Reaction mass of 1-methyl-4-(1-methylethyl)-7-oxabicyclo[2.2.1]heptane and cineole

Acute Toxicity: dermal

Administrative data

Endpoint:

acute toxicity: dermal

Type of information:

experimental study

Adequacy of study:

key study

Study period:

17-31 May 2016

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Remarks:

GLP study performed according to OECD Guideline 402 without any deviation

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2017

Report date:

2017

Materials and methods

Test guideline

Test guideline 1

Qualifier:

according to guideline

Guideline:

OECD Guideline 402 (Acute Dermal Toxicity)

Version / remarks:

dated 24 February 1987

Deviations:

no

Test guideline 2

Qualifier:

according to guideline

Guideline:

EU Method B.3 (Acute Toxicity (Dermal))

Version / remarks:

dated 30 May 2008

Deviations:

no

Principles of method if other than guideline:

Not applicable

GLP compliance:

yes (incl. QA statement)

Remarks:

23 October 2015

Test type:

standard acute method

Limit test:

yes

Test material

Test material information

Constituent 1

Reference substance name:

1-methyl-4-(1-methylethyl)-7-oxabicyclo[2.2.1]heptane

EC Number:

207-428-9

EC Name:

1-methyl-4-(1-methylethyl)-7-oxabicyclo[2.2.1]heptane

Cas Number:

470-67-7

Molecular formula:

C10H18O

IUPAC Name:

1-isopropyl-4-methyl-7-oxabicyclo[2.2.1]heptane

Constituent 2

Reference substance name:

Cineole

EC Number:

207-431-5

EC Name:

Cineole

Cas Number:

470-82-6

Molecular formula:

C10H18O

IUPAC Name:

1,3,3-trimethyl-2-oxabicyclo[2.2.2]octane

impurity 1

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

Molecular formula:

C10H16

IUPAC Name:

(4R)-isopropenyl-1-methylcyclohexene

impurity 2

Reference substance name:

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

EC Number:

227-815-6

EC Name:

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

Cas Number:

5989-54-8

Molecular formula:

C10H16

IUPAC Name:

(4S)-isopropenyl-1-methylcyclohexene

impurity 3

Reference substance name:

p-mentha-1,3-diene

EC Number:

202-795-1

EC Name:

p-mentha-1,3-diene

Cas Number:

99-86-5

Molecular formula:

C10H16

IUPAC Name:

1-isopropyl-4-methylcyclohexa-1,3-diene

impurity 4

Reference substance name:

(1R)-2,2-dimethyl-3-methylenebicyclo[2.2.1]heptane

EC Number:

227-336-2

EC Name:

(1R)-2,2-dimethyl-3-methylenebicyclo[2.2.1]heptane

Cas Number:

5794-03-6

Molecular formula:

C10H16

IUPAC Name:

(1R,4S)-2,2-dimethyl-3-methylenebicyclo[2.2.1]heptane

impurity 5

Reference substance name:

(1S)-2,2-dimethyl-3-methylenebicyclo[2.2.1]heptane

EC Number:

227-337-8

EC Name:

(1S)-2,2-dimethyl-3-methylenebicyclo[2.2.1]heptane

Cas Number:

5794-04-7

Molecular formula:

C10H16

IUPAC Name:

(1S,4R)-2,2-dimethyl-3-methylenebicyclo[2.2.1]heptane

impurity 6

Reference substance name:

(+)-pin-2(3)-ene

EC Number:

232-087-8

EC Name:

(+)-pin-2(3)-ene

Cas Number:

7785-70-8

Molecular formula:

C10H16

IUPAC Name:

(1R,5R)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene

impurity 7

Reference substance name:

(-)-pin-2(3)-ene

EC Number:

232-077-3

EC Name:

(-)-pin-2(3)-ene

Cas Number:

7785-26-4

Molecular formula:

C10H16

IUPAC Name:

(1S,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-2-ene

impurity 8

Reference substance name:

7,7-dimethyl-2-methylene-(1R,4S)-bicyclo[2.2.1]heptane

Cas Number:

116724-26-6

Molecular formula:

C10H16

IUPAC Name:

7,7-dimethyl-2-methylene-(1R,4S)-bicyclo[2.2.1]heptane

impurity 9

Reference substance name:

7,7-dimethyl-2-methylene-, (1S,4R)-bicyclo[2.2.1]heptane

Cas Number:

7378-37-2

Molecular formula:

C10H16

IUPAC Name:

7,7-dimethyl-2-methylene-, (1S,4R)-bicyclo[2.2.1]heptane

impurity 10

Reference substance name:

1,7,7-trimethyltricyclo[2.2.1.02,6]heptane

EC Number:

208-083-7

EC Name:

1,7,7-trimethyltricyclo[2.2.1.02,6]heptane

Cas Number:

508-32-7

Molecular formula:

C10H16

IUPAC Name:

1,7,7-trimethyltricyclo[2.2.1.0~2,6~]heptane

impurity 11

Reference substance name:

(5S)-isopropyl-2-methylcyclohexa-1,3-diene

Cas Number:

2243-33-6

Molecular formula:

C10H16

IUPAC Name:

