Reaction mass of (3R)-3-methyl-5-[(1R,3R)-2,2,3-trimethylcyclopentyl]pentan-2-one and (3S)-3-methyl-5-[(1R,3R)-2,2,3-trimethylcyclopentyl]pentan-2-one

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

Between 30 June 2014 and 29 July 2014

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted to GLP and in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not effect the quality of the relevant results.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Report date:

2014

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 420 (Acute Oral Toxicity - Fixed Dose Method)

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.1 bis (Acute Oral Toxicity - Fixed Dose Procedure)

Deviations:

no

Test guideline 3

Qualifier:

according to guideline

Guideline:

other: Japanese MAFF, 2000

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

fixed dose procedure

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

NACET00502

IUPAC Name:

NACET00502

Constituent 2

Reference substance name:

3-Methyl-5-((1R)-2,2,3-trimethylcyclopentyl)pentan-2-one

IUPAC Name:

3-Methyl-5-((1R)-2,2,3-trimethylcyclopentyl)pentan-2-one

Constituent 3

Reference substance name:

119464-63-0 (planar)

IUPAC Name:

119464-63-0 (planar)

Test material form:

other: liquid

Details on test material:

Identification: NACET00502
Common/Commercial name: NACET00502
Chemical name: 3-Methyl-5-((1R)-2,2,3-trimethylcyclopentyl)pentan-2-one
CAS number: 119464-63-0 (planar)
EC number: not allocated
Batch: S-13-11-1
Purity: 98.5%
Physical state / Appearance: clear colorless liquid
Expiry date: 24 December 2015
Storage Conditions: room temperature in the dark

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

Female Wistar (RccHan™:WIST) strain rats were supplied by Harlan Laboratories UK Ltd., Oxon, UK. On receipt the animals were randomly allocated to cages. The females were nulliparous and non pregnant. After an acclimatization period of at least five days the animals were selected at random and given a number unique within the study by indelible ink marking on the tail and a number written on a cage card. At the start of the study the animals were eight to twelve weeks of age. The body weight variation did not exceed ±20% of the body weight of the initially dosed animal.

The animals were housed in groups of up to four in suspended solid floor polypropylene cages furnished with woodflakes. With the exception of an overnight fast immediately before dosing and for approximately three to four hours after dosing, free access to mains drinking water and food (2014C Teklad Global Rodent diet supplied by Harlan Laboratories UK Ltd., Oxon, UK) was allowed throughout the study. The diet, drinking water and bedding were routinely analyzed and were considered not to contain any contaminants that would reasonably be expected to affect the purpose or integrity of the study.

The temperature and relative humidity were set to achieve limits of 19 to 25 °C and 30 to 70% respectively. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.

The animals were provided with environmental enrichment items which were considered not to contain any contaminant of a level that might have affected the purpose or integrity of the study.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Remarks:

For the 300 mg/kg dose level the test item prepared as a solution in arachis oil BP

Details on oral exposure:

All animals were dosed once only by gavage, using a metal cannula attached to a graduated syringe.

Doses:

In the absence of data regarding the toxicity of the test item, 300 mg/kg was chosen as the starting dose.

A single animal was treated as follows:

Dose Level(mg/kg) Concentration(mg/mL) Dose Volume(mL/kg) Number of Rats (Female)
300, 30, 10, 1,

In the absence of toxicity at a dose level of 300 mg/kg, an additional animal was treated as follows:

Dose Level(mg/kg) Specific Gravity Dose Volume(mL/kg) Number of Rats (Female)
2000, 0.875, 2.29, 1

In the absence of mortality at a dose level of 2000 mg/kg, an additional group of animals was treated as follows:

Dose Level(mg/kg) Specific Gravity Dose Volume(mL/kg) Number of Rats (Female)
2000, 0.875, 2.29, 4

No. of animals per sex per dose:

1 female at 300 mg/kg
1 female at 2000 mg/kg
4 females at 2000 mg/kg

Control animals:

no

Details on study design:

All animals were dosed once only by gavage, using a metal cannula attached to a graduated syringe. The volume administered to each animal was calculated according to the fasted body weight at the time of dosing. Treatment of animals was sequential. Sufficient time was allowed between each dose level to confirm the survival of the previously dosed animals.

Clinical observations were made ½, 1, 2, and 4 hours after dosing and then daily for fourteen days. Morbidity and mortality checks were made twice daily.
Individual body weights were recorded on Day 0 (the day of dosing) and on Days 7 and 14.

At the end of the observation period the animals were killed by cervical dislocation. All animals were subjected to gross necropsy. This consisted of an external examination and opening of the abdominal and thoracic cavities. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.

