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Diss Factsheets

Administrative data

Description of key information

The acute oral study was performed according to OECD Guideline 423 and GLP principles and the acute dermal study was performed according to OECD Guideline 402 and GLP principles. Based on the results, the oral and dermal LD50 of KY-EU in rats were establised to exceed 2000 mg/kg bw.

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:
September 03 - 26, 2002
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
other: Sprague-Dawley Rj: SD (IOPS Han)
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Source: Janvier, Le Genest-Saint-Isle, France
- Age at study initiation: approx. 6 weeks old
- Weight at study initiation: mean body weight 181 ± 6 g for the males and 175 ± 6 g for the females
- Housing: The animals were group housed in polycarbonate cages with stainless steel lid (48 cm x 27 cm x 20 cm). Each cage contained one to seven animals of the same sex during the acclimation period and three rats of the same sex and group during the treatment period. Each cage contained autoclaved sawdust (SICSA, Alfortville, France).
- Diet (e.g. ad libitum): Free access to A04 C pelleted diet (UAR, Villemoisson, Epinay-sur-Orge, France)
- Water (e.g. ad libitum): Free access to drinking water filtered by a FG Millipore membrane (0.22 micron)
- Acclimation period: The acclimatization period was at least 5 days before the start of treatment

Sawdust is analysed by the supplier for composition and contaminant levels. Each batch of food is analysed by the supplier for composition and contaminant levels. Bacteriological and chemical analyses of water are performed regularly by external laboratories. These analyses include the detection of possible contaminants (pesticides, heavy metals and nitrosamines).

No contaminants were known to have been present in the diet, drinking water or bedding material at levels which may be expected to have interfered with or prejudiced the outcome of the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 ºC
- Humidity (%): 30 - 70%
- Air changes (per hr): approximately 12 (filtered, non-recycled air)
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 03 September 2002 to 26 September 2002
Route of administration:
oral: gavage
Vehicle:
other: 0.5% methylcellulose
Details on oral exposure:
GAVAGE METHOD: metal gavage tube fitted to a 5 ml glass syringe

VEHICLE
- Justification for choice of vehicle: No data

MAXIMUM DOSE VOLUME APPLIED: 2000 mg/kg (10 mL/kg) body weight.

DOSAGE PREPARATION: The test item was prepared at the chosen concentration in the vehicle. Each test item preparation was made freshly on the morning of administration by the CIT Pharmacy and any unused material was discarded that same day.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: As no information on the toxic potential of the test item was available, for animal welfare reasons, the starting dose-level of 200 mg/kg bw was chosen. Three males were used in the initial step.
After the first assay, as no mortality occurred, another assay was carried out on three males at the dose-level 2000 mg/kg bw.
After the second assay, as no mortality was observed, the results were confirmed in three females at the dose-level 2000 mg/kg bw.
Doses:
Initial step 200 mg/kg body weight.
First and second assay 2000 mg/kg body weight.
No. of animals per sex per dose:
200 mg/kg bw: 3 males
2000 mg/kg bw: 3 males and 3 females
Control animals:
no
Details on study design:
The animals were fasted for an overnight period of approximately 18 hours before dosing. Water was available ad libitum. Food was given back approximately 4 hours after administration of the test item.

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/Viability: Time of death was recorded individually, in terms of the number of hours or days after dosing.
Body weights: The animals were weighed individually just before administration of the test item on day 1 and then on days 8 and 15.
Clinical signs: The animals were observed frequently during the hours following administration of the test item for detection of possible treatment-related clinical signs. Thereafter, observation of the animals was made at least once a day.
- Necropsy of survivors performed: On day 15, all animals were killed by carbon dioxide asphyxiation. All study animals were subjected to a macroscopic examination as soon as possible after death. After opening the thoracic and abdominal cavities, a macroscopic examination of the main organs (digestive tract, heart, kidneys, liver, lungs, pancreas, spleen and any other organs with obvious abnormalities) was performed.
- Other examinations performed: none.
Statistics:
No statistical analysis was performed (The method used is not intended to allow the calculation of a precise LD50 value).
Preliminary study:
No deaths occurred in the initial step of 200 mg/kg body weight.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred during the study.
Clinical signs:
other: No clinical signs were observed in any of the treated animals.
Gross pathology:
Macroscopic examination of the main organs of the animals revealed no apparent abnormalities.
Other findings:
None.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
KY-EU was administered by oral gavage to two subsequent groups of three male Sprague-Dawley rats at 200 and 2000 mg/kg body weight and three female rats at 2000 mg/kg body weight. The study was conducted according to OECD 423 and GLP guidelines.

The oral LD50 value of KY-EU in Sprague-Dawley rats was established to exceed 2000 mg/kg body weight.

Based on these results, KY-EU does not have to be classified and has no obligatory labelling requirement for acute oral toxicity according to Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The study has a klimisch code 1.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

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:
October 10 - 24, 2002
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
other: Sprague-Dawley Rj: SD (IOPS han)
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Source: Janvier, Le Genest-Saint-Isle, France
- Age at study initiation: approx. 9 weeks old
- Weight at study initiation: mean body weight of 402 ± 7 g for the males and 251 ± 4 g for the females.
On day 1, all males had a body weight higher than 300 g. This minor deviation was not considered to have compromised the validity or integrity of the study.
- Housing: During the acclimation period, one to seven animals of the same sex were housed in polycarbonate cages with stainless steel lid (48 cm x 27 cm x 20 cm). During the treatment period, the animals were housed individually in polycarbonate cages with stainless steel lid (35.5 cm x 23.5 cm x 19.3 cm). Each cage contained autoclaved sawdust (SICSA, Alfortville, France).
- Diet (e.g. ad libitum): Free access to A04 C pelleted diet (UAR, Villemoisson, Epinay-sur-Orge, France)
- Water (e.g. ad libitum): Free access to drinking water filtered by a FG Millipore membrane (0.22 micron)
- Acclimation period: The acclimatization period was at least 5 days before the start of treatment.