(5S)-isopropyl-2-methylcyclohexa-1,3-diene

impurity 12

Reference substance name:

(R)-5-isopropyl-2-methylcyclohexa-1,3-diene

EC Number:

224-167-6

EC Name:

(R)-5-isopropyl-2-methylcyclohexa-1,3-diene

Cas Number:

4221-98-1

Molecular formula:

C10H16

IUPAC Name:

(5R)-isopropyl-2-methylcyclohexa-1,3-diene

impurity 13

Reference substance name:

p-cymene

EC Number:

202-796-7

EC Name:

p-cymene

Cas Number:

99-87-6

Molecular formula:

C10H14

IUPAC Name:

1-isopropyl-4-methylbenzene

impurity 14

Reference substance name:

Non identified impurities

Molecular formula:

Not applicable

IUPAC Name:

Non identified impurities

Test material form:

liquid

Details on test material:

Batch No.: 174984
Purity: 76.7% (sum of the two main constituents)
Name of test material (as cited in study report): REACTION MASS OF 1,4-CINEOLE AND 1,8-CINEOLE
Physical state: colourless liquid
Storage conditions: +2°C to +8°C, under nitrogen and protected from light
Expiry date: 16 December 2016

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Elevage JANVIER LABS, France
- Females (if applicable) nulliparous and non-pregnant: Yes
- Age at study initiation: 7 or 8 weeks
- Weight at study initiation: 249-280 g (males); 201-220 g (females)
- Housing: On Day 1 of the study, animals were housed by group of five in solid-bottomed clear polycarbonate cages with a stainless steel mesh lid. During the treatment, the animals were kept in individual cages.
- Diet (e.g. ad libitum): Foodstuff (SAFE - A04), ad libitum
- Water (e.g. ad libitum): Drinking water (tap-water from public distribution system), ad libitum
- Acclimation period: At least 5 days

ENVIRONMENTAL CONDITIONS
- Temperature: 19-25°C
- Humidity: 30-70%
- Air changes: At least 10/hour
- Photoperiod: 12 hours dark / 12 hours light

Administration / exposure

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on dermal exposure:

TEST SITE
- Area of exposure: Dorsal area of the trunk (50 mm X 50 mm)
- % coverage: At least 10% of the body surface area
- Type of wrap if used: Animals from treated groups received the topical application of the test material under non occlusive porous gauze dressing (50 mm x 50 mm non-woven swab of 4-layer patch from MEDISTOCK) secured in position with a strip of surgical adhesive tape (50 mm wides hypoallergenic microporeTM adhesive tape from 3M).

REMOVAL OF TEST SUBSTANCE
- Time after start of exposure: 24 hours
- Washing (if done): After removal of the gauze dressings, the treated area was rinsed with distilled water.


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2.23 mL/kg bw

Duration of exposure:

24 hours

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

5

Control animals:

other: historical control

Details on study design:

- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: Clinical observations and mortality were recorded at 1 hour, 3 hours, 5 hours, and then once daily for 14 days. Animals were weighed on Day D0 (just before administering the test item) and then on Day 2, Day 7, and Day 14.
- Necropsy of survivors performed: Yes; animals were euthanized with sodium pentobarbital on Day 14 and macroscopic observations were noted.

Statistics:

No data

Results and discussion

Preliminary study:

Not applicable

Effect levels

Key result

Sex:

male/female

Dose descriptor:

LD50

Effect level:

> 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

other: erythema was noted in all animals at 24-hour post-dose and was totally reversible on Day 6.

Mortality:

No mortality occurred during the study.

Clinical signs:

No systemic clinical signs related to the administration of the test substance were observed.

Body weight:

Body weight gain of the animals remained normal throughout the study.

Gross pathology:

The macroscopic examination of the animals at the end of the study did not reveal any treatment-related changes.

Other findings:

Erythema was noted in all animals at 24-hour post-dose and was totally reversible on Day 6.

Any other information on results incl. tables

None

Applicant's summary and conclusion

Interpretation of results:

GHS criteria not met

Conclusions:

The dermal LD50 of the test substance is > 2000 mg/kg bw in rats, therefore it is not classified according to Regulation (EC) No. 1272/2008 and according to the GHS. No signal word or hazard statement is required.

Executive summary:

In an acute dermal toxicity study performed according to OECD Guideline 402 and in compliance with GLP, a single dose of 2000 mg/kg bw of the test substance was applied onto the intact skin of 5 male and 5 female Sprague Dawley rats under occlusive conditions for 24 hours. Animals were then observed for mortality, dermal reactions, body weight changes and clinical signs of toxicity for 14 days.

No mortality occurred during the study. No systemic clinical signs related to the administration of the test substance were observed. Erythema was noted in all animals at 24-hour post-dose and was totally reversible on Day 6. Body weight gain of the animals remained normal throughout the study. The macroscopic examination of the animals at the end of the study did not reveal any treatment-related changes.

Rat Dermal LD50 > 2000 mg/kg bw.

Therefore, the dermal LD50 of the test substance is > 2000 mg/kg bw in rats and it is not classified according to Regulation (EC) No. 1272 /2008 and according to the GHS. No signal word or hazard statement is required.