1,4-bis(methoxymethyl)benzene

Acute Toxicity: oral

Administrative data

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

From 2010-07-15 to 2010-10-25

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2010

Report date:

2010

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

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

Version / remarks:

2001

Deviations:

no

GLP compliance:

yes

Test type:

acute toxic class method

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

1,4-bis(methoxymethyl)benzene

EC Number:

229-828-2

EC Name:

1,4-bis(methoxymethyl)benzene

Cas Number:

6770-38-3

Molecular formula:

C10H14O2

IUPAC Name:

1,4-bis(methoxymethyl)benzene

Test material form:

liquid

Specific details on test material used for the study:

Purity: 99.80％

Test animals

Species:

rat

Strain:

other: Crl: CD(SD)

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Hino Breeding Center of Charles River Laboratories Japan, Inc.
- Age at study initiation: 8 weeks
- Weight at study initiation: 194.0-194.8 g at step 1 and 195.3-195.9 g at step 2
- Fasting period before study: about 17.5 hours
- Housing: Stainless steel cages with a wire mesh floor were used. Three animals were housed per cage of W260 x D380 x H180 mm before grouping, while animals were individually housed in cages of W165 x D300 x H150 mm after grouping. Polycarbonate cages (W265 x D426 x H150 mm) were used when animals were taken out of animal rooms for autopsy.
- Diet: pellet food, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-25ºC
- Humidity (%): 40-70%
- Air changes (per hr): 10-15 times/hour
- Photoperiod: a light/dark cycle of 12 hours (light on 7:00 and off at 19:00)

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

olive oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 20.0 w/v%
- Amount of vehicle (if gavage): 10 mL/kg
- Justification for choice of vehicle:
- Lot/batch no. (if required): 050ORS

MAXIMUM DOSE VOLUME APPLIED: 10 mL/kg

DOSAGE PREPARATION: The test substance was precisely weighed into a measuring flask and dissolved by adding olive oil. Dosing solutions were prepared by further adding olive oil to volume.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: The 50% cell growth inhibition concentration (IC50) was calculated to be 1,100 μg/mL at the minimum in the chromosomal aberration study conducted at this laboratory. The LD50 in rodents was calculated to be 1,590 mg/kg using the formula of correlation between the IC50 of cytotoxicity and the LD50 of acute toxicity proposed by the ICCVAM. The oral LD50 of this substance in male mice was reported to be 2,750 mg/kg by University of Shizuoka Institute of Traditional Chinese Medicine in 2000. Therefore, the starting dose (step 1) was set at 2,000 mg/kg judging that no animal would die at a single dose of 2,000 mg/kg based on these reports.

Doses:

Step 1: 2,000 mg/kg
Step 2: 2,000 mg/kg

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:
Observation of clinical signs and symptoms: All animals were observed 0, 5, 10 and 30 minutes and 1, 2 and 4 hours after administration on the day of administration and once in the morning from 1 to 14 days after administration.
Weighing: weighed shortly after administration and 1, 7 and 14 days after administration
- Necropsy of survivors performed: yes

Results and discussion

Effect levels

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Mortality:

No death occurred in the 2,000 mg/kg group (at either Step 1 or 2).

Clinical signs:

Spontaneous locomotion and respiratory rate decreased 30 min after treatment in one animal from the 2,000 mg/kg group, and decreases persisted 4 hours after treatment. Incomplete eyelid opening was also seen 2 hours after treatment. In three other animals from this group, decreases in spontaneous locomotion and respiratory rate occurred 2 hours after treatment and persisted until 4 hours after treatment. Spontaneous locomotion also decreased in another animal 4 hours after treatment.　All symptoms of toxicity which were observed on the day of treatment disappeared by the time of observation in the morning the following day. No abnormality or death occurred thereafter until 14 days after treatment. One animal showed no abnormality from the day of treatment through 14 days after treatment.

Body weight:

Body weight gain was inhibited 1 day after treatment in the 2,000 mg/kg group. When animals are fasted from the day before treatment, body weight generally increases by about 15 g 1 day after treatment. In the 2,000 mg/kg group, however, weight gain was 1.0 g at the minimum and 8.1 g at the maximum 1 day after treatment. Normal weight gains were observed 7 and 14 days after treatment.

Gross pathology:

No animal from the 2,000 mg/kg group showed any abnormality.

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The oral LD50 value of test item in Female Crl:CD(SD) rats was established to be >2000 mg/kg body weight.

Executive summary:

According to the OECD 423 test guideline, initially, the test substacne was administered by oral gavage to three female Crl:CD(SD) rats at 2000 mg/kg body weight. In a stepwise procedure one additional group of three females were dosed at 2000 mg/kg body weight.

Animals were observed with respect to clinical signs and symptoms including deaths. All animals were observed 0, 5, 10 and 30 minutes and 1, 2 and 4 hours and once in the morning from 1 to 14 days after administration Animals were weighed shortly after administration and 1, 7 and 14 days after administration. All animals were euthanized for autopsy by exsanguinating from the common carotid artery under ether anesthesia after completing observations 14 days after administration.

Decreased spontaneous locomotion, decreased respiratory rate and incomplete eyelid opening were observed. No death was observed under the test condition. Body weight gain was inhibited 1 day after treatment in the 2,000 mg/kg group but became normal 7 and 14 days after treatment. No abnormality was found at necropsy.

The oral LD50 value of test item in Female Crl:CD(SD) rats was established to be >2000 mg/kg body weight.