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

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Based on a read across evaluation, the registered substance has a comparable physicochemical and toxicological profile to d-limonene. The study was conducted according to valid methods, however standards were slightly different at time of testing and limited data were available. In combination with the other weight of evidence, the data are considered relevant, reliable and adequate for classification.

Data source

Reference

Reference 1

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., Lucas C., 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

Reference 2

Reference Type:

publication

Title:

Studies on D-limonene as a gallstone solubilizer (V) effects on development of rat fetuses and offsprings

Author:

Tsuji, M., Fujiski, Y., Okubo, A., Arikawa, Y., Noda, K., Ide, H., Ikeda, T.

Year:

1975

Bibliographic source:

Oyo Yakuri 10, 179–186

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

not specified

Principles of method if other than guideline:

Groups of pregnant Wistar rats (20/dose: 15 for teratogenicity study, 5 for postnatal development)

GLP compliance:

not specified

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

Details on test material:

- Name of test material (as cited in study report): d-limonene
- Molecular formula (if other than submission substance): C10-H16
- Molecular weight (if other than submission substance): 136.24 g/mol
- Smiles notation (if other than submission substance): C([C@@H]1CCC(C)=CC1)(C)=C
- InChl (if other than submission substance): InChI=1S/C10H16/c1-8(2)10-6-4-9(3)5-7-10/h4,10H,1,5-7H2,2-3H3/t10-/m0/s1
- Structural formula attached as image file (if other than submission substance): See illustration attached
- Substance type: Organic monoconstituent
- Physical state: Clear, colorless liquid

Test animals

Species:

rat

Strain:

Wistar

Details on test animals or test system and environmental conditions:

TEST ANIMALS
Pregnant Wistar rats

Administration / exposure

Route of administration:

oral: unspecified

Vehicle:

other: 1% gum-arabic solution

Details on exposure:

Volume administered: 5 mL/kg bw for all doses

Duration of treatment / exposure:

Days 9-15 of gestation.

Frequency of treatment:

Once daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 591, or 2869 mg/kg bw/day
Basis:
no data

No. of animals per sex per dose:

20

Control animals:

yes

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
Maternal toxicity was noted in the high-dose (40% mortality and decreased body weight on gestation day 16 compared to controls); however, by gestation day 20, body weights of high-dose dams were not significantly different from controls. No effects were seen in the low-dose group (591 mg/kg bw/day).

Effect levels (maternal animals)

Dose descriptor:

NOAEL

Effect level:

591 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
The offspring of dams in the high-dose group showed several signs of toxicity including significant decreases in body weight in males, absolute and relative weights of the thymus and spleen in males and females, and absolute and relative ovary weights in females. High-dose offspring also exhibited delayed ossification of the metacarpal bone and proximal phalanx. However, any retarded ossification returned to normal within several weeks of birth. In the offspring of low-dose dams, males were reported to have significantly increased relative testes weights, while females exhibited significantly decreased absolute kidney weights compared to controls.

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

591 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: embryotoxicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Applicant's summary and conclusion

Executive summary:

In a prenatal developmental toxicity study, three groups of 20 female Wistar rats were orally administered 0, 591 and 2869 mg/kg bw/day of d-limonene on days 9–15 of gestation. Caesarean sections were performed on 15/20 rats and the number of dead, live or resorbed fetuses, sex ratio and number of implantation sites were recorded. Fetuses were weighed and examined for external, visceral and skeletal malformations. On the other 5/20, the number of live offsprings, gross differentiation and organ weights of offsprings were recorded until postnatal week 7.Maternal toxicity was noted in the high dose group, including increased mortality (40%) and decreased body weight on gestation day 16 compared to controls; however, by gestation day 20, body weights of high dose dams were not significantly different from controls. No effects were seen in the low-dose group (591 mg/kg bw/day). The offspring of dams in the high-dose group showed several signs of toxicity including significant decreases in body weight in males, absolute and relative weights of the thymus and spleen in males and females, and absolute and relative ovary weights in females. High-dose offspring also exhibited delayed ossification of the metacarpal bone and proximal phalanx. However, any retarded ossification returned to normal within several weeks of birth. In the offspring of low-dose dams, males were reported to have significantly increased relative testes weights, while females exhibited significantly decreased absolute kidney weights compared to controls.

Under the test conditions, the NOAEL for maternal toxicity was considered to be 591 mg/kg bw/day based on the deaths and decreased bodyweight gain. The NOAEL for fetal toxicity was considered to be 591 mg/kg bw/day based on the delayed skeletal formation and decreased bodyweight gain.