2-chloro-N,N-dimethyl-3-oxobutyramide

Acute Toxicity: oral

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: OECD Guideline Study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1995

Report date:

1995

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

standard acute method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

2-chloro-N,N-dimethyl-3-oxobutyramide

EC Number:

227-372-9

EC Name:

2-chloro-N,N-dimethyl-3-oxobutyramide

Cas Number:

5810-11-7

Molecular formula:

C6H10ClNO2

IUPAC Name:

2-chloro-N,N-dimethyl-3-oxobutanamide

Details on test material:

Name: Dimetbyl-2-ch1oroacetoacetamide
Batch No.: 502001
Physical state: clear yellowish liquid
Density: 1.20 g/m3
Storage: ambient, protected from light

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

Species: rat
Strain: Hsd/Cpb:WU
Source: Fa. Harlan Winkelmann GmbH, Gartenstr. 27, 33178 Borchen
Date of receipt: March 15, 1995 (females), April 19 and May 10, 1995 (males)
Acclimatization period: at least 5 days
Animal selection: random
Animal identification: with colored markings; cage labelled with dosage, sex, date of study initiation, project no.
Weight range at study initiation: m: 210 - 302 g, f: 170 - 210 g

Husbandry
Housing: collective housing up to a maximum of 5 animals per cage (Makrolon@ type 111)
lllumination: artificial lighting (120 lux) from 7.00 a.m. - 7.00 p.m.
Temperature: 22:+/-3 °C
Relative humidity: 30 -70 %
Measurement: twice daily

Prior to study initiation, the animals were acclimatized to laboratory conditions for at least 5 days. Only healthy animals were used in the test. The animals were fasted from 16 h before until 3 - 4 h after administration of the test article.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

A preliminary range finding test with doses of 2000, 1000, 500 and 200 mg/kg body weight was conducted using two female rats per dose. Due to a marked sex difference observed in the main test at the dose of 500 mg/kg body weight, a range finding test with doses of 2000 and 1000 mg/kg body weight was additionally conducted in two male rats.

Doses:

Doses: 200, 500, and 1000 mg/kg

No. of animals per sex per dose:

5 females (200 mg/kg bw), 5 males and 5 females (500 mg/kg bw), 5 males (1000 mg/kg bw)

Control animals:

yes

Details on study design:

In each animal a number of clinical-toxicological signs were evaluated according to a modified Irwin-Screening procedure (Screening Methods in Pharmacology, R. A. Turner, 1965, p. 26). Any change from the normal condition was noted (increase or decrease) and the degree of severity of any clinical symptoms was assessed. The animals were examined at the following post-treatment intervals: 5 min (at 1000 mg/kg) 10 min, 1 h, 2 h, 6 h, 24 h, and thereafter once daily up to day 14. The body weights of all animals were recorded immediately before treatment (day 0) and surviving animals were reweighed on days 7 and 14 p.a. (termination). Animals found dead were immediately necropsied. The survlvmg animals were sacrificed by CO2 asphyxiation after 14 days and gross pathological examinations were subsequently performed.

Statistics:

LDSO values were calculated by the linear interpolation.

Results and discussion

Effect levels

Effect levels 1

Sex:

male

Dose descriptor:

LD50

Effect level:

917 mg/kg bw

Based on:

test mat.

Remarks on result:

other: no condfidence interval given

Effect levels 2

Sex:

female

Dose descriptor:

LD50

Effect level:

275 mg/kg bw

Based on:

test mat.

Remarks on result:

other: no condfidence interval given

Mortality:

females: 2/5 at 200 mg/kg Bw; 4/5 at 500 mg/kg Bw
males: 0/5 at 500 mg/kg Bw; 3/5 at 1000 mg/kg Bw

Clinical signs:

other: Marked clinical signs were observed mainly within 24 h p.a. in animals which died subsequently. The most frequent findings were reduced activity, abdominal and squatting position, abnormal gait, reduced reflexes, piloerection, increased salivation and dec

Gross pathology:

Gross pathological examinations on animals found dead and at 14 days p. a. (terminal necropsy) revealed alterations in the stomach, in the intestinal tract and in the kidney which were considered to be test article-related. In animals found dead the most striking findings were redness of the mucous membrane in the gastro-instinal tract associated with bleeding, redness of the renal medulla and the renal pelvis and induration of the caecum. In animals of group I and II sacrificed at day 14 p.a. the most striking findings was adhesion of the forestomach with inner organs.

Applicant's summary and conclusion

Interpretation of results:

harmful

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The test article Dimetbyl-2-ch1oroacetoacetamide is harmful to rats under the conditions used.

Executive summary:

The acute oral toxicity of Dimetbyl- 2-ch1oroacetoacetamide was investigated according to OECD guideline 401 in 3 groups of Wistar rats, containing 5 males and 5 females (group II), 5 females (group I) or 5 males (group III). On the basis of the range finding results, the animals were given a single oral administration of "DMCAA" at doses of 200 mg/kg (group I), 500 mg/kg (group II) and 1000 mg/kg (group III).

Clinical observations were conducted at regular intervals during the 14-day observation period. Body weights were measured at days 0, 7 and 14 p.a. Gross pathological examinations were performed immediately on animals found dead and at termination on surviving animals. LD50 values were determined after 24 hand 14 days.

9 of 20 animals died pre-terminally. Marked clinical signs were observed mainly within 24 h p.a. in animals which died subsequently. The most striking findings were reduced activity, tremor, twitches, abdominal and squatting position, decreased reflexes, abnormal gait, increased salivation, piloerection and decreased respiratory rate. In the surviving animals there were normal or reduced weight gains as well as unaltered or decreased body weights. Gross pathological examinations in animals found dead and at 14 days p.a. (terminal necropsy) revealed alterations in the gastro-intestinal tract, in the kidney and in the abdominal cavity which were considered to be test article-related. Approx. 917 mg/kg and approx. 275 mg/kg bw were determined as LD50 values were determined for males and females respectively.