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Toxicological information

Developmental toxicity / teratogenicity

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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:
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:
SIDS Initial Assessment Report 2003 evaluated L, D, and racemic L/D mentols together and gives the rational for a menthol category as follows:
"Category Rationale: The menthols category is comprised of the isomers L-menthol, D-menthol, the racemate and menthol (unspecified
isomers). The menthols can be considered as a category because of their similarity in physico-chemical, toxicological,
ecotoxicological and environmental fate properties.
...
In summary, the available toxicity data indicate very similar toxicity profiles for all of the menthol isomers investigated."

The category justification is documented in a comprehensive 15 page annex to the SIDS Assessment report (Annex 1: Menthols Category JustificationCategory Justification). The annex is attached to the study record entry on the OECD SIDS evaluation as attached background material.
Reason / purpose:
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

Reference
Name:
Unnamed
Type:
Constituent
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

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.