4-methylanisole

Endpoint summary

Description of key information

Acute oral toxicity was assessed in two studies similar to OECD test guideline 401, resulting in a LD50 of 1920 mg/kg body weight in rats and an LD50 between 1940 and 4850 mg/kg body weight in mice indicating a low acute oral toxicity. Similarly, based on the LD50 and LC50 values from the dermal study conducted in rabbits, and inhalaton study in rats, the test material shows low acute toxicity via the dermal and inhalation routes.  

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1971

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 401 (Acute Oral Toxicity)

GLP compliance:

no

Remarks:

GLP was not compulsory at the time the study was conducted.

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

SD rats of both sex weiging 150-300 grams were individually housed and fed commercial diet and water ad libitum.

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

The test material was administered as a 50 % (w/v or v/v) solution or suspension in corn oil as a single dose by gastric intubation and observed up to 14 days.

Doses:

Preliminary test: 5000 mg/kg bw
Main study: 1000-6810 mg/kg bw (6 dose groups). Not further specified.

No. of animals per sex per dose:

5 animals per dose in the main study, 2 animals in the preliminary test

Control animals:

not specified

Details on study design:

Male and female Sprague-Dawley rats weighing 150-130 grams were individually housed, fed and allowed water ad libitum. The animals were fasted over night and 2 animals per dose group were administered a single dose of the test substance at 5 ml/kg (5 g/kg) by gastric intubation. The test material was administered as a 50% (w/v or v/v) solution or suspension in corn oil. Following dosing, signs of toxicity and mortality were recorded at 1 and 4 hours and then once daily for 14 days. If no deaths occurred, an additional 8 rats were administered the same dose via the same route. The LD50 was determined if 1 or 2 animals in the first pair died within 48 hours, or if more than 2 of the total number of rats (n=10) died within the 14-day observation period. At the end of the study period, gross necropsy was performed on animals that survived as well as those that died during the study.

Key result

Sex:

not specified

Dose descriptor:

LD50

Effect level:

1 920 mg/kg bw

Based on:

test mat.

95% CL:

>= 1 510 - <= 2 450

Mortality:

At 5000 mg/kg bw (preliminary test) 2/2 animals died. At dlose level of 1000-6810 mg/kg, mortality was seen at 3160 mg/kg and higher.

Clinical signs:

other: Signs of toxicity included blood crust nose; diarrhea; depression; ataxia; hypopnea; lacrimation; salivation

Gross pathology:

Animals that died, necropsy revealed darkened lungs which appeared to be firm. There were no gross abnormalities in animals sacrificied at termination.

Interpretation of results:

Category 4 based on GHS criteria

Conclusions:

Under the experimental conditions of the test, the LD50 for acute toxicity after oral administration was reported as 1920 mg/kg bw in rats.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LD50

Value:

1 920 mg/kg bw

Acute toxicity: via inhalation route

Link to relevant study records

Reference

Endpoint:

acute toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study (OECD).

Qualifier:

according to guideline

Guideline:

OECD Guideline 403 (Acute Inhalation Toxicity)

GLP compliance:

no

Test type:

standard acute method

Limit test:

no

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Dr. K. Thomae GmbH, Biberach, Germany
- Age at study initiation: approx. 8-9 weeks
- Average weight at study initiation: males 272 +/- 9.6 g; females 192 +/- 4.5 g
- Housing: in groups of 5 animals in cages type D III of Becker without bedding
- Diet: KLIBA rat/mouse laboratory diet 24-343-4 10 mm pellets, Klingentalmühle AG, Kaiseraugst, Switzerland, ad libitum during post exposure observation period
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature: 20 - 24 °C
- Humidity: 30 - 70 %
- Air changes per hr: fully air-conditioned rooms
- Photoperiod (hrs dark/hrs light): 12/12

Route of administration:

inhalation: vapour

Type of inhalation exposure:

whole body

Vehicle:

other: unchanged (no vehicle)

Details on inhalation exposure:

Exposure system
Whole-body inhalation system : IKA 02 (glass-steel construction ; BASF Aktiengesellschaft, volume ca. 200 l). The animals were kept singly in compartmentalized wire cages, and were exposed in the chamber.

Generation of the inhalation atmosphere
The test substance was dosed unchanged. A vapor air mixture was generated by means of a
- continuous infusion pump UNITA I (B . Braun)
- glass vaporizer with thermostat (BASF)
By means of the continuous infusion pump the test substance was supplied to the heated vaporizer. The vapors that developed were mixed with supply air and passed into the inhalation system.

Exposure
The following air flow/s (supply air) was set:
blast air : 3000 l/h
The supply air was conditioned via a central air-conditioning system. The exposure system was placed in an air-conditioned laboratory. Temperatures in the exposure system were 19-25°C. Deviations from this specification which would have had any adverse effect on the results of the study did not occur. The inhalation atmosphere was offered to the animals for inhalation for 4 hours.

Analytical verification of test atmosphere concentrations:

yes

Remarks:

Gas chromatographical method.

