N,2-dimethyl-N-phenylbutyramide

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1988-03-17 to 1988-04-21

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study was conducted to GLP. Limited details on test substance.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1988

Report date:

1988

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

N,2-dimethyl-N-phenylbutyramide

EC Number:

282-817-4

EC Name:

N,2-dimethyl-N-phenylbutyramide

Cas Number:

84434-18-4

Molecular formula:

C12H17NO

IUPAC Name:

N,2-dimethyl-N-phenylbutanamide

impurity 1

Reference substance name:

Unknown impurities

Molecular formula:

Unknown

IUPAC Name:

Unknown impurities

Test material form:

liquid

Specific details on test material used for the study:

Test substance name: Gardamide
Purity: 100%
Colour: Clear liquid
Storage: Ambient temperature in the dark

Test animals

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Details on test animals or test system and environmental conditions:

Equal numbers of male and female CD rats [Crl: CD(SD)BR] were obtained from Charles River U.K. Ltd., Margate, Kent. They were in a weight range of 106 to 152 g prior to dosing {Day 1} and approximately four to six weeks of age. All the rats were acclimated to the experimental environment for a period of 8 days prior to the stat of the study.
The rats were allocated to cages within the treatment groups. They were housed in groups by sex in metal cages with wire mesh floors. A standard laboratory rodent diet (Labsure LAD 1) and water were provided ad libitum. The batch of diet used for the study was analysed for certain chemical and microbiological contaminants. Access to food only was prevented overnight prior to and approximately four hours after dosing.
Results of routine chemical examination of water at source (Grafham Final Water) as conducted by the Anglian Water Authority, are made available to Huntingdon Research Centre.
The mean daily minimum and maximum temperature of the animal room were 22 °C and 24 °C respectively and the mean daily relative humidity value was 50%. The rate of air exchange was maintained at approximately 15 air changes/hour. Lighting was controlled by means of a time switch to provide 12 hours artificial light in each 24 hour period.
Each animal was identified by cage number and ear punching.
Each cage was idenitified by a colour label displaying the dose level, study schedule number and the initials of the Study Director.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 5.06 mL/kg. The test material was administered at dose volumes of 2.03 and 5.06 mL/kg.

DOSAGE PREPARATION: The test material was administered as supplied (specific gravity 0.99).

Doses:

2000 and 5000 mg/kg bw

No. of animals per sex per dose:

3 animals per sex per dose

Control animals:

no

Results and discussion

Effect levels

Sex:

male/female

Dose descriptor:

LD50

Effect level:

2 000 - 5 000 mg/kg bw

Based on:

test mat.

Mortality:

One female rat was found dead three hours after oral administration of Gardamide 2.0 g/kg. Four rats died after treatment at 5.0 g/kg. These deaths occured within two hours of dosing or, in one case, on Day 2.
Slight vascular congestion and moderate congestion of the glandular zone of the stomach were apparent in the female rat found dead after treatment at 2.0 g/kg. Autopsy of other rats that died revealed no macroscopic abnormalities.
Bodywight losses (<10 g) were recorded for all rats that died.

Clinical signs:

Pilo-erection and increased salivation were observed in all the rats within five minutes of dosing. Other clinical signs first apparent within two hours of doing were:
- abnormal body carriage (hunched posture), abnormal gait (waddling), descreased respiratory rate, ptsosis and prostration amongst rats treated at both dose levels
- lethargy and pallor of the extremities amongst rats dosed at the higher dose level
- body tremors in signle male and female rats treated at 2.0 g/kg
- twitching amongst rats of both sexes dosed at 5.0 g/kg.

Lethargy and pallor of the extremities were observed on Day 2 in one male dosed at the lower dose level. There were no other signs of reaction to treatment. Recovery of surviving rats, as judged by external appearance and behavious, was generally advanced by Day 2 and cpmplete by Day 3 or 4 (2.0 g/kg) or Day 7 (5.0 g/kg).

Body weight:

Low body weight gains during the first week of the study were recorded for all surviving rats.
All rats achieved anticipated body weight gains between Days 8 and 15.

Gross pathology:

Slight vascular congestion and moderate congestion of the glandular zone of the stomach were apparent in the female rat found dead after treatment at 2000 mg/kg. Autopsy of other rats that died revealed no macroscopic abnormalities.
All other terminal autopsy findings were normal.

Any other information on results incl. tables

Table 1: Individual and Group Mean Body Weights

Sex	Dose (mg/kg)	Body weight (g)
		Day 1	Day 8	Day 15	Death
Male	2000	142 152 136	203 220 180	252 274 238	- - -
	Mean	143	201	255	-
	5000	124 142 133	- 200 -	- 274 -	123 - 123
	Mean	133	-	-	-
Female	2000	131 106 122	- 138 165	- 160 190	128 - -
	Mean	120	152	175	-
	5000	128 127 109	- 152 -	- 199 -	127 - 103
	Mean	121	-	-	-

 

Table 2: Clinical Signs and Severity

Sign	No. of Rats in Group Showing Signs
	Dose (mg/kg)
	2000		5000
	Male	Female	Male	Female
Pilo-erection	3	3	3	3
Hunched posture	3	2	3	3
Waddling	3	2	1	2
Lethargy	1	0	1	2
Decreased respiratory rate	1	1	3	3
Ptosis	1	1	3	3
Pallor of extremities	1	0	3	3
Body tremors	1	1	0	0
Prostrate	1	1	3	2
Twitching	0	0	3	2
Increased salivation	3	3	3	3

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

Under the conditions of this study, the acute median lethal oral dose of the test material to rats was found to be between 2000 and 5000 mg/kg bodyweight.

Executive summary:

The acute oral toxicity of the test material was investigated in a study which was conducted under GLP conditions using methodology that was equivalent to the standardised guideline OECD 401.

During the study, groups of 3 male and female Crl: CD (SD) Br rats received a single dose of undiluted test material, by gavage, at dose levels of 2000 and 5000 mg/kg. Animals were observed for 14 days for mortality and toxic signs. Body weights were monitored. At the end of the observation period, surviving rats were euthanised and subjected to a macroscopic post mortem investigation.

One female rat was found dead three hours after oral administration of the test material at 2000 mg/kg. Four rats died after treatment at 5000 mg/kg. Pilo-erection and increased salivation were observed in all rats within five minutes of dosing. Other clinical signs included abnormal body carriage (hunched posture), abnormal gait (waddling), decreased respiratory rate, ptosis and prostration, lethargy and pallor of the extremities, body tremors and twitching.

Recovery of surviving rats, as judged by external appearance and behaviour, was generally advanced by Day 2 and complete by Days 3 or 4 (2000 mg/kg) or Day 7 (5000 mg/kg).

Under the conditions of this study, the acute median lethal oral dose of the test material to rats was found to be between 2000 (i.e. >2000 mg/kg) and 5000 mg/kg bodyweight.