2,4-dimethyl-4-phenyltetrahydrofuran

Endpoint summary

Description of key information

Skin irritation: not irritating (no guideline followed, K, Rel.2)

Eye irritation: not irritating (equivalent to OECD 405, K, Rel.2)

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Reference 1

Endpoint:

skin irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro skin irritation study does not need to be conducted because adequate data from an in vivo skin irritation study are available

Justification for type of information:

In accordance with section 1.1 (Use of existing data) of Annex XI to the REACH Regulation, the in-vitro skin irritation study (required in section 8.1) does not need to be conducted as a reliable in-vivo study is available and provides sound conclusive evidence that the substance is non-irritating.

Reference 2

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

June 1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Study may be used for classification purposes although there are deviations in its study protocol from the OECD TG 404. They do not include a 48-hour observation time and involve a 24-hour test material exposure followed by observations at 24 hour and 72 hours. Moreover, the test material is patched both on abraded and on intact skin of six rabbits per condition. The study is terminated after 72 hours.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Version / remarks:

Study may be used for classification purposes although there are deviations in its study protocol from the OECD TG 404. They do not include a 48-hour observation time and involve a 24-hour test material exposure followed by observations at 24 hour and 72 hours. Moreover, the test material is patched both on abraded and on intact skin of six rabbits per condition. The study is terminated after 72 hours.

Principles of method if other than guideline:

Study may be used for classification purposes although there are deviations in its study protocol from the OECD TG 404. They do not include a 48-hour observation time and involve a 24-hour test material exposure followed by observations at 24 hour and 72 hours. Moreover, the test material is patched both on abraded and on intact skin of six rabbits per condition. The study is terminated after 72 hours.

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

Not reported

Type of coverage:

occlusive

Preparation of test site:

other: Abraded or clipped

Vehicle:

unchanged (no vehicle)

Controls:

no

Amount / concentration applied:

0.5 ml

Duration of treatment / exposure:

24 hours

Observation period:

24 and 72 hours

Number of animals:

Twelve animals (6 per condition)

Details on study design:

Primary irritation to the skin is measured by a patch-test technique on the abraded and intact skin of albino rabbits.
Twelve healthy adult New Zealand White albino rabbits are used for 1-4 test substances. Twenty four hours prior to applying the materials, the hair is removed from the backs of the animals with an electric clipper in such a way as to avoid abrasions.
An mount of 0.5 mL of the test substance is brought on the intact or abraded skin under a surgical patch measuring 1 inch x 1 inch. The patches are fixed to the application site by means of adhesive tape and the entire trunk of the rabbits is wrapped with an impervious material to maintain the test patches in position and to retard evaporation of volatiles substances.
Six rabbits are treated on the intact skin , the other six on the abraded skin. The abrasions are minor incisions through the stratum corneum, but not sufficiently deep to disturb the derma or to produce bleeding.
After an exposure period of 24 hours the patches and the material applied are removed and the resulting skin reactions are evaluated by the method of Draize. A second reading is made 48 hours later (72 hours after application).

Irritation parameter:

edema score

Remarks:

Mean 24 and 72 hours

Basis:

animal #1

Time point:

24/48/72 h

Score:

1.5

Max. score:

4

Reversibility:

not specified

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Remarks:

Mean 24 and 72 hours

Basis:

animal #2

Time point:

24/48/72 h

Score:

0.5

Max. score:

4

Reversibility:

not specified

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Remarks:

Mean 24 and 72 hours

Basis:

animal #3

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

not specified

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Remarks:

Mean 24 and 72 hours

Basis:

animal #4

Time point:

24/48/72 h

Score:

0.5

Max. score:

4

Reversibility:

not specified

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Remarks:

Mean 24 and 72 hours

Basis:

animal #5

Time point:

24/48/72 h

Score:

0.5

Max. score:

4

Reversibility:

not specified

Remarks on result:

probability of weak irritation

Irritation parameter:

edema score

Remarks:

Mean 24 and 72 hours

Basis:

animal #6

Time point:

24/48/72 h

Score:

0.5

Max. score:

4

Reversibility:

not specified

Remarks on result:

probability of weak irritation

Irritation parameter:

erythema score

Remarks:

Mean 24 and 72 hours

Basis:

animal #1

Time point:

24/48/72 h

Score:

3.5

Max. score:

4

Reversibility:

not specified

Remarks on result:

positive indication of irritation

Irritation parameter:

erythema score

Remarks:

Mean 24 and 72 hours

Basis:

animal #2

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

not specified

Remarks on result:

probability of weak irritation

Irritation parameter:

erythema score

Remarks:

Mean 24 and 72 hours

Basis:

animal #3

Time point:

24/48/72 h

Score:

1.5

Max. score:

4

Reversibility:

not specified

Remarks on result:

probability of mild irritation

Irritation parameter:

erythema score

Remarks:

Mean 24 and 72 hours

Basis:

animal #4

Time point:

24/48/72 h

Score:

1.5

Max. score:

4

Reversibility:

not specified

Remarks on result:

probability of mild irritation

Irritation parameter:

erythema score

Remarks:

Mean 24 and 72 hours

Basis:

animal #5

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

not specified

Remarks on result:

probability of weak irritation

Irritation parameter:

erythema score

Remarks:

Mean 24 and 72 hours

Basis:

animal #6

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

not specified

Remarks on result:

probability of weak irritation

Irritant / corrosive response data:

Rhubafurane caused moderate skin irritation. The dermal effects observed after 24 hours generally consisted of slight or well-defined erythema and/or very slight edema. Very slight ischemia, focal haemorrhages and slight edema were noted at one intact and one abraded site.
After 72 hours slight to distinct scaliness was observed at five intact and three abraded sites while two abraded sites by then showed slight incrustation.

Table 1: Individual and Average Skin Irritation Scores of Pure and Undiluted Rhubafurane

Rabbit No.	Intact skin				Rabbit No.	Abraded skin
	24 hours		72 hours			24 hours		72 hours
	A	B	A	B		A	B	A	B
1	4	2	3	1	7	4	2	4	2
2	1	0	1	1	8	1	0	2	1
3	2	1	1	1	9	0	0	0	0
4	1	0	2	1	10	1	1	4	1
5	1	1	1	0	11	1	1	1	0
6	0	0	2	1	12	0	0	1	1

A = Erythema

B = Edema

Interpretation of results:

GHS criteria not met

Conclusions:

Under the test conditions, the test material is not classified as irritant to the skin according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) and the GHS.

Executive summary:

In a dermal irritation study comparable to the OECD guideline 404, the primary irritation to the skin is measured by a patch-test technique on the abraded and intact skin of albino rabbits.

An amount of 0.5 mL of the test substance is brought on the intact or abraded skin of six healthy adult New Zealand White albino rabbits under a surgical patch fixed to the application site by means of adhesive tape.
After an exposure period of 24 hours the patches and the