Registration Dossier

Administrative data

Description of key information

There are no human data on acute toxicity for the test item. In animals, test results with this substance are available for the oral route of exposure indicating a LD50 cut-off value of 2000 mg/kg body weight. For animal welfare reasons, no experimental studies have been conducted using the inhalation and/or dermal route of exposure. Studies concerning these endpoints have been waived according to REACH Regulation (EC) 1907/2006, Annex VIII, point 8.5, column 2 ("acute toxicity studies does not generally need to be conducted if the substance is classified as corrosive to skin").

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
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline Study according to GLP
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
GLP compliance:
yes (incl. certificate)
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST SYSTEM
Test system: Rat, HanRcc:WIST (SPF)
Rationale: Recognized by the international guidelines as a recommended test system.
Source: RCC Ltd, Laboratory Animal Services, CH-4414 Füllinsdorf / Switzerland
Number of animals per group 3 females
Total number of animals 12 females
Age when treated: 12-13 weeks
Identification: Unique cage number and corresponding color-coded spots on the tail. The animalswere marked at acclimatization start.
Randomization: Selected by hand at time of delivery. No computer generated randomization program.
Acclimatization:
Under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.

HUSBANDRY
Room no.: 0105 / RCC Ltd, Füllinsdorf
Conditions: Standard Laboratory Conditions. Air-conditioned with 10-15 air changes per hour, and continuously monitored environment with ranges for room temperature 22 ± 3 °C and for relative humidity between 30-70 % (values above 70 % during cleaning process possible), automatically controlled light cycle of 12 hours light and 12 hours dark, music during the daytime light period.

Accommodation: In groups of three in Makrolon type-4 cages with wire mesh tops and standard softwood bedding ('Lignocel' Schill AG, CH-4132 Muttenz/Switzerland).

Diet: Pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch nos. 25/05 and 39/05 (Provimi Kliba AG, CH-4303 Kaiseraugst/Switzerland) ad libitum. Results of analyses for contaminants are archived at RCC Ltd.

Water: Community tap water from FOllinsdorf ad libitum. Results of bacteriological, chemical and contaminant analyses are archived at RCC Ltd.
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
(purified)
Details on oral exposure:
VEHICLE
The following information was provided by RCC Ltd:
Purified water prepared at RCC Ltd (deionised water which was processed and treated by the PURELAB Option-R unit. This latter links four purification technologies: reverse osmosis,adsorption, ion-exchange and photo oxidation). Purified water was found to be a suitable vehicle. The vehicle was chosen after a non-GLP solUbility trial which was performed before the study initiation date. This formulation trial is excluded from the GLP statement of compliance.
Doses:
2
No. of animals per sex per dose:
6 females per dose group
Control animals:
no
Details on study design:
DOSE FORMULATION
Dose levels are in terms of the test item as supplied by the sponsor.
The dose formulations were made shortly before each dosing occasion using a magnetic
stirrer as homogenizer. The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle added (weightvolume). Homogeneity of the test item in the vehicle was maintained during administration using a magnetic stirrer.

TREATMENT
The animals received a single dose of the test item by oral gavage administration at 2000 mg/kg or 300 mg/kg body weight after being fasted for approximately 17 to 19 hours (access to water was permitted). Food was provided again approximately 3 hours after dosing. The application volume was 10 mL/kg body weight.
Rationale: Oral administration was considered to be an appropriate application method as it is a possible route of human exposure during manufacture, handling and use of the test item.

OBSERVATIONS
Mortality / Viability
Body weights
Clinical signs
Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15. On test days 1 (prior to administration), 8 and 15. Daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1. Once daily during days 2-15. All abnormalities were recorded.
Statistics:
no
Sex:
female
Dose descriptor:
LD50
Effect level:
>= 2 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: LD50 given as "cut off value"
Mortality:
2000 mg/kg body weight: 2/6
300 mg/kg body weight: 0/6
Clinical signs:
2000 mg/kg body weight: ruffled fur, hunched posture, sedation
300 mg/kg body weight: no clinical signs of intoxication
Body weight:
The body weight of the animals was within the range commonly recorded for this strain and age.
Gross pathology:
All animals which died spontaneously during the observation period were necropsied as soon as they were found dead. All surviving animals at the end of the observation period.
Other findings:
MACROSCOPIC FINDINGS
In three animals treated at 2000 mg/kg, liquid contents were found in the stomach and/or duodenum, jejunum, ileum and caecum at necropsy, whereas no macroscopic findings were recorded in the remaining animals.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on the OECD 423, the LD50 - cut off value of the test substance after single oral administration to female rats, observed over a period of 14 days is:
LD50 - cut off value (female rat) = 2000 mg/kg b.w.
Executive summary:

