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EC number: 451-060-3 | CAS number: 122886-55-9
- 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
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- Flash point
- Auto flammability
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- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
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- Endpoint summary
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- Environmental data
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- 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
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- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
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- Genetic toxicity
- Carcinogenicity
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Endpoint summary
Administrative data
Description of key information
A repeated dose 28-day oral toxicity study in rats performed according to EC guideline B7 with neurotoxicological investigation according to OECD 424 and GLP principles is available, the NOAEL was determined to be 1000 mg/kg bw/day.
Key value for chemical safety assessment
Repeated dose toxicity: via oral route - systemic effects
Link to relevant study records
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- October-November 2003
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- OECD Guideline 424 (Neurotoxicity Study in Rodents)
- Version / remarks:
- 1997
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Version / remarks:
- 1996
- Deviations:
- no
- Qualifier:
- equivalent or similar to guideline
- Guideline:
- other: EPA, Guideline 799, 9620-62-158, 1997
- Deviations:
- no
- GLP compliance:
- yes
- Limit test:
- no
- Species:
- rat
- Strain:
- Sprague-Dawley
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Janvier, Le Genet-Saint-Isle, France
- Age at study initiation: approximately 6 weeks old
- Weight at study initiation: 196 g to 227 g (males) and 172 g to 191 g (females)
- Fasting period before study: no
- Housing: individually housed in suspended wire-mesh cages, with autoclaved sawdust in metal tray under each cage
- Diet: ad libitum A04 C pelleted maintenance diet, batch No. 30905 (SAFE, Villemoisson, Epinay-sur-Orge, France)
- Water: ad libitum tap water
- Acclimation period: 7 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2°C
- Humidity (%): 50 ± 20%
- Air changes (per hr): approximately 12 cycles of filtered, non-recycled air
- Photoperiod (hrs dark / hrs light): 12/12
IN-LIFE DATES: From: 16 October 2003 To: 21 November 2003 - Route of administration:
- oral: gavage
- Vehicle:
- other: 0.5% aqueous methylcellulose solution
- Details on oral exposure:
- PREPARATION OF DOSING SOLUTIONS:
The test item was administered as a suspension in the vehicle.
The test item was ground to fine powder using a mortar and pestle, suspended in the vehicle to concentrations of 30, 90 and 200 mg/mL and homogenized by magnetic stirrer.
The test item dosage forms were prepared on a weekly basis and stored at +4 °C and protected from light prior to use.
VEHICLE
- Amount of vehicle (if gavage): 5 mL/kg/day
- Batch no. (if required): 112K0988 - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Homogeneity:
Before the treatment period, two dosage forms were prepared, under conditions representative of those of the study: a dosage form at 1 mg/mL and a dosage form at 200 mg/mL. From each dosage form, duplicate samples were taken at three different levels of the container (top, middle, bottom) and analyzed for concentration of the test item to evaluate the homogeneity on the day of preparation.
Stability:
Each dosage form prepared for homogeneity analysis was sampled after 0 (just after preparation), 4 and 9 days' storage at +4°C. Each sample taken was analyzed as soon as possible after sampling. In each case, the mean result of the homogeneity analysis was taken as the initial value for the stability test.
Concentration:
The concentration of samples taken from each dosage form (including the control) prepared for use in weeks 1 and 4 was determined. - Duration of treatment / exposure:
- 29 days
- Frequency of treatment:
- daily
- Remarks:
- Doses / Concentrations:
0, 150, 450, 1000 mg/kg bw/day
Basis:
actual ingested - No. of animals per sex per dose:
- 5
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale: The dose-levels were selected on the basis of the results of a 7-day range-finding toxicity study by oral route performed in the same species (CIT/Study No. 26491 TSR). In this study, there were no mortality, clinical signs or effects on body weight and food consumption at any dose-level (150, 450 and 1000 mg/kg/day). No treatment-related necropsy findings were noted.
