Methyl anthranilate

Endpoint summary

Description of key information

Repeated Dose Toxicity Study (Oral):

No Observed Adverse Effect Level (NOAEL) is considered to be 500 mg / kg body weight when male and female rats were orally treated with test substance for chronic study.

Repeated Dose Toxicity Study (Dermal):

The acute toxicity value for the test chemical (as provided in section 7.2.3) is >5000 mg/kg body weight. Also, given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that the test chemical  shall not exhibit  toxicity by the dermal route after repeated exposure. In addition, there is no data available that suggests that the test chemical would exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Repeated Dose Toxicity Study (Inhalation):

The acute inhalation toxicity study need not be conducted because exposure to humans via inhalation route is not likely taking into account due to low vapour pressure of the test chemical, which is reported to be 1.599 Pa (0.012 mmHg). Thus, exposure to inhalable dust, mist and vapour of the chemical is highly unlikely. Therefore this study is considered for waiver.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Justification for type of information:

Data is from publication

Qualifier:

according to guideline

Guideline:

other: As mentioned below

Principles of method if other than guideline:

13 weeks repeated oral toxicity study of test chemical in rats.

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Osborne-Mendel

Details on species / strain selection:

not specified

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: not specified
- Females (if applicable) nulliparous and non-pregnant: [yes/no] not specified
- Age at study initiation: not specified
- Weight at study initiation: not specified
- Fasting period before study: not specified
- Housing: The animals were housed individually in wire cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: not specified

DETAILS OF FOOD AND WATER QUALITY:

ENVIRONMENTAL CONDITIONS
- Temperature (°C): not specified
- Humidity (%): not specified
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): not specified

IN-LIFE DATES: From: To:not specified

Route of administration:

oral: gavage

Details on route of administration:

stomach tube

Vehicle:

corn oil

Details on oral exposure:

PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): Fresh diets were made and distributed weekly
- Mixing appropriate amounts with (Type of food): The concentration of the solution was adjusted for each level so that all rats received a constant volume of 1 ml of solution/kg daily
- Storage temperature of food: Not specified

VEHICLE
- Justification for use and choice of vehicle (if other than water): The test chemical was soluble in corn oil
- Concentration in vehicle: Not specified
- Amount of vehicle (if gavage): Not specified
- Lot/batch no. (if required): Not specified
- Purity:Not specified

Analytical verification of doses or concentrations:

not specified

Details on analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

Daily

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

0 ppm

Dose / conc.:

50 mg/kg bw/day (nominal)

Remarks:

1000 ppm

Dose / conc.:

500 mg/kg bw/day (nominal)

Remarks:

10000 ppm

No. of animals per sex per dose:

Total: 40 animals
Test group: 10 males and 10 females
Control group: 10 males and 10 females

Control animals:

yes, concurrent vehicle

Details on study design:

Not specified

Positive control:

not specified

Observations and examinations performed and frequency:

The rat's weight, food intake and general condition were recorded every week. Haematological examinations were made at 3, 6, 12 and 22 months in the chronic experiments. These examinations included white cell counts, red cell counts, haemoglobins and haematocrits.

Sacrifice and pathology:

GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes
At the termination of the experiments the rats were sacrificed and exsanguinated

Other examinations:

The tissues of all the rats were examined macroscopically at the time of sacrifice. The viscera were removed and the liver, kidneys, spleen, heart, and testes were weighed. These organs, the remaining abdominal and thoracic viscera, and one hind leg, for bone, bone marrow, and muscle, were preserved in 10 ~o buffered formalin-saline solution for histopathological examination. For routine histopathology, sections were embedded in paraffin wax and stained with haematoxylin and eosin. Tissues from rats dying during the experiment were examined for gross changes and were preserved if autolysis was not advanced. Organs were
not weighed but abnormalities and the suspected reason for death were noted.

Statistics:

not specified

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Key result

Dose descriptor:

NOAEL

Effect level:

500 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

food consumption and compound intake

haematology

mortality

Remarks on result:

not determinable due to absence of adverse toxic effects

Critical effects observed:

no

Conclusions:

No Observed Adverse Effect Level (NOAEL) is considered to be 500 mg / kg body weight when male and female rats were orally treated with test substance for chronic study.