Duration of exposure:

4 h

Concentrations:

6.1 mg/l (maximum technically achievable concentration)

No. of animals per sex per dose:

5 animals per sex per dose

Control animals:

no

Details on study design:

The test method was based on OECD 403.
Test Animals: male and female rats
Mean concentration of four samples: 6.10 +/- 0.24 mg/l
Control group: historical (air)
Vehicle: air
Air flow: 3000 l/h
Generation of the inhalation atmosphere: via a continuous infusion pump and a heated vaporizer; developed vapors were mixed with supply air; tested was the maximum concentration that could be achieved technically
Observation period: 14 d post-exposure
Observations:
Body weight: checked before the beginning of the test, after 7 days, at the end of the observation period
Clinical findings: recorded several times during exposure and at least once/work day during the observation period.
Mortality: daily
Pathology: gross necropsy

Statistics:

Concentration/effect relationship: Binomial test following Wittig H: Mathematische Statistik 1974, pp. 32-35

Sex:

male/female

Dose descriptor:

LC0

Effect level:

6.1 mg/L air

Exp. duration:

4 h

Sex:

male/female

Dose descriptor:

LC50

Effect level:

> 6.1 mg/L air

Exp. duration:

4 h

Mortality:

No mortality occured during the study.

Clinical signs:

other: Clinical signs during exposure: Accelerated respiration was observed within the first hour, then turning into irregular or intermittent respiration. Eyelid closure was also observed shortly after exposure; salivation within 30 minutes, while abdominal po

Body weight:

Slightly change in body weight gain observed in the second week of the observation period in males compared to the historical controls (decreased in males and increase in females)

Gross pathology:

No pathological findings were noted.

Table 1: Mean body weight of the treated animals compared to historical controls

Mean body weight (g)	before the study		after 7 days		after 14 days
	male	female	male	female	male	female
test group	272	192	300	213	310	220
historical (air) control	248	177	285	196	318	211

Interpretation of results:

Category 3 based on GHS criteria

Conclusions:

Based on these study results the test material has low acute inhalation toxicity.

Executive summary:

No mortality occured to rats, exposed to a 6.1 mg/l vapor-air mixture of the test material for 4 hours under the experimental conditions chosen (tested was the maximum concentration that could be achieved technically). The LC0 was therefore 6.1 mg/l air.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LC50

Value:

6 100 mg/m³ air

Quality of whole database:

Study ws conductied in 1989 in accordance with OECD 403

Acute toxicity: via dermal route

Link to relevant study records

Reference

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Basic data given.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

GLP compliance:

no

Remarks:

; GLP was not compulsory at the time the study was conducted.

Test type:

standard acute method

Limit test:

yes

Species:

rabbit

Strain:

New Zealand White

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 2.5 - 3 kg

Type of coverage:

occlusive

Vehicle:

not specified

Details on dermal exposure:

TEST SITE
- Area of exposure: approx. 240 cm2 (approximately 10% of body surface)
- Type of wrap if used: test material was delivered under a rubber sleeve which was covered with Webril padding
- Test site was clipped and left intact in half of the animals, while lightly abraded in the remaining animals
- Amount(s) applied: 5 ml/kg bw

Duration of exposure:

Twenty four hours following exposure local dermal reactions were scored according to the Draize method. Toxicity , dermal reactions and mortality were recorded for 14 days.

Doses:

5 ml/kg bw => 4850 mg/kg bw (calculated using density : 970 g/l)

No. of animals per sex per dose:

6 animals per dose (no further data)

Control animals:

not specified

Details on study design:

Male and female New Zealand Albino rabbits weighing 2.5- 3 kg were individually house, fed a commercial diet and allowed water ad libitum. The test material was used as it was received. Groups of 3-6 rabbits were used and test material was applied to the test site measuring 240 cm2. The test sight on half the animals was abraded while the other half were left intact. The test material was delivered under a rubber sleeve which was covered with Webril padding to form an occlusive dressing. Twenty four hours later, the binders were removed and local dermal reactions scored according to Draize, J.H., 1959. Observations for toxicity, dermal reactions and mortality were performed once daily for 14 days. Necropsy was performed on animals that died during the study and those which were killed at termination of the study.

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 4 850 mg/kg bw

Remarks on result:

other: >5 ml/kg bw (calculation based on a density of 970 g/l)

Mortality:

No deaths occured, all animals survived.

Clinical signs:

other: Erythema score: 2-3 in 6/6 animals Edema score: 1-3 in 5/6 animals Scaling in 5/6 animals Eschar in 3/6 animals One animal showed apparent skin disease on lower trunk during days 9-12 According to the authors, no other effects were seen.

Gross pathology:

Necropsy showed no gross findings.

Interpretation of results:

GHS criteria not met

Conclusions:

LD50 for acute toxicity after dermal administration was > 5 ml/kg bw (4850 mg/kg bw) in rabbits and by consequence doesn't trigger any classification for this end-point.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

4 850 mg/kg bw

Additional information

Acute oral toxicity.

In the key study, similar to OECD test guideline 401, acute oral toxicity of 4-methylanisole was assessed in six groups of 5 Sprague-Dawley rats. Rats were treated with a single oral dose in corn oil via gavage at dose levels ranging from 1000-6810 mg/kg body weight (not further specified). Under the conditions of this study, LD50 was found to be 1920 mg/kg body weight for rats (RIFM1971).

In the supportive study, similar to OECD test guideline 401, 10 fasted mice were treated with a single oral dose of unchanged 4-methylanisole via gavage at dose levels of 2 ml/kg bw (2 animals), 5 ml/kg bw (6 animals), 10 ml/kg bw (2 animals) and observed over a period of 7 days for signs of toxicity. Under the conditions of this study, LD50 was defined to be between 2 and 5 ml/kg bw for mice, representing 1940 and 4850 mg/kg bw respectively, (Givaundan MT1971).

Justification for classification or non-classification

Based on the available data, 4-methylanisole is to be classified as as acute toxic / oral (Category 4) according to the criteria laid down under 67/548/EEC and regulation (EU) 1272/2008.