Exo-1-methyl-4-(1-methylethyl)-7-oxabicyclo[2.2.1]heptan-2-ol

Endpoint summary

Description of key information

Skin irritation: in a 4 hour skin irritation test, the test item caused no skin reactions and thus is not a skin irritant in rabbits.

Eye irritation: the test substance caused severe irritation in rabbits..

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

1981

GLP compliance:

yes

Specific details on test material used for the study:

STABILITY AND STORAGE CONDITIONS OF TEST MATERIAL
- Storage condition of test material: The test substance was stored in the dark at ambient temperature

FORM AS APPLIED IN THE TEST
Preparation of the test substance for formulation: The test substance as received was contained in a narrow necked vessel. Before being used for formulation purposes all of the test substance was melted in an oven at 70 °C, well mixed, and then sub-sampled into smaller vessels. One of these sub-samples was submitted to the Analytical Chemistry Division for analysis.
Formulation of the test substance: The test substance was supplied as a ground up solid for the skin irritancy test. Grinding was carried out using a pestle and mortar.

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Rabbits were obtained from Sittingbourne Research Centre Breeding unit.
- Age at study initiation: 4 - 9 months
- Weight at study initiation: Males: 3486 to 4124 g; Females: 4560 to 4868 g
- Housing: The animals were singly housed in hanging, stainless-steel cages with perforated dimple or all-mesh floors, all mesh tops and half-mesh fronts; each cage mesured 67 cm x 43 cm x 45 cm. The cages were mounted in three rows of two on a single-sided rack (total of six cages).
- Diet: Standard Rabbit Diet, S.Q.C., Special Diet Services Ltd., Essex; provided ad libitum by means of a top-loading food hopper
- Water: Water (filtered but untreated from public supply) was provided ad libitum by means of an automatic valve-regulated drinking line.
- Acclimation period: At least two weeks.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 16-19 °C
- Photoperiod (hrs dark / hrs light): 12/12

Type of coverage:

semiocclusive

Preparation of test site:

shaved

Vehicle:

water

Controls:

no

Amount / concentration applied:

TEST MATERIAL
- Amount applied: 250 mg (this dose equating the largest dose that could practicably be used)

Duration of treatment / exposure:

4 h

Observation period:

7 days

Number of animals:

6 (3 animals per sex)

Details on study design:

TEST SITE
- Area of exposure: 2 cm x 2 cm
- Type of wrap if used: The test powder and surrounding skin were covered by a single layer of gauze and held in place by means of an elastic adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing: Yes. After 4 hours the wrapping and patch were removed and the test site washed with water and gently dried.
- Time after start of exposure: 4h

OBSERVATION TIME POINTS: 30 min, 24h, 48h, 72h and 7 days

SCORING SYSTEM: See table 1 for details.

Irritation parameter:

edema score

Basis:

mean

Time point:

other: 4, 24, 48, 72 h and 7d

Score:

0

Max. score:

4

Remarks on result:

other: See table 2 for detailed information

Irritation parameter:

erythema score

Basis:

mean

Time point:

other: 4, 24, 48, 72 h and 7d

Score:

0

Max. score:

4

Remarks on result:

other: See table 2 for detailed information

Table 2: Primary irritation of semi-occluded rabbit skin after a single application of the test item (4 hours exposure)

Animal No & sex	Response	4 hours	24 hours	48 hours	72 hours	7 days
937 M	Erythema	0	0	0	0	0
	Oedema	0	0	0	0	0
934 M	Erythema	0	0	0	0	0
	Oedema	0	0	0	0	0
935 M	Erythema	0	0	0	0	0
	Oedema	0	0	0	0	0
917 F	Erythema	0	0	0	0	0
	Oedema	0	0	0	0	0
920 F	Erythema	0	0	0	0	0
	Oedema	0	0	0	0	0
915 F	Erythema	0	0	0	0	0
	Oedema	0	0	0	0	0
Mean Erythema score		0	0	0	0	0
Mean Oedema score		0	0	0	0	0

Scale:

Erythema readings 0 = No erythema to 4 = Beet redness

Oedema readings 0 = No oedema to 4 = Severe oedema

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

Observation period of only 7 days instead of 21 days

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Scarlet's Rabbitry, Harveys Lake, PA
- Age at study initiation: Young adult
- Housing: The animals were individually housed in wire mesh bottom cages in an environment-controlled room.
- Diet: NIH 09 Rabbit Ration (Zeigler Brothers, Gardners, PA); ad libitum
- Water: Water; ad libitum
- Acclimation period: At least of 5 days

Vehicle:

unchanged (no vehicle)

Controls:

yes

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL

Duration of treatment / exposure:

Single treatment. 0.1 mL of the test article was instilled in to one eye of each rabbit.

