Thymol

Toxicity to reproduction: other studies

Administrative data

Endpoint:

toxicity to reproduction: other studies

Remarks:

Reproductive organs in a 19 weeks study were examined.

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: scientifically acceptable and well documented

Cross-reference

Reason / purpose for cross-reference:

reference to same study

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:

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

Qualifier:

no guideline followed

Principles of method if other than guideline:

5 male and 5 female rats per group were fed 1000, 10000 ppm thymol in the diet (= ca. 67, 667 mg/kg bw/day) for 19 weeks.

GLP compliance:

no

Limit test:

no

Specific details on test material used for the study:

Commercially-available materials, rather than pure chemicals, were used since the purpose of these studies was to evaluate the toxicity of these materials in relation to their use as food additives.

Species:

rat

Strain:

Osborne-Mendel

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: weanling
- Housing: individually in wire cages
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Details on oral exposure:

DIET PREPARATION
- Rate of preparation of diet (frequency): weekly

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

19 weeks

Frequency of treatment:

daily via food

Dose / conc.:

1 000 ppm

Remarks:

1000 ppm nominal in diet (= ca. 67 mg/kg bw/day)

Dose / conc.:

10 000 ppm

Remarks:

10000 ppm nominal in diet (= 667 mg/kg bw/day)

No. of animals per sex per dose:

5 male and 5 female rats/dose

Control animals:

yes, plain diet

Details on study design:

Rationale for animal assignment (if not random): litter mates were used for the study
Post-exposure period: no

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: weekly

DETAILED CLINICAL OBSERVATIONS: Not specified

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Time schedule for examinations: weekly

HAEMATOLOGY: Yes
- Time schedule for collection of blood: after 3, 6, 12 and 22 months
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- Parameters checked examined: red cell counts, white cell counts, haemoglobins, haematocrits

Sacrifice and pathology:

GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not specified

Food efficiency:

not specified

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Endocrine findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Other effects:

not examined

Details on results:

10000 ppm (667 mg/kg bw/d): no effect on growth or haematology, and no macroscopic or microscopic change in the tissues
1000 ppm ( 67 mg/kg bw/d): no macroscopic effect, thus histopathology not performed

Dose descriptor:

NOAEL

Effect level:

> 667 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

gross pathology

haematology

histopathology: neoplastic

Remarks on result:

not determinable due to absence of adverse toxic effects

Critical effects observed:

no

At the dose of 10000 ppm (667 mg/kg bw/d) there was no effect on growth or haematology, and no macroscopic or microscopic change in the tissues.

Conclusions:

The NOAEL was 10000 ppm (ca. 667 mg/kg bw/d); there was no effect on growth orhaematology, and no macroscopic or microscopic change in the tissues.

Executive summary:

5 male and 5 female rats per group were fed 1000, 10000 ppm thymol in the diet (= ca. 67, 667 mg/kg bw/day) for 19 weeks. The rat's weight, food intake and  general condition were recorded every week. Haematological examinations were made after 3, 6, 12 and 22 months. At the termination of the experiments the rats were sacrificed and exsanguinated. The tissues of all 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 thoraic viscera, and one hind leg (for the examination of bone, bone marrow and muscle), were preserved in 10% buffered formalin-saline solution for histopathological examination. The NOAEL was 10000 ppm (ca. 667 mg/kg bw/d); there was no effect on growth or haematology, and no macroscopic or microscopic change in the tissues.

Data source

Reference

Reference Type:

publication

Title:

Food flavourings and compounds of related structure. II.Subacute and Chronic Toxicity

Author:

Hagan EC, Hansen O, Fitzhug OG, Jenner PM, Jones WI, Taylor JM, Long EL, Nelson AA, Brouwer JB

Year:

1967

Bibliographic source:

Fd Cosmet Toxicol 5, 141-157

Materials and methods

Principles of method if other than guideline:

5 male and 5 female rats per group were fed 1000, 10000 ppm thymol in the diet (= ca. 67, 667 mg/kg bw/day) for 19 weeks.
At the termination of the study all animals were killed and necropsied; gross and microscopic examination of all major organs, including reproductive organs (testis).

GLP compliance:

no

Type of method:

in vivo

Test material

Test material information

Constituent 1

Reference substance name:

Thymol

EC Number:

201-944-8

EC Name:

Thymol

Cas Number:

89-83-8

Molecular formula:

C10H14O

IUPAC Name:

5-methyl-2-(propan-2-yl)phenol

Test animals

Species:

rat

Strain:

Osborne-Mendel

Sex:

male/female

Administration / exposure

Route of administration:

oral: feed

Vehicle:

other: feed

Duration of treatment / exposure:

19 weeks

Frequency of treatment:

daily

Doses / concentrations

Remarks:

Doses / Concentrations:
1000, 10000 ppm food (= ca. 67, 667 mg/kg bw/day)
Basis:
nominal in diet

No. of animals per sex per dose:

5 males and 5 females

Control animals:

yes, concurrent vehicle

Details on study design:

Reproduction organs were examined.

Results and discussion

Effect levels

Dose descriptor:

NOAEL

Effect level:

667 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

other: (highest dose tested) no effects on reproductive organs.

Remarks on result:

not determinable due to absence of adverse toxic effects

Observed effects

667 mg/kg bw/d administered daily for 19 weeks had no adverse effects on the reproductive organs (testis).

Any other information on results incl. tables

5 male and 5 female rats per group were fed 1000, 10000 ppm thymol in the diet (= ca. 67, 667 mg/kg bw/day) for 19 weeks.

At the termination of the study all animals were killed and necropsied; gross and microscopic examination of all major organs, including reproductive organs (testis).

NOAEL = 667 mg/kg bw/d (male and female rats), the pathological examination revealed no relevant findings.

Applicant's summary and conclusion

Executive summary:

5 male and 5 female rats per group were fed 1000, 10000 ppm thymol in the diet (= ca. 67, 667 mg/kg bw/day) for 19 weeks.

At the termination of the study all animals were killed and necropsied; gross and microscopic examination of all major organs, including reproductive organs (testis).

NOAEL = 667 mg/kg bw/d (male and female rats), the pathological examination revealed no relevant findings.