- Observations and examinations performed and frequency:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once before the beginning of the treatment period and then once a week until the end of the study
BODY WEIGHT: Yes
- Time schedule for examinations: once before allocation of the animals to groups, on the first day of treatment, and then once a week until the end of the study
FOOD CONSUMPTION: yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
FOOD EFFICIENCY: No
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: part of the FOB
- Dose groups that were examined: all
HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the treatment period
- Anaesthetic used for blood collection: Yes (isoflurane)
- Animals fasted: Yes (at least 14 hours)
- How many animals: all surviving animals
- Parameters checked according to guidelines.
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the treatment period
- Animals fasted: Yes (at least 14 hours)
- How many animals: all surviving animals
- Parameters checked according to guidelines.
URINALYSIS: No
NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: at the end of the treatment period
- Dose groups that were examined: all
- Battery of functions tested: sensory activity / grip strength / motor activity (see also under 'other examinations'
Additional: rectal temperature (Day 26) - Sacrifice and pathology:
- GROSS PATHOLOGY: Yes (according to guidelines)
HISTOPATHOLOGY: Yes (according to guidelines) - Other examinations:
- All animals were evaluated once at the end of the treatment period, including a detailed clinical examination, measurement of reactivity to manipulation or to different stimuli and motor activity.
The animals were randomized. All animals were observed in the cage, in the hand and in the standard arena.
The following parameters were assessed and graded:
"touch escape" or ease of removal from the cage, in the hand: fur appearance, salivation, lachrymation, piloerection, exophthalmos, reactivity to handling, pupil size (presence of myosis or mydriasis), in the standard arena (2-minute recording): grooming, palpebral closure, defecation, urination, tremors, twitches, tonic and clonic convulsions, gait, arousal (hypo- and hyper-activity), posture, stereotypy, behavior, breathing, ataxia and hypotonia.
Then, the following parameter measurements, reflexes and responses were recorded:
touch response,
forelimb grip strength,
pupillary reflex,
visual stimulus response,
auditory startle reflex,
tail pinch response,
righting reflex,
landing foot splay,
rectal temperature.
Finally, motor activity of all animals was measured once by automated infra-red sensor equipment (not validated) over a 15-minute period. - Statistics:
- see attached figure
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- effects observed, treatment-related
- Description (incidence and severity):
- mid and high dose females: lower mean bw gain first week and higher mean bw gain third week
- Food consumption and compound intake (if feeding study):
- effects observed, treatment-related
- Description (incidence and severity):
- lower mean food consumption first week in 450 and 1000 mg/kg bw/day groups.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- effects observed, treatment-related
- Description (incidence and severity):
- Higher cholesterol level was noted in females given 450 and 1000 mg/kg/day, together with higher levels of triglycerides in these groups
- Urinalysis findings:
- not examined
- Behaviour (functional findings):
- no effects observed
- 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:
- no effects observed
- Details on results:
- CLINICAL SIGNS AND MORTALITY: no mortality; chromodacryorrhea was observed in 1/5 and 3/5 males given 450 and 1000 mg/kg/day, respectively, during the second part of the treatment period. Although this sign only appeared in intermediate- and high-dose groups, it was seen in some ·individuals, not associated with other clinical signs and it is a clinical observation commonly reported in untreated laboratory rats; consequently, it is considered not test substance related.
BODY WEIGHT AND WEIGHT GAIN: overall mean body weight gain was similar in control and treated animals; however, lower mean body weight gain was noted in females given 450 and 1000 mg/kg/day during the first week of treatment (12 and 8 grams in 450 and 1000 groups, respectively, vs 23 grams in controls) whereas moderately higher mean body weight gain was recorded during the third week of treatment in the same female groups (20 and 25 grams, respectively in 450 and 1000 groups, respectively, vs 9 grams in controls). These effects on body weight gain are considered test substance related. However, as the observed effect on body weight gain was transient and final mean body weight gain was not affected compared to controls, this effect is considered not toxicologically relevant.
FOOD CONSUMPTION: statistically significant slightly lower mean food consumption was noted in females given 1000 mg/kg/day during the first week of treatment (15.5 vs. 19.9 g/animal/day in controls). Although these effects on food consumption are considered test substance related, this effect was restricted to 1 week in the dosing period and overall mean food consumption was similar in control and treated animals, and the lower mean food consumption had no effect on overall mean body weigh gain.