Observation period (in vivo):

7 days

Number of animals or in vitro replicates:

6

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing: None

SCORING SYSTEM: Draize Scale

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

fully reversible

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

fully reversible

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

2.7

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

fully reversible

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

fully reversible

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

3

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

cornea opacity score

Basis:

animal #4

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

iris score

Basis:

animal #4

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

conjunctivae score

Basis:

animal #4

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

not fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal #4

Time point:

24/48/72 h

Score:

3.3

Max. score:

4

Reversibility:

not fully reversible within: 7 days

Irritation parameter:

cornea opacity score

Basis:

animal #5

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

iris score

Basis:

animal #5

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

conjunctivae score

Basis:

animal #5

Time point:

24/48/72 h

Score:

3

Max. score:

3

Reversibility:

not fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal #5

Time point:

24/48/72 h

Score:

3

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

cornea opacity score

Basis:

animal #6

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

iris score

Basis:

animal #6

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

conjunctivae score

Basis:

animal #6

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

fully reversible

Irritation parameter:

chemosis score

Basis:

animal #6

Time point:

24/48/72 h

Score:

3.3

Max. score:

4

Reversibility:

fully reversible

Irritant / corrosive response data:

No effects were observed in the control eyes.

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

Observation period of only 7 days instead of 21 days

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Scarlet's Rabbitry, Harveys Lake, PA
- Age at study initiation: Young adult
- Housing: The animals were individually housed in wire mesh bottom cages in an environment-controlled room.
- Diet: NIH 09 Rabbit Ration (Zeigler Brothers, Gardners, PA); ad libitum
- Water: Water; ad libitum
- Acclimation period: At least of 5 days

Vehicle:

unchanged (no vehicle)

Controls:

yes

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL

Duration of treatment / exposure:

Single treatment. 0.1 mL of the test article was instilled in to one eye of each rabbit.

Observation period (in vivo):

7 days

Number of animals or in vitro replicates:

6

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing: None

SCORING SYSTEM: Draize Scale

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

3

Max. score:

3

Reversibility:

not fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

3.7

Max. score:

4

Reversibility:

not fully reversible within: 7 days

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

3

Max. score:

3

Reversibility:

not fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

3.3

Max. score:

4

Reversibility:

not fully reversible within: 7 days

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

2.7

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

3

Max. score:

3

Reversibility:

not fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

4

Max. score:

4

Reversibility:

not fully reversible within: 7 days

Irritation parameter:

cornea opacity score

Basis:

animal #4

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

iris score

Basis:

animal #4

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

conjunctivae score

Basis:

animal #4

Time point:

24/48/72 h

Score:

3

Max. score:

3

Reversibility:

not fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal #4

Time point:

24/48/72 h

Score:

4

Max. score:

4

Reversibility:

not fully reversible within: 7 days

Irritation parameter:

cornea opacity score

Basis:

animal #5

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

iris score

Basis:

animal #5

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

conjunctivae score

Basis:

animal #5

Time point:

24/48/72 h

Score:

3

Max. score:

3

Reversibility:

not fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal #5

Time point:

24/48/72 h

Score:

4

Max. score:

4

Reversibility:

not fully reversible within: 7 days

Irritation parameter:

cornea opacity score

Basis:

animal #6

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

not fully reversible within: 7 days

Irritation parameter:

iris score

Basis:

animal #6

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

conjunctivae score

Basis:

animal #6

Time point:

24/48/72 h

Score:

2.3

Max. score:

3

Reversibility:

not fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal #6

Time point:

24/48/72 h

Score:

4

Max. score:

4

Reversibility:

not fully reversible within: 7 days

Irritant / corrosive response data:

No effects were observed in the control eyes.

Reference 3

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

Observation period of only 7 days instead of 21 days

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: Ace Animals, Inc., Boyertown, Pa for use in this study
- Age at study initiation: Young adult
- Housing: The animals were individually housed in wire mesh bottom cages in an environment-controlled room.
- Diet: NIH 09 Rabbit Ration (Zeigler Brothers, Gardners, PA); ad libitum
- Water: Water; ad libitum
- Acclimation period: At least of 5 days

Vehicle:

unchanged (no vehicle)

Controls:

yes

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL

Duration of treatment / exposure:

Single treatment. 0.1 mL of the test article was instilled in to one eye of each rabbit.