Executive summary:

13 weeks repeated oral toxicity study was performed on rats to determine the toxic nature of test chemical. The study was performed on 10 male and 10 female Osborne-Mendel rats, a control group containing the same number of rats as the test groups was included with test compound. The animals were housed individually in wire cages and had access to food and water at all times. The test chemical was administered via stomach tube in corn oil solution at a dose range of 0, 1,000 and 10,000 ppm (approximately equivalent to 50 and 500 mg/kg bw). The concentration of the solution was adjusted for each level so that all rats received a constant volume of 1 ml of solution/kg daily. The control animals were given an equal volume of corn oil. The rat's weight, food intake and general condition were recorded every week. Hematological examinations were made at 3, 6, 12 and 22 months. These examinations included white cell counts, red cell counts, hemoglobin and hematocrits. At the termination of the experiments the rats were sacrificed and exsanguinated. The tissues of all the rats were examined macroscopically at the time of sacrifice. The viscera were removed and the liver, kidneys, spleen, heart, and testes were weighed. These organs, the remaining abdominal and thoracic viscera, and one hind leg, for bone, bone marrow, and muscle, were preserved in 10 % buffered formalin-saline solution for histopathological examination. For routine histopathology, sections were embedded in paraffin wax and stained with haematoxylin and eosin. Tissues from rats dying during the experiment were examined for gross changes and were preserved if autolysis was not advanced. Organs were not weighed but abnormalities and the suspected reason for death were noted. After 13 weeks, No adverse effects were observed on body weights, appearance, food intake, hematology, organ weights, macroscopic or microscopic (at highest dietary level) examination of the major organs. Pathological changes attributable to disease or age were observed. Thus based on observations, No Observed Adverse Effect Level (NOAEL) is considered to be 500 mg / kg body weight indicating that the test chemical is not toxic in nature.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

Data is from a Klimisch 2 database.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Repeated Dose (Oral) Toxicity:

The data of the repeated dose toxicity of the test chemicals is as follows:

A 13 weeks repeated oral toxicity study was performed on rats to determine the toxic nature of test chemical. The study was performed on 10 male and 10 female Osborne-Mendel rats, a control group containing the same number of rats as the test groups was included with test compound. The animals were housed individually in wire cages and had access to food and water at all times. The test chemical was administered via stomach tube in corn oil solution at a dose range of 0, 1,000 and 10,000 ppm (approximately equivalent to 50 and 500 mg/kg bw). The concentration of the solution was adjusted for each level so that all rats received a constant volume of 1 ml of solution/kg daily. The control animals were given an equal volume of corn oil. The rat's weight, food intake and general condition were recorded every week. Hematological examinations were made at 3, 6, 12 and 22 months. These examinations included white cell counts, red cell counts, hemoglobin and hematocrits. At the termination of the experiments the rats were sacrificed and exsanguinated. The tissues of all the rats were examined macroscopically at the time of sacrifice. The viscera were removed and the liver, kidneys, spleen, heart, and testes were weighed. These organs, the remaining abdominal and thoracic viscera, and one hind leg, for bone, bone marrow, and muscle, were preserved in 10 % buffered formalin-saline solution for histopathological examination. For routine histopathology, sections were embedded in paraffin wax and stained with haematoxylin and eosin. Tissues from rats dying during the experiment were examined for gross changes and were preserved if autolysis was not advanced. Organs were not weighed but abnormalities and the suspected reason for death were noted. After 13 weeks, No adverse effects were observed on body weights, appearance, food intake, hematology, organ weights, macroscopic or microscopic (at highest dietary level) examination of the major organs. Pathological changes attributable to disease or age were observed. Thus based on observations, No Observed Adverse Effect Level (NOAEL) is considered to be 500 mg / kg body weight indicating that the test chemical is not toxic in nature.

Similarly, 115 days repeated oral toxicity study was performed on rats to determine the toxic nature of test chemical. The study was performed on 10 male and 10 female weanling rats. The test animals were given diets containing test chemical at a concentration of 0, 3000 or 10 000 mg/kg of diet, approximately equivalent to 0, 150-300 and 500-1000 mg/kg bw per day, respectively. During the observation period there was no evidence of adverse effects at 3000 ppm, as judged by appearance, behaviour, growth, mortality, terminal haematological examination, final body weights and gross and microscopic examination. The only effects observed at 10 000 ppm were increased average weights of the liver and kidneys and slight (minimal) histological changes in the kidneys. Thus based on observations, the No Observed Effect Level (NOEL) of the test chemical was determined to be 150 mg/kg bw indicating that the test chemical is not toxic in nature.

Repeated Dose Toxicity Study (Dermal):

The acute toxicity value for the test chemical (as provided in section 7.2.3) is >5000 mg/kg body weight. Also, given the use of the chemical; repeated exposure by the dermal route is unlikely since the use of gloves is common practice in industries. Thus, it is expected that the test chemical  shall not exhibit  toxicity by the dermal route after repeated exposure. In addition, there is no data available that suggests that the test chemical would exhibit repeated dose toxicity by the dermal route. Hence this end point was considered for waiver.

Repeated Dose Toxicity Study (Inhalation):

The acute inhalation toxicity study need not be conducted because exposure to humans via inhalation route is not likely taking into account due to low vapour pressure of the test chemical, which is reported to be 1.599 Pa (0.012 mmHg). Thus, exposure to inhalable dust, mist and vapour of the chemical is highly unlikely. Therefore this study is considered for waiver.

Justification for classification or non-classification

Based on the above information and CLP criteria for the test chemical, the test chemical is not likely to exhibit toxicity upon repeated exposure by oral, inhalation and dermal route.