3-tert-butyladipic acid

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2016-11-29 to 2016-12-17

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2016

Report date:

2017

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

Version / remarks:

17th December 2001

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

3-tert-butyladipic acid

EC Number:

233-759-3

EC Name:

3-tert-butyladipic acid

Cas Number:

10347-88-3

Molecular formula:

C10H18O4

IUPAC Name:

3-tert-butylhexanedioic acid

Test material form:

solid: particulate/powder

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and batch No.of test material: Changzhou Sunlight Pharmaceutical Co., Ltd., China; 20160505 / 116727
- Expiration date of the batch: May 2017

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: at room temperature
- Stability under test conditions: stable

Test animals

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Toxi-Coop Zrt. 1103 Budapest, Cserkesz u. 90., Hungary
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 11 weeks old
- Weight at study initiation:
first group: 238 - 242 g
second group: 229 - 246 g
third group: 256 - 271 g
- Fasting period before study: yes, overnight
- Housing: 3 animals/sex/cage (Type II polypropylene/polycarbonate)
- Diet: ad libitum, ssniff® SM R/M-Z+H complete diet (ssniff Spezialdiäten GmbH, D-59494 Soest Germany)
- Water: ad libitum, tap water
- Acclimation period: 26 days in first group, 28 days in second group and 29 days in third group

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 30 - 70
- Air changes (per hr): above 10 air exchanges/hour
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 30, 200 mg/mL
- Amount of vehicle: 10 mL/kg bw
- Lot/batch no.: 1608-5511

CLASS METHOD
- Rationale for the selection of the starting dose: The starting dose was selected on the basis of the available information about the test item.

Doses:

300, 2000 mg/kg bw

No. of animals per sex per dose:

3

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: twice daily; weighing was peformed on days 0 (before treatment), 2, 7 and 15
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight

Statistics:

Not applicable

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 300 - <= 2 000 mg/kg bw

Based on:

test mat.

Mortality:

Two female rats dosed at 2000 mg/kg bw died on Day 2. No mortality occurred at 300 mg/kg single oral dose of the test item. All rats in group 2 and 3 survived until the end of the 14-day observation period.

Clinical signs:

In group 1 treated with 2000 mg/kg bw clinical signs comprised of decreased activity (4 cases out of 31 observations), pain reaction (2/31), vocalisation (2/31), abnormal gait (2/31), incoordination (2/31), bedding chewing (3/31), decreased righting reflex (2/31), decreased body tone (2/31), closed eyes (2/31) and piloerection (2/31). Decreased activity (score -1, -2) and bedding chewing (score +2) occurred in all animals. Pain reaction (score +2), abnormal gait (score +2), incoordination (score +2), decreased righting reflex (score -1), decreased body tone (score -2), closed eyes (score +2) and piloerection (score +2) were observed in two animals. Vocalisation (score +2) was recorded in two animals. These symptoms were observed between DayNo treatment related symptoms were observed in the 300 mg/kg bw test item dose groups (group 2 and 3) throughout the 14-day post-treatment period. 1 and Day 2, except for bedding chewing, that was detected on the treatment day 30 minutes after the treatment.

Body weight:

The mean body weight and body weight gain data of group 1 (2000 mg/kg) could not be evaluated, because two rats died in this group. The body weight and body weight gain of the surviving animal of this group corresponded to their species and age throughout the study.
In group 2 and 3 (300 mg/kg bw) the mean body weight and body weight gain of the animals corresponded to their species and age throughout the study.

Gross pathology:

A cannibalized cheek was found in one animal (external macroscopic change). Internal pathological changes like decreased spleen, lungs reddish mottled, stomach wall attenuated and membranous and peripyloric area thickened by oedema were found in two animals. A ruptured stomach wall was recorded in animal No.: 3710.
Severe hydrometra was found in female No.: 3700 of group 2. Hydrometra is a physiological finding and connected to the estrous cycle of the animal. No pathological changes were found related to the effect of the test item during the macroscopic examination of animals of group 2 and 3 (300 mg/kg bw), as well as in the surviving animal of group 1.

Applicant's summary and conclusion

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

Based on the results of the acute oral toxicity study (Acute Toxic Class Method) with 3-tert-butyladipic acid an LD50 between 300 and 2000 mg/kg bw could be derived.

Executive summary:

An acute oral toxicity study was carried out using the class method according to OECD guideline 423. The method was conducted using a stepwise procedure with the use of 2000 mg/kg bw as the starting dose in three female rats (Wistar strain; 11 weeks old). The starting dose was selected on the basis of the available information about the test item. Since two female animals died the test was continued at 300 mg/kg bw dose level on further three female rats. No animal died in the second step at 300 mg/kg bw dose level, thus three further female rats were treated with the same (300 mg/kg bw) dose. No animal died in the third step, too, so the test was finished, because the stopping criteria of Annex 2d of OECD Guideline No. 423 were met. Animals were weighed, observed for lethality and toxic symptoms for 14 days after the treatment. Gross pathological examination was carried out in animals that died on Day 2, as well as on the 15th day after the treatment in surviving animals. Two of three animals treated with 2000 mg/kg bw died on Day 2. No lethality was noted at a single oral dose of 300 mg/kg bw. In the first step at a dose level of 2000 mg/kg bw, decreased activity, pain reaction, vocalisation, bedding chewing, closed eyes, disturbances of the coordination (abnormal gait, incoordination), decreased righting reflex, decreased muscular tension (body tone) and disturbance of the autonomic functions (piloerection) were observed in animals 30 minutes after the treatment (bedding chewing) and between Day 1 and Day 2. In the second step at a dose level of 300 mg/kg bw, no clinical symptoms were observed on the day of the treatment and during the 14-day observation period, the general state and behaviour of all experimental animals were normal. The body weight development was normal in all surviving animals.

A cannabalised cheek was observed in one animal of the 2000 mg/kg bw group (external finding). Internal findings included decreased spleen, lungs reddish mottled, stomach wall attenuated, ruptured and membranous, peripyloric area thickened by oedema were recorded in animals treated with 2000 mg/kg bw dose. These internal alterations were regarded as test item related, excluding cannibalism. All organs of the animals treated with 300 mg/kg bw dose proved to be free of treatment related gross pathological changes.

The method used is not intended to allow for the calculation of a precise LD50 value. However for this acute oral toxicity study with the test item 3-tert-butyladipic acid in rats the determined LD50 is between 300 and 2000 mg/kg bw.