, Animal Production, CH-4332 Stein, Switzerland.
- 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
Administration / exposure
- 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
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 ppm
- Remarks:
- Negative control
- Dose / conc.:
- 10 ppm
- Remarks:
- nominal in diet
- Dose / conc.:
- 100 ppm
- Remarks:
- nominal in diet
- Dose / conc.:
- 1 000 ppm
- Remarks:
- nominal in diet
- Dose / conc.:
- 2 000 ppm
- Remarks:
- 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
Examinations
- 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.
Results and discussion
Results of examinations
- 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
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- 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.
- Histopathological findings: neoplastic:
- no effects observed
Effect levels
open allclose all
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 100 ppm
- Based on:
- test mat.
- Sex:
- 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
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 4.33 mg/kg diet
- Based on:
- test mat.
- Sex:
- female
- Basis for effect level:
- histopathology: non-neoplastic
Target system / organ toxicity
- Key result
- Critical effects observed:
- yes
- Lowest effective dose / conc.:
- 1 000 ppm
- System:
- endocrine system
- Organ:
- thyroid gland
- Treatment related:
- yes
- Dose response relationship:
- yes
- Relevant for humans:
- yes
Any other information on results incl. tables
Table 2: Test compound consumption: The average test article intake based on nominal and actual dietary concentrations
Dose of test material |
Test article intake |
Test article intake |
10 ppm |
m: 0.387 mg/kg |
m: 0.365 mg/kg |
100 ppm |
m: 3.947 mg/kg |
m: 3.773 mg/kg |
1000 ppm |
m: 39.10 mg/kg |
m: 36.36 mg/kg |
2000 ppm |
m: 78.56 mg/kg |
m: 73.40 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 |
Applicant's summary and conclusion
- 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:
The chronic repeated dose toxicity of the substance to the rat via the oral route was studied under GLP to OECD TG 451. 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 bw/day in males and females respectively.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
