Dimethyl cyclohexane-1,4-dicarboxylate

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1996

Report date:

1996

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:

Dimethyl cyclohexane-1,4-dicarboxylate

EC Number:

202-347-5

EC Name:

Dimethyl cyclohexane-1,4-dicarboxylate

Cas Number:

94-60-0

Molecular formula:

C10H16O4

IUPAC Name:

1,4-dimethyl cyclohexane-1,4-dicarboxylate

Constituent 2

Reference substance name:

DIMETHYL 1,4-CYCLOHEXANEDICARBOXYLATE, MIXED ISOMER

IUPAC Name:

DIMETHYL 1,4-CYCLOHEXANEDICARBOXYLATE, MIXED ISOMER

Details on test material:

PM Number: 03041-00
CAS Registry Number: 000094-60-0
HAEL Laboratory Number: 95-0212
EAN: 907570
SRID or Lot I.D. Number: X24652-38
Physical State and Appearance: Colorless liquid
Received at Performing Laboratory: August 24, 1995

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Housing:
All animals were individually housed in suspended, stainless-steel, mesh cages.

Environmental Conditions:
A photoperiod of 12 hours light from 6 a.m. to 6 p.m. was maintained. Room temperature was maintained at 66-71 oF. Relative humidity was maintained at 4 7-61 %.

Diet and Water:
PMI,. Feeds, Inc. Certified Rodent Diet (5002) pellets and water (Monroe County (NY) Water Authority) were available ru!. libitum. No known contaminants which would interfere with the outcome of the study were expected to be present in feed or water from these sources. Analyses of feed and semi-annual analyses of water are maintained on file within the testing laboratory.

Isolation:
Animals were isolated and monitored for at least five days after arrival to the testing facility.

Animal Identification:
All animals were identified by cage numbers and uniquely-numbered metal ear tags.

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Control animals:

no

Details on study design:

Randomization:
A clinical examination was performed on each animal to ensure that only healthy animals wereutilized. The procedure for including animals in the study was to randomly select and assignanimals from the same shipment to the study. Randomization was done by computergenerated lists using the Automated Animal Toxicology System. After assignment of animals to the study, the body weights were determined to ensure that individual body weights did not exceed 20% of the mean weight for each sex.

Clinical Observations:
Animals were observed three times on the day of dosing (Day 0), and once each day thereafter for the duration of the experiment. Observations included, but were not limited to, changes in the skin; fur; feces; urine; eyes; mucous membranes; respiratory, circulatory, and autonomic and central nervous systems; somatomotor activity; and behavior pattern.

Body Weight Determinations:
Body weights were collected on Days 0 (prior to treatment), 7, and 14.

Necropsy
Animals that died during the study were necropsied as soon as possible. Surviving animals were necropsied at the completion of the 14-day observation period.

Statistics:

The LD50 was obtained using the method of Wei! (1952). The results were as follows:

LD50 for male rats: 5000 mg/kg (95% C.I. = No range calculable)
LD50 for female rats: 2812 mg/kg (95% C.I. = 2357- 3354 mg/kg)

No dose/mortality curve was constructed since graphs become statistically useful only with the use of large numbers of animals and dose groups.

Results and discussion

Effect levels

Effect levels 1

Sex:

male

Dose descriptor:

LD50

Effect level:

> 5 000 mg/kg bw

Based on:

test mat.

Effect levels 2

Sex:

female

Dose descriptor:

LD50

Effect level:

ca. 2 812 mg/kg bw

Based on:

test mat.

Mortality:

For male rats, mortality was 40% at a dose of 5000 mg/kg. For the females, mortality was 20% at 2500 mg/kg and 100% at 4000 and 5000 mg/kg. No mortality was noted after Day 2 of the study for any group. Details are presented in Table 1.

Clinical signs:

other: Abnormal clinical signs evident during the study included slight to severe weakness, prostration, diarrhea, and a reduced amount or lack of feces. Weakness was noted only on the day of dosing or the day following dosing. Severe weakness and prostration we

Gross pathology:

The major treatment-related changes observed at necropsy provided evidence that the test material was a gastric irritant. These changes included necrosis and hemorrhage in the glandular gastric mucosa and the presence of increased amounts of mucus in the small intestines. Selected organs from two females that died on Day 2 of the study were processed for microscopic examination.