Observation period (in vivo):

7 days

Number of animals or in vitro replicates:

6

Details on study design:

REMOVAL OF TEST SUBSTANCE
- Washing: None

SCORING SYSTEM: Draize Scale

Irritation parameter:

cornea opacity score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

iris score

Basis:

animal #1

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

not reversible

Irritation parameter:

conjunctivae score

Basis:

animal #1

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

not reversible

Irritation parameter:

chemosis score

Basis:

animal #1

Time point:

24/48/72 h

Score:

3

Max. score:

4

Reversibility:

not reversible

Irritation parameter:

cornea opacity score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 7 days

Irritation parameter:

iris score

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

fully reversible within: 7 days

Irritation parameter:

conjunctivae score

Basis:

animal #2

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

not fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal #2

Time point:

24/48/72 h

Score:

3

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

cornea opacity score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

iris score

Basis:

animal #3

Time point:

24/48/72 h

Score:

0.7

Max. score:

2

Reversibility:

fully reversible

Irritation parameter:

conjunctivae score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1.3

Max. score:

3

Reversibility:

fully reversible

Irritation parameter:

chemosis score

Basis:

animal #3

Time point:

24/48/72 h

Score:

1.3

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

cornea opacity score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

iris score

Basis:

animal #4

Time point:

24/48/72 h

Score:

0.3

Max. score:

2

Reversibility:

fully reversible

Irritation parameter:

conjunctivae score

Basis:

animal #4

Time point:

24/48/72 h

Score:

1.7

Max. score:

3

Reversibility:

fully reversible

Irritation parameter:

chemosis score

Basis:

animal #4

Time point:

24/48/72 h

Score:

1.7

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

cornea opacity score

Basis:

animal #5

Time point:

24/48/72 h

Score:

0.3

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

iris score

Basis:

animal #5

Time point:

24/48/72 h

Score:

1

Max. score:

2

Reversibility:

fully reversible

Irritation parameter:

conjunctivae score

Basis:

animal #5

Time point:

24/48/72 h

Score:

2

Max. score:

3

Reversibility:

fully reversible

Irritation parameter:

chemosis score

Basis:

animal #5

Time point:

24/48/72 h

Score:

2.3

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

cornea opacity score

Basis:

animal #6

Time point:

24/48/72 h

Score:

0.7

Max. score:

4

Reversibility:

fully reversible

Irritation parameter:

iris score

Basis:

animal #6

Time point:

24/48/72 h

Score:

0.7

Max. score:

2

Reversibility:

fully reversible

Irritation parameter:

conjunctivae score

Basis:

animal #6

Time point:

24/48/72 h

Score:

1.7

Max. score:

3

Reversibility:

not fully reversible within: 7 days

Irritation parameter:

chemosis score

Basis:

animal #6

Time point:

24/48/72 h

Score:

1.7

Max. score:

4

Reversibility:

not fully reversible within: 7 days

Irritant / corrosive response data:

No effects were observed in the control eyes.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (irreversible damage)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation: 

In a skin irritation study according to OECD guideline 404 (1981) six New Zealand White rabbits (3/sex) were dermally exposed to 250 mg of the test substance in water under semi-occlusive conditions. After 4 hours the wrapping and patch were removed and the test site was washed with water. The site was examined and scored for erythema and oedema after 4 h, 24 h, 48 h, 72 h and 7 days after patch removal. The test item caused no skin reactions when applied to the back of six rabbits and thus is not considered to be a skin irritant.

Additionally, two skin irritation tests with 24 hours exposure time under occlusive conditions exist. In both tests, the substance showed erythema, but only barely perceptible edema at 24.5 and 72 hours following start of exposure. These findings were made with abraded and non-abraded skin. These studies have several limitations: The purity of the test material was not stated, analytical verification of test material identiy is unlcear. The exposure time was very long with 24 hours and read-outs were performed only at 0.5 and 48 hours following removal of the wrapping. Additionally, the reversibility of effects could not be assessed since 72 hours following start of exposure was the last observation time point. Therefore, these studies are not considered adequate for evaluation of the skin irration endpoint and have been disregarded in favor of the guideline study mentioned above.

Eye irritation:

An eye irritation/corrosion test for three batches of the test substance in New Zealand White rabbits is available equivalent to OECD guideline 405. A volume of 0.1 mL of the test item was instilled into one eye of each rabbit. The other eye served as the untreated control. All eyes were examined with fluorescein and the grade of ocular reaction for each animal was recorded at 24, 48 and 72 hours post-treatment and again at 7 days using the Draize scale. Instead of an observation period of 21 days, which is recommended in the guideline, only a 7 day observation period was conducted and thus the reversibility could not be adequately addressed. Under the conditions of these tests, the test substance had effects on the rabbit eyes that were not fully reversible within an observation period of 7 days. Due to worst case considerations, this substance is considered to cause serious eye damage.

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on available data on skin and eye irritation/corrosion, the test item is to be classified as an eye irritant cat 1, H318 ('causes serious eye damage') according to Regulation (EC) No 1272/2008 (CLP), as amended for the tenth time in Regulation (EU) No 2017/776.