Four groups, each of three female HanRcc:WIST (SPF) rats, were treated with the test substance by oral gavage administration at a dosage of 2000 mg/kg or 300 mg/kg body weight. The test item was diluted in vehicle (purified water) at a concentration of 0.2 g/mL or 0.03 g/mL and administered at a volume dosage of 10 mL/kg. The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs at approximately 30 minutes, 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Mortality/viability was recorded at approximately 30 minutes, 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15. Body weights were recorded on day 1 (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically. The following animals were treated and percentage of mortality was observed:

6 females treated at 2000 mg/kg 33 %

6 females treated at 300 mg/kg 0 %

Two animals treated at 2000 mg/kg were found dead four or six hours after treatment, whereas all animals treated at 300 mg/kg survived until the end of the study period. Slightly to moderately ruffled fur was observed in five animals treated at 2000 mg/kg from the 30-minute or 1-hour reading to the 2-hour examination and persisted in four of these animals up to the 3- or 5-hour observation or until test day 4. Hunched posture was noted in two animals at the 1-hour reading and persisted in one female until the 2-hour reading, whereas three other animals showed this symptom from the 2- to 3- or 5-hour observation or at the 3-hour examination only. Slight to moderate sedation was noted in four animals at the 1-hour reading and persisted in three of them until two, three or five hours after treatment. Slight to moderate tremor was seen in two animals treated at 2000 mg/kg prior to their spontaneous death three or five hours after treatment. Ventral recumbency was noted in one of these animals at the 5-hour reading. No clinical signs were observed during the course of the study in all animals treated at 300

mg/kg. The body weight of the animals was within the range commonly recorded for this strain and age. In three animals treated at 2000 mg/kg, liquid contents were found in the stomach and/or duodenum, jejunum, ileum and caecum at the unscheduled necropsy, whereas no macroscopic findings were recorded in the remaining animals.

 

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
Guideline study according to GLP available. No derivations and/or confounders. Klimisch rating 1 representing reliability without restrictions. Information valid and meets data requirements.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

There are no human data on acute toxicity for the test item. In animals, the test item (2,2`- [cyclohexylimino]diethanol) was tested for acute oral toxicity in a GLP compliant study according to OECD test guideline 423. The test item was apllied via gavage to groups of 6 female Wistar rats at dosages of 2000 mg/kg or 300 mg/kg body weight in water as vehicle. Two out of 6 animals treated at 2000 mg/kg body weight died within 6 hours after administration. Clinical signs at this dose level included hunched posture and sedation. No mortalities and no clinical signs of intoxication occurred at 300 mg/kg body weight. Gross necroscopy revealed no obvious macroscopical findings. Based on the findings in this guideline study, the acute oral toxicity (LD50) cut-off was 2000 mg/kg body weight. No data concerning acute dermal and/or acute inhalation toxicity are available which ist justifiable by the corrosive properties of this substance.


Justification for selection of acute toxicity – oral endpoint
Guideline study according to GLP with a Klimisch rating 1

Justification for selection of acute toxicity – inhalation endpoint
Waiving for animal welfare reasons according to REACH Regulation (EC) 1907/2006, Annex VIII, point 8.5, column 2 ("acute toxicity studies does not generally need to be conducted if the substance is classified as corrosive to skin")

Justification for selection of acute toxicity – dermal endpoint
Waiving for animal welfare reasons according to REACH Regulation (EC) 1907/2006, Annex VIII, point 8.5, column 2 ("acute toxicity studies does not generally need to be conducted if the substance is classified as corrosive to skin").

Justification for classification or non-classification

Based on the LD50 cut-off value of 2000 mg/kg body weight, the test item has to be classified as acute toxic (category 4) with the hazard statement H302 - harmful if swallowed regarding to acute oral toxicity.

For acute dermal and/or inhalation toxicity, no data are available. However, due to the corrosive nature of the test item appropriate labelling and classification as to the hazard potential also for these endpoints is guaranteed.