Any other information on results incl. tables

Table 1: Mortality

DOSE (mg/kg)	NUMBER OF RATS EXPOSED (Male, Female)	NUMBER OF DEATHS (Male, Female)	TIME OF DEATH
2500	0,5	NA,1	Day 1
4000	0,5	NA,5	Day 1 or 2
5000	5,5	2,5	Day 1 or 2

NA = not applicable

Table 2: Clinical Observations

DOSE (mg/kg)	TIME	CLINICAL SIGNS	NUMBER OF AFFECTED ANIMALS
2500	Day 0	appeared clinicall normal slight weakness	4/5 Females 1/5 Females
2500	Day 1	death appeared clinically normal	1/5 Females 4/4 Females
2500	Days 2 -14	appeared clinically normal	4/4 Females
4000	Day 0	appeared clinically normal slight weakness moderate weakness	2/5 Females 1/5 Females 2/5 Females
4000	Day 1	death moderate weakness reduced amount of feces	3/5 Females 2/2 Females 2/2 Females
4000	Day 2	death	2/2 Females
5000	Day 0	slight weakness moderate weakness severe weakness prostration diarrhea	3/5 Males 4/5 Females 2/5 Males, 1/5 Females 1/5 Males 1/5 Females
5000	Day 1	death slight weakness moderate weakness lack of feces diarrhea	2/5 Males, 4/5 Females 3/5 Males 1/1 Females 3/5 Males 1/1 Females
5000	Day 2	death appeared clinically normal	1/1 Females 3/5 Males
5000	Days 3 -14	appeared clinically normal	3/5 Males

Table 3: Body Weight

animal no. (sex)	DOSE (mg/kg)	Day 0 Body Wt. (gm)	Day 7 Body Wt. (gm)	Day 14 Body Wt. (gm)
591 (M)	5000	205	266	316
592 (M)	5000	206	265	320
593 (M)	5000	201	died day 1	*
594 (M)	5000	214	died day 1	*
595 (M)	5000	200	264	321
651 (F)	2500	157	207	240
652 (F)	2500	163	213	254
653 (F)	2500	163	died day 1	*
654 (F)	2500	158	212	239
655 (F)	2500	166	219	240
656 (F)	4000	155	died day 1	*
657 (F)	4000	162	died day 2	(133)
658 (F)	4000	157	died day 1	*
659 (F)	4000	156	died day 1	*
660 (F)	4000	160	died day 2	(132)
596 (F)	5000	168	died day 1	*
597 (F)	5000	177	died day 2	(153)
598 (F)	5000	173	died day 1	*
599 (F)	5000	181	died day 1	*
600 (F)	5000	184	died day 1	*

* A terminal body weight was not recorded for any animal which died within 24 hours of dosing.

Applicant's summary and conclusion

Interpretation of results:

sligthly toxic

Remarks:

Migrated information Criteria used for interpretation of results: not specified

Conclusions:

Based on the oral LD50 for male and female rats, the test material was classified as slightly toxic in rats according to the criteria set forth by Hodge and Sterner (1949) and requires no toxicity classification as defined in the 18th Adaptation on the EC Classification, Packaging, and Labelling of Dangerous Substances.

Executive summary:

In this acute oral toxicity study, mortality was 40% at a dose of 5000 mg/kg for male rats. For female rats, mortality was 20% at 2500 mg/kg and 100% at 4000 and 5000 mg/kg. No mortality was noted after Day 2 of the study. Abnormal clinical signs evident during the study included slight to severe weakness, prostration, diarrhea, and a reduced amount or lack of feces. Weakness was noted only on the day of dosing or the day following dosing. Severe weakness and prostration were only seen prior to death. By Day 2 of the study, all surviving animals appeared clinically normal. All animals which survived to termination of the 14-day observation period gained weight. The cause of death for rats which died after exposure to the test material was not determined. However, necrosis and hemorrhage in the glandular gastric mucosa may have contributed to the deaths. Based on these findings at necropsy, the test material was considered to be a gastric irritant. The acute oral LD50 for this test material was greater then 5000 mg/kg for male rats and was calculated to be 2812 mg/kg for female rats. Based on the oral LD50 for male and female rats, the test material was classified as slightly toxic in rats according to the criteria set forth by Hodge and Sterner (1949) and requires no toxicity classification as defined in the 18th Adaptation on the EC Classification, Packaging, and Labelling of Dangerous Substances.