p-mentha-1,4-diene

Repeated dose toxicity: oral

Administrative data

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2017

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

1

Reference substance name:

p-mentha-1,4-diene

EC Number:

202-794-6

EC Name:

p-mentha-1,4-diene

Cas Number:

99-85-4

Molecular formula:

C10H16

IUPAC Name:

p-mentha-1,4-diene

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

olive oil

Duration of treatment / exposure:

28 days

Frequency of treatment:

Once per day.
Females were treated during:
 14-day pre-mating,
 14-day mating (maximum)
 22-day gestation (approximately)
 13-day lactation
Males were treated during:
 14-day pre-mating,
 14-day mating (maximum)
The animals designated for post-treatment observation (5 animals per sex in control and high groups, respectively) remained untreated for subsequent 14 days.

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

25 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

100 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

250 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Results and discussion

Results of examinations

Clinical signs:

not specified

Description (incidence and severity):

There were no test item-related deaths of animals during the study. Animals lived through the observation period without significant visible clinical signs.
Lethargy in 2 males (ID 4-Control and 33-Mid) was observed on Day 7 of treatment. Lethargy, spasm and tremor was observed in females: ID 102, 103, 108 (High) and ID 84, 89, 63 (Mid) between Day 4 and Day 7 of treatment. No other signs were observed.

Body weight and weight changes:

not specified

Description (incidence and severity):

The body weight of males of all dose groups was mildly increasing during the study. No significant differences between control and dose groups were observed. The body weight of High dose satellite males was similar in comparison with recovery control males during the whole study.
The body weight of females of all dose groups was mildly increasing during the study. Only significant difference between Control group and Low group on Day1 of the treatment in females was noticed. The body weight of recovery High dose females was similar in comparison with recovery control females during the whole study.

Food consumption and compound intake (if feeding study):

not specified

Description (incidence and severity):

Food consumption of males of all dose groups was similar to the control males during the whole study. Food consumption of recovery treated males was similar in comparison with control group during the whole application and recovery period.
Food consumption of treated females was similar or slightly lower in comparison with control group during the whole application period. Food consumption of recovery treated females was similar in comparison with recovery control females for the whole study.

Haematological findings:

not specified

Description (incidence and severity):

Only statistically significant decrease of haemoglobin in males of High group and females of Mid group against Control group were registered. These sporadic changes had no dose relationship; they were considered to be a result of intra-individual and inter-individual variability for this species or they have only statistical character.
No test item related effect on the haematology parameters were observed in this study. During the study, haematology parameters in both sexes were within or close to the historical control data for this species.

Clinical biochemistry findings:

not specified

Description (incidence and severity):

There were no findings in clinical chemistry parameters which could be definitively attributed to the treatment.
Statistical evaluation of clinical chemistry results showed no differences between control and dose groups. The average values of clinical chemistry parameters in all animals were within or slightly outside the serum historical control data.

Urinalysis findings:

not specified

Description (incidence and severity):

No significant changes against normal physiological conditions were detected. In the urine of some animals, small amounts of protein, ketones and presence of blood (erythrocytes) were observed. There are no differences between control and the dose groups. These findings considered to be normal (9). No test item related effect was observed.

Behaviour (functional findings):

not specified

Description (incidence and severity):

Open field test
The locomotor activity was not influenced by the administration of tested compounds in neither experimental group compared to Control.
Tail flick Test
In comparison with Control group, the reaction time was not significantly influenced by the administration of test item.
Grip Strength Test
Statistically significant difference between the Control and the Low group was observed. This significance has probably statistical character. Other differences observed within the males group were not statistically significant.
As to the group of females, male satellites and female satellites, there is not a statistically significant difference between the means of component groups.

Organ weight findings including organ / body weight ratios:

not specified

Description (incidence and severity):

Relative weights of the liver in the Low, Mid and High dose males were significantly increased compared to Control group. Significant increase of kidney and spleen relative weight and decrease of relative weight of thymus in High dose against Control were observed. In satellite males no differences between Control and High dose were observed. No findings were seen in females.

Gross pathological findings:

not specified

Description (incidence and severity):

All animals were necropsied. During necropsy, hydrometra and uterus filled with blood were observed in two females. No other macroscopically changes were noticed.

Effect levels

1

Key result

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Remarks on result:

other: Based on the reproduction toxicity

2

Key result

Dose descriptor:

NOAEL

Effect level:

100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Remarks on result:

other: Based on the reproduction toxicity

3

Key result

Dose descriptor:

NOAEL

Effect level:

250 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Remarks on result:

other: Based on the systemic toxicity

Target system / organ toxicity

1

Critical effects observed:

no

System:

haematopoietic

2

Critical effects observed:

no

System:

urinary

Any other information on results incl. tables

After consideration of the results of this study following conclusions were made regarding the test item Gamma Terpinene.

The test item

- did not cause mortality of animals

- had no visible toxic effect on animals

- had no influence on haematological and clinical chemistry parameters

- did not cause changes in urine

- did not cause of macroscopic findings on the examined organs

- had no influence on the locomotor activity, reaction time and grip strength

- did not cause histopathological changes on examined organs

The test item Gamma Terpinene had effect on reproduction parameters

- High dose group – 250 mg/kg showed significant decrease in pregnancy achievement and decreased number of implantations

- increase of preimplantation loss in all treatment groups, with marked influence in the High dose group

The test item Gamma Terpinene applied 28 days to males caused reversible changes

- in all used doses significant increase of relative weight of liver

- in High dose – 250 mg/kg increase relative weight of spleen and decrease of thymus

No-observed-adverse-effect level (NOAEL)

Based on the reproduction toxicity

• NOAEL for females was concluded to be 100 mg/kg

• NOAEL for males was concluded to be 250 mg/kg

Based on the systemic toxicity

• NOAEL for systemic toxicity in males and females was concluded to be 250 mg/kg