Cyclohexane, 1-methyl-4-(1-methylethyl)-, tetradehydro deriv.

Repeated dose toxicity: oral

Administrative data

Endpoint:

chronic toxicity: oral

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: Based on a read across evaluation, the registered substance has a comparable physicochemical and toxicological profile to d-limonene. Current study has limited data, however it has contributed to the understanding of the safety profile.

Data source

Reference

Reference Type:

review article or handbook

Title:

The FEMA GRAS assessment of aliphatic and aromatic terpene hydrocarbons used as flavor ingredients

Author:

Adams T.B., Gavin C.L., McGowen M.M., Waddell W.J., Cohen S.M. , Feron V.J., Marnett L.J., Munro I.C. , Portoghese P.S., Rietjens I.M.C.M., Smith R.L.

Year:

2011

Bibliographic source:

Food and Chemical Toxicology 49 (2011) 2471-2494

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 409 (Repeated Dose 90-Day Oral Toxicity Study in Non-Rodents)

Deviations:

not specified

Principles of method if other than guideline:

6 months dosing; small group sizes; limited No. of parameters.

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

D-Limonene

IUPAC Name:

D-Limonene

Constituent 2

Reference substance name:

(R)-p-mentha-1,8-diene

EC Number:

227-813-5

EC Name:

(R)-p-mentha-1,8-diene

Cas Number:

5989-27-5

IUPAC Name:

4-isopropenyl-1-methylcyclohexene

Test material form:

other: liquid

Test animals

Species:

dog

Strain:

Beagle

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Duration of treatment / exposure:

6 months

Frequency of treatment:

in divided doses twice a day

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 100, or 1000 mg /kg bw/day
Basis:
actual ingested

No. of animals per sex per dose:

5

Examinations

Observations and examinations performed and frequency:

OBSERVATIONS: Yes
- Time schedule: Observations were made following each dose for 1 h to assess effects of treatment.

BODY WEIGHT: Yes

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined : Yes

HAEMATOLOGY: Yes
.
CLINICAL CHEMISTRY: Yes

URINALYSIS: Yes

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Sporadic diarrhea and emesis in high and low-dose groups.

Mortality:

mortality observed, treatment-related

Description (incidence):

Sporadic diarrhea and emesis in high and low-dose groups.

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

35% increase in serum cholesterol and a 2-fold increase in serum alkaline phosphatase levels in high-dose dogs of both sexes.

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

A small increase (not statistically significant) in relative kidney weight in the low-dose group, but a significant increase in relative kidney weight in the high-dose group.

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Target system / organ toxicity

Critical effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Since there were no nephrotoxic effects observed in the kidneys of male and female dogs administered either dose of d-limonene for 180 consecutive days, it was concluded by the authors that the effects of d-limonene on the male rat kidney reported in NTP (1990) were specific to that sex and species.

Executive summary:

D-limonene was administered by oral gavage to groups of five male and five female adult beagle dogs in a 6-month study at doses of 0, 100, or 1000 mg /kg bw/day in divided doses twice a day. Diarrhea and emesis occurred periodically with the same frequency in high- (1000 mg/kg bw/day) and low-dose (100 mg/kg bw/day) groups. At the termination of the experiment, blood and urine samples of d-limonene-treated dogs were comparable with control groups, with the exception of a 35% increase in serum cholesterol and a 2-fold increase in serum alkaline phosphatase levels in high-dose dogs of both sexes. No significant changes were reported in the body weights or consumption of feed in either treatment group. No histological abnormalities were noted in any major organ or tissue. No hyaline droplets or histopathological changes were reported in the kidneys. A small increase (not statistically significant) in relative kidney weight was reported in the low-dose group, but a significant increase in relative kidney weight was reported in the high-dose group. Since there were no nephrotoxic effects observed in the kidneys of male and female dogs administered either dose of d-limonene for 180 consecutive days, it was concluded by the authors that the effects of d-limonene on the male rat kidney reported in NTP (1990) were specific to that sex and species.