Sawdust is analysed by the supplier for composition and contaminant levels. Each batch of food is analysed by the supplier for composition and contaminant levels. Bacteriological and chemical analyses of water are performed regularly by external laboratories. These analyses include the detection of possible contaminants (pesticides, heavy metals and nitrosamines).

No contaminants were known to have been present in the diet, drinking water or bedding material at levels which may be expected to have interfered with or prejudiced the outcome of the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2 ºC
The temperature recorded in the animal room was sometimes outside of the target ranges specified in the Study plan. This minor deviation was not considered to have compromised the validity or integrity of the study.
- Humidity (%): 30 - 70%
- Air changes (per hr): approximately 12 (filtered, non-recycled air)
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 10 October 2002 to 24 October 2002
Type of coverage:
semiocclusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
On the day before treatment, the dorsal area of each animal was clipped (area of approximately 6x8 cm) using an electric clipper. Only animals with healthy intact skin were used for the study.

A single dose of 2000 mg/kg of the test item in its original form was placed on a hydrophilic gauze pad (pre-moistened with 2 mL of purified water) and than applied to an area of the skin respresenting approximately 10% of the total body surface of the animals, calculated according to Meeh's formula (i.e. approximately 5 cm x 6 cm for the females and 5 cm x 7 cm for the males). The test item and the gauze pad were held in contact with the skin for 24 hours by means of an adhesive hypoallergenic aerated semi-occlusive dressing and a restraining bandage. This dressing prevented ingestion of the test item by the animal.

Washing: No, on removal of the dressing, any residual test item was removed using a dry cotton pad.
Duration of exposure:
24 hours.
Doses:
As the test item was anticipated to be non-toxic at 2000 mg/kg, a limit test was performed by application of 2000 mg/kg of the test item to one group of ten animals.

No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
Dose volume: 5 mL/kg

Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
Mortality/Viability: Time of death was recorded individually, in terms of the number of hours or days after dosing.
Body weights: The animals were weighed individually just before administration of the test item on day 1 and then on days 8 and 15.
Clinical signs: The animals were observed frequently during the hours following administration of the test item, for detection of possible treatment-related clinical signs. Thereafter, observation of the animals was made at least once a day until day 15. Type, time of onset and duration of clinical signs were recorded for each animal individually. From day 2, any local cutaneous reaction was recorded.
- Necropsy of survivors performed: On day 15, all animals were killed by carbon dioxide asphyxiation. All study animals were subjected to a macroscopic examination as soon as possible after death. After opening the thoracic and abdominal cavities, a macroscopic examination of the main organs (digestive tract, heart, kidneys, liver, lungs, pancreas, spleen and any other organs with obvious abnormalities) was performed.
- Other examinations performed: none.
Statistics:
None.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred during the study.
Clinical signs:
other: No clinical signs and no cutaneous reactions were observed during the study.
Gross pathology:
Macroscopic examination of the main organs of the animals revealed no apparent abnormalities.
Other findings:
A white coloration of the skin due to the test item and which could have masked a very slight erythema, was noted in all animals on day 2 only.
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
KY-EU was dermally applied under semiocclusive conditions to two subsequent groups of five male and five female Sprague-Dawley rats at 2000 mg/kg body weight. The study was conducted according to OECD 402 guideline and GLP principles.

The dermal LD50 value of KY-EU in Sprague-Dawley rats was established to exceed 2000 mg/kg body weight.

Based on these results, KY-EU does not have to be classified and has no obligatory labelling requirement for acute dermal toxicity according to Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
The study has a klimisch code 1.

Additional information

Oral:

In an acute oral toxicity study, according to OECD 423, rats were exposed by gavage to 200 mg/kg bw (3 males) and 2000 mg/kg bw (3 males and 3 females) of KY-EU. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice. No mortality occurred and no clinical signs were observed among the animals. Bodyweight gain was considered normal and no abnormalities at macroscopic examination were found. Based on these results, the oral LD50 of KY-EU in rats was establised to exceed 2000 mg/kg bw.

Dermal:

In an acute dermal study, performed according to OECD 402, male and female rats were exposed by a single semiocclusive dermal application to 2000 mg/kg bw of KY-EU for 24 hours. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice. No mortality occurred and no clinical signs were observed among the animals. A white coloration of the skin due to the test item and which could have masked a very slight erythema, was noted in all animals on day 2 only. A reduced body weight gain or a slight body weight loss was seen in 2/5 females between day 1 and day 8 and in 1/5 females between day 8 and 15. The overall body weight gain of the other animals was similar to that of CIT historical control animals. Based on these results, the dermal LD50 of KY-EU in rats was establised to exceed 2000 mg/kg bw.

Justification for classification or non-classification

Based on results from acute oral and dermal toxicity studies, KY-EU does not have to be classified and has no obligatory labelling requirement for acute oral toxicity and acute dermal toxicity according to Regulation (EC) No 1272/2008 on classification, labelling and packaging of substances and mixtures.