Menthol

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: well documented and scientifically acceptable

Cross-reference

Reason / purpose for cross-reference:

read-across: supporting information

Reference

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

key study

Justification for type of information:

See 'Attached justification' document: Justification for a read-across approach from L-Menthol (CAS No 2216-51-5, EC No 218-690-9) [Source] to D/L-Menthol (CAS No 89-78-1, EC No 201-939-0) [Target].

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOEL

Effect level:

218 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks on result:

other: no efects observed at the highest applied dose

Abnormalities:

no effects observed

Dose descriptor:

NOAEL

Effect level:

218 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Remarks on result:

other: no effects observed at the highest applied dose

Abnormalities:

no effects observed

Developmental effects observed:

no

Conclusions:

The administration of up to 218 mg/kg (body weight) of the test material to pregnant rats for 10 consecutive days had no clearly descernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.

Executive summary:

The administration of up to 218 mg/kg (body weight) of the test material to pregnant rats for 10 consecutive days had no clearly descernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1973

Materials and methods

Principles of method if other than guideline:

Virgin adult female albino rats (Wistar derived stock) were individually housed in mesh bottom cages in temperature and humidity-controlled quarters with free access to food and fresh tap water.
They were mated with young adult males, and observation of the vaginal sperm plug was considered Day 0 of gestation. Beginning on Day 6 and continuing daily through Day 15 of gestation, the females were dosed with the indicated dosage s by oral intubations. The controls were sham treated with the vehicle at a level equivalent to the group receiving the highest test dose.
Body weights were recorded on Days 0, 6, 11, 15, and 20 of gestation. All animals were observed daily for appearance and behavior with particular attention to food consumption and weight, in order to rule out any abnormalities which may have occurred as a result of anorexic effects in the pregnant female animal.
On Day 20 all dams were subjected to Caesarean section under surgical anesthesia and the numbers of implantation sites, resorption sites, and live and dead fetuses were recorded. The body weights of the live pups were also recorded. The urogenital tract of each dam was examined in detail for anatomical normality.
All fetuses were examined grossly for the presence of external congenital abnormalities. One-third of the fetuses of each litter underwent detailed visceral examinations employing l0 x magnification. The remaining two-thirds were cleared in potassium hydroxide (KOH), stained with alizarin red S dye and examined for skeletal defects.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

L-menthol

EC Number:

218-690-9

EC Name:

L-menthol

Cas Number:

2216-51-5

Molecular formula:

C10H20O

IUPAC Name:

(1R,2S,5R)-2-isopropyl-5-methyl-cyclohexanol

Specific details on test material used for the study:

Menthol natural, brazilian (FDA 71-57).
Menthol natural, brazilian (FDA 71-57) is L-menthol (CAS 2216-51-5). L-menthol is a constituent of menthol racemic (CAS 89-78-1).

Test animals

Species:

rat

Strain:

Wistar

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

not specified

Details on mating procedure:

They were mated with young adult males, and observation of the vaginal sperm plug was considered Day 0 of gestation

Duration of treatment / exposure:

Beginning on Day 6 and continuing daily through Day 15 of gestation, the females were dosed with the indicated dosage s by oral intubations. The controls were sham treated with the vehicle at a level equivalent to the group receiving the highest test dose.
On Day 20 all dams were subjectcd to Cacsarean section under surgical anesthesia

Frequency of treatment:

daily

Duration of test:

20 days

No. of animals per sex per dose:

22-23 animals/dose

Control animals:

other: sham treated with corn oil

Details on study design:

Sex: female

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Dose descriptor:

NOEL

Effect level:

218 mg/kg bw/day (nominal)

Based on:

test mat.

Remarks on result:

other: no efects observed at the highest applied dose

Maternal abnormalities

Abnormalities:

no effects observed

Results (fetuses)

Effect levels (fetuses)

Dose descriptor:

NOAEL

Effect level:

218 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Remarks on result:

other: no effects observed at the highest applied dose

Fetal abnormalities

Abnormalities:

no effects observed

Overall developmental toxicity

Developmental effects observed:

no

Any other information on results incl. tables

All dose groups: no clearly discernible effect on nidation or on maternal or fetal survival; the number of abnormalities seen in either soft or skeletal tissues not differing from the number occuring  spontaneously in the controls.

Reproduction data:

Group: Dose (mg/kg):	Sham	2.18	10.15	47.05	218.0
Pregnancies Total. No. Died or aborted (before day 20) To term (on day 20)	25 0 25	22 0 22	23 0 23	23 0 23	22 0 22
Live Litters Total No.*	25	22	23	23	22
Implant sites total No. Average/dam*	241  9.64	256 11.6	266 11.6	275 12.0	250 11.4
Resorptions Total No.* Dams with 1 or more sites resorbed Dams with all sites resorbed Per cent partial resorptions Per cent complete resorptions	5 4 - 16 .0 -	8 3 - 13.6 -	- - - - -	2 2 - 8.70 -	4 4 - 18.2 -
Live Fetuses Total No.. Average/dam* Sex ratio (M//F)	236 9.44 0.79	248 11.3 1.07	266 11.6 0.72	273 11.9 0.82	246 11.2 0.85
Dead Fetuses Total* Dans with 1 or more dead Dams with all dead Per cent partial dead Per cent all dead	- - - - -	- - - - -	- - - - -	- - - - -	- - - - -
Average Fetus Weight, g	3.82	3.82	3.82	3.85	3.88

* Includes only those dams examined at term.

Summary of skeletal findings*

Findings Dose (mg/kg)	Sham	2.18	10.15	47.05	218.0
Live Fetuses Examined (at term)	167/25	175/22	183/23	190/23	173/22
Sternebrae Incomplete oss. Scrambled Bipartite Fused Extra Missing Other	80/22 1/1 14/6	92/20 11/8	93/22 2/2 17/5	101/19 11/4	92/19 1/1
Ribs Incomplete oss. Fused/split Wavy Less than 12 More than 13 Other	25/10 3/3	33/13 5/3	1/1 19/10 2/2	21/10 2/2	16/8 3/3
Vertebrae Incomplete oss. Scrambled Fused Extra ctrs. oss. Scoliosis Tail defects Other	9/5	11/6	12/7	14/7	10/7
Skull Incomplete closure Missing Craniostosis Other	41/16	46/15	63/16	67/20	49/17
Extremities Incomplete oss. Missing Extra	1/1
Miscellaneous Hyoid; missing Hyoid; reduced	18/13 13/10	18/8 25/1	27/12 16/10	22/13 20/10	15/9 19/7

* Numerator = Number of fetuses affected; Denominator = Number of litters

Summary of Soft Tissue Abnormalities

Group	Material	Dose level mg/kg	Dam	Number of pubs	Description
254	FDA 71 -57	10.15	K 4044 K 4053	1 1	Petechiae Anophthalmia
255	FDA 71 -57	40.05	K 4064 K 4066 K 4072 K 4075 K 4084	1 1 1 1 1	Hydrocephalus: lobster claw Anophthalmia Anophthalmia Gastroschisis Gastroschisis

Applicant's summary and conclusion

Executive summary:

The administration of up to 218 mg/kg (body weight) of the test material to pregnant rats for 10 consecutive days had no clearly descernible effect on nidation or on maternal or fetal survival. The number of abnormalities seen in either soft or skeletal tissues of the test groups did not differ from the number occurring spontaneously in the sham-treated controls.