HAEMATOLOGY: no test substance related differences between control and treated animals. The observed higher mean prothrombine time in males given 150 mg/kg bw/day is considered not toxicologal relevant, as this effect was not observed at higher dose levels.
CLINICAL CHEMISTRY: higher mean cholesterol level in females given 450 and 1000 mglkg/day (2. 7 and 2.5 mmol/L,
respectively, vs. 1.9 mmol/L in controls, together with higher levels of triglycerides (0.62 vs 0.38 mmol/L in dosed groups versus controls); As these efffects were not observed in males, are not statistically significant at the high dose-level, and absence of a dose-relationship, these effects are considered not toxicologically relevant. The observed slightly lower levels of protein in high dose males and calcium in mid dose females are considered not toxicologically relevant.
NEUROBEHAVIOUR: FOB: There were no treatment-related changes in autonomic, physiological or neurotoxicological parameters. Motor activity was unaffected by treatment with the test item.
ORGAN WEIGHTS: no treatment related effects on organ weights
GROSS PATHOLOGY: no treatment related necropsy findings were observed
HISTOPATHOLOGY: NON-NEOPLASTIC no test substance related changes have been observed
Additonal: no effect on rectal temperature (Day 26) - Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (actual dose received)
- Based on:
- test mat.
- Sex:
- male/female
- Remarks on result:
- other: No toxicologically relevant adverse effects up to and including the highest dose tested.
- Critical effects observed:
- not specified
- Conclusions:
- In a 28-day repeated dose oral toxicity study with rats, KY-UN did not result in toxicologically relevant adverse effects. Based on these observations, the NOAEL for KY-UN is 1000 mg/kg bw/day.
- Executive summary:
Sprague-Dawley rats were administered KY-UN daily by gavage at dose levels of 0, 150, 450 or 1000 mg/kg bw/day for 4 weeks according to EC guideline B7 with neurotoxicological investigation according to OECD 424. Formulation analysis confirmed that formulations were prepaed accurately and homogenously, and were stable under the conditions used in the study.
Transient effects on food consumption and on mean body weight gain was observed in mid and high dose females, but had no effect on overall mean food consumtion and on overall mean body weight gain. Slightly higher mean cholesterol level in females given 450 and 1000 mglkg/day and slightly higher levels of triglycerides were not observed in males. In the absence of clear statistical significancy and absence of a dose-relationship, these effects are considered not toxicologically relevant.
Based on the absence of toxicologically relevant adverse effects in this study, the NOAEL for KY-UN is 1000 mg/kg bw/day.
Reference
homogeneity:
mean values were between 0 and -4% of nominal values, with a coefficicent variation (100 x SD/mean) of 4 and 10%
stability:
deviation on day 9 from initial value on day 0 was 5 to 9%
deviations from nominal values in administered dosage forms were 1 to 4% in week 1 and 0 to 6% in week 4
Accuracy was 97 to 102% (with precision, CV% of 5 -10%)
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: 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
Endpoint conclusion
- Endpoint conclusion:
- no study available
Repeated dose toxicity: dermal - local effects
Endpoint conclusion
- Endpoint conclusion:
- no study available
Additional information
Sprague-Dawley rats were administered KY-UN daily by gavage at dose levels of 0, 150, 450 or 1000 mg/kg bw/day for 4 weeks according to EC guideline B7 with neurotoxicological investigation according to OECD 424. Formulation analysis confirmed that formulations were prepared accurately and homogenously, and were stable under the conditions used in the study.
Transient effects on food consumption and on mean body weight gain was observed in mid and high dose females, but had no effect on overall mean food consumption and on overall mean body weight gain. Slightly higher mean cholesterol level in females given 450 and 1000 mg/kg/day and slightly higher levels of triglycerides were observed in males. In the absence of clear statistical significancy and absence of a dose-relationship, these effects are considered not toxicologically relevant.
Based on the absence of toxicologically relevant adverse effects in this study, the NOAEL for KY-UN is 1000 mg/kg bw/day.
Justification for classification or non-classification
Based on the available information on the substance KY-UN, the substance does not have to be classified for oral repeated dose toxicity according to Regulation (EC) no. 1272/2008 and its amendments.
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