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Toxicological information

Acute Toxicity: oral

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Administrative data

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: Well documented study according to GLP and following OECD guideline.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991
Report date:
1991

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 (Acute Toxicity (Oral))
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
2-hydroxymethyl-9-methyl-6-(1-methylethyl)-1,4-dioxaspiro[4.5]decane
EC Number:
408-200-3
EC Name:
2-hydroxymethyl-9-methyl-6-(1-methylethyl)-1,4-dioxaspiro[4.5]decane
Cas Number:
63187-91-7
Molecular formula:
C13H24O3
IUPAC Name:
[9-methyl-6-(propan-2-yl)-1,4-dioxaspiro[4.5]decan-2-yl]methanol
Test material form:
other: liquid

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
HUSBANDRY

Room Number: 13

Conditions:
Standard Laboratory Conditions. The room was air-conditioned with 15 air changes per hour and the environment controlled with optimal conditions
410 considered as being a temperature of 21°C and a relative humidity of 55%. Occasional fluctuations from these optimal conditions were noted, but were considered not to have affected study integrity. Lighting was 12 hours artificial fluorescent light and 12 hours dark per day.

Accommodation
Group housed, five per sex to a cage, using polycarbonate cages containing purified sawdust as bedding material (Woody SPF, supplied by Broekman
Institute, Someren, The Netherlands). Certificates of sawdust analysis were examined and then retained in the RCC NOTOX archives.

Diet
Free access to standard pelleted laboratory animal diet (Kliba 343 from Klingentalmühle AG, Kaiseraugst, Switzerland). Certificates of analysis were examined and then retained in the RCC NOTOX archives.

Water
Free access to tap-water. Certificates of analysis (performed quarterly) were examined and then retained in the RCC NOTOX archives.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
Fasting: Feed was withheld overnight prior to dosing until approximately 3-4 hours after administration of the test substance.

Frequency: Once, on day 1.
Doses:
Dose level
Group 1: 5000 mg/kg body weight.
Group 2: 3750 mg/kg body weight.
Group 3: 2800 mg/kg body weight.

Dose level:
Group 1: 4.8 ml/kg body weight.
Group 2: 3.6 ml/kg body weight.
Group 3: 2.7 ml/kg body weight.
Calculated as follows:
dose level (g/kg): specific gravity (g/ml). The specific gravity used was 1.04 g/ml.
No. of animals per sex per dose:
5
Details on study design:
DOSE SELECTION
Initially a "Limit study" with the test substance at a dose level of 5000 mg/kg body weight was performed. Due to the mortality and signs of toxicity noted among animals receiving 5000 mg/kg body weight, two further groups were selected for the "Full study" and dosed at 3750 and 2800 mg/kg body weight.

OBSERVATIONS
Mortality / Viability:
At periodic intervals on the day of dosing (day 1) and twice daily thereafter for 14 days.

Body Weights:
Days 1 (pre-administration), 8 and 15 and at death (if found dead after day 1).

Symptoms:
At periodic intervals on the day of dosing (day 1) and once daily thereafter for 14 days. All signs of reaction to treatment were recorded with particular attention paid to changes in the skin, fur, eyes and mucous membranes, as well as to behaviour pattern, tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.

PATHOLOGY
Necropsy:
All animals surviving to the end of the observation period were sacrificed by oxygen/carbon dioxide asphyxiation. All animals assigned to the study were subjected to necropsy and descriptions of all macroscopic abnormalities recorded.
Statistics:
The LD50 values and the associated 95% confidence interval, the slope of the dose mortality curve were calculated using the Maximum likelihood method (Finney, D.J. Probit Analyses, 3rd Edn., Cambridge University Press, 1971).

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
5 716 mg/kg bw
Based on:
test mat.
Mortality:
The following mortality rates were observed:
Dose level Males Females Sexes Combined
5000 mg/kg 2/5 2/5 4/10
3750 mg/kg 0/5 0/5 0/10
2800 mg/kg 0/5 0/5 0/10
Body weight:
All animals found dead between days 2-5 showed body weight lass an the day of death. The body weight gain shown by all surviving animals over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain.
Gross pathology:
5000 mg/kg body weight: Irregular areas in forestomach.
3750 mg/kg body weight: Irregular areas in forestomach.
2800 mg/kg body weight: No abnormalities.
Other findings:
All surviving animals treated at 5000 mg/kg body weight had recovered by day 4. All animals treated at 3750 and 2800 mg/kg body weight had recovered by day 3 and 2, respectively.

Applicant's summary and conclusion

Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The oral LD50 value of the test substance in rats was 5716 mg/kg body weight for the males only and for the females only. Due to the mortality distribution, only an estimated oral LD50 value of HR 91/917 247 could be calculated for the males and females combined. The estimated LD50 value for the sexes combined was 5716 mg/kg body weight.
Executive summary:

The purpose of this study was to assess the toxicity of the test article when administered to rats as a single oral dose. The study was carried out in accordance with OECD Guideline No. 401, "Acute Oral Toxicity" and EEC Directive 84/449/EEC, Part B.1, "Acute Toxicity-Oral". The test substance was administered by oral gavage to five rats of each sex per group, at 5000, 3750 or 2800 mg/kg body weight. Macroscopic examination was performed at the end of the experimental period. The incidence of mortality among the sexes combined from high to low dose group, was 4, 0 and 0. Major changes in clinical appearance included lethargy, no reaction to external stimuli, bradypnoea, piloerection and ataxia. All surviving animals treated with 5000 mg/kg body weight had recovered by day 4. Animals treated with 3750 and 2800 mg/kg body weight had recovered by day 3 and 2, respectively. Animals of the 5000 mg/kg body weight group, which were found dead between day 2-5, showed body weight loss an the day of death. The body weight gain shown by all surviving animals over the study period was considered to be similar to that expected of normal untreated animals of the same age and strain. Macroscopic post mortem examination of the animals that died during the study revealed yellow fluid contents of the stomach and grey-green areas in the forestomach. Macroscopic post mortem examination of the surviving animals at termination revealed irregular areas in the forestomach. The oral LD50 value for male or female rats alone, treated with the test substance, was 5716 mg/kg body weight. Due to the mortality distribution, only estimated oral L050 values of the test substance could be calculated for males and females combined and amounted to 5716 mg/kg body weight. Based an these results,the substance should not be classified as acute toxic according to the criteria described in EU Regulation No. 1272/2008 on the Classification, Labelling and Packaging of Substances and Mixtures (CLP).

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