Statistics:

None reported

Results and discussion

Effect levels

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: 95% confidence limits not given in study report.

Mortality:

Dose Level - 300 mg/kg
Mortality data are given in Table 1.
There was no mortality.

Dose Level - 2000 mg/kg
Mortality data are given in Table 4.
There were no deaths.

Clinical signs:

Dose Level - 300 mg/kg
Individual clinical observations are given in Table 1.
No signs of systemic toxicity were noted during the observation period.

Dose Level - 2000 mg/kg
Individual clinical observations are given in Table 4.
No signs of systemic toxicity were noted during the observation period.

Body weight:

Dose Level - 300 mg/kg
Individual body weights and body weight changes are given in Table 2.
The animal showed expected gains in body weight over the observation period.

Dose Level - 2000 mg/kg
Individual body weights and body weight changes are given in Table 5.
All animals showed expected gains in body weight over the observation period.

Gross pathology:

Dose Level - 300 mg/kg
Necropsy findings are given in Table 3.
No abnormalities were noted at necropsy.

Dose Level - 2000 mg/kg
Individual necropsy findings are given in Table 6.
No abnormalities were noted at necropsy.

Any other information on results incl. tables

Table 1     Individual Clinical Observations and Mortality Data - 300mg/kg

Dose Level mg/kg	Animal Number and Sex	Effects Noted After Dosing (Hours)				Effects Noted During Period After Dosing (Days)
		½	1	2	4	1	2	3	4	5	6	7	8	9	10	11	12	13	14
300	1-0 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

0=   No signs of systemic toxicity

Table 2     Individual Body Weights and Body Weight Changes - 300mg/kg

Dose Level mg/kg	Animal Number and Sex	Body Weight (g) at Day			Body Weight Gain (g) During Week
		0	7	14	1	2
300	1-0 Female	176	193	200	17	7

Table 3     Necropsy Findings - 300 mg/kg

Dose Level mg/kg	Animal Number and Sex	Time of Death	Macroscopic Observations
300	1-0 Female	Killed Day 14	No abnormalities detected

Table 4     Individual Clinical Observations and Mortality Data - 2000mg/kg

Dose Level mg/kg	Animal Number and Sex	Effects Noted After Dosing (Hours)				Effects Noted During Period After Dosing (Days)
		½	1	2	4	1	2	3	4	5	6	7	8	9	10	11	12	13	14
2000	2-0 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-0 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-1 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-2 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0
	3-3 Female	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0	0

0=   No signs of systemic toxicity

Table 5     Individual Body Weights and Body Weight Changes - 2000mg/kg

Dose Level mg/kg	Animal Number and Sex	Body Weight (g) at Day			Body Weight Gain (g) During Week
		0	7	14	1	2
2000	2-0 Female	176	193	204	17	11
	3-0 Female	171	180	193	9	13
	3-1 Female	161	172	177	11	5
	3-2 Female	182	187	205	5	18
	3-3 Female	181	190	210	9	20

Table 6     Individual Necropsy Findings - 2000mg/kg

Dose Level mg/kg	Animal Number and Sex	Time of Death	Macroscopic Observations
2000	2-0 Female	Killed Day 14	No abnormalities detected
	3-0 Female	Killed Day 14	No abnormalities detected
	3-1 Female	Killed Day 14	No abnormalities detected
	3-2 Female	Killed Day 14	No abnormalities detected
	3-3 Female	Killed Day 14	No abnormalities detected

Applicant's summary and conclusion

Interpretation of results:

study cannot be used for classification

Remarks:

Migrated information

Conclusions:

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 2000 mg/kg body weight (Globally Harmonized Classification System - Unclassified).

The test item does not meet the criteria for classification according to Regulation (EC) No 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures.

Executive summary:

Introduction

The study was performed to assess the acute oral toxicity of the test item in the Wistar strain rat.

Methods

Following a sighting test at dose levels of 300 mg/kg and 2000 mg/kg, a further group of four fasted females was given a single oral dose of test item at a dose level of 2000 mg/kg body weight. Clinical signs and body weight development were monitored during the study. All animals were subjected to gross necropsy.

Results

Mortality. There were no deaths.

Clinical Observations. There were no signs of systemic toxicity.

Body Weight. All animals showed expected gains in body weight.

Necropsy. No abnormalities were noted at necropsy.

Conclusion

The acute oral median lethal dose (LD₅₀) of the test item in the female Wistar strain rat was estimated to be greater than 2000 mg/kg body weight (Globally Harmonized Classification System - Unclassified).

 

The test item does not meet the criteria for classification according to Regulation (EC) No 1272/2008, relating to the Classification, Labelling and Packaging of Substances and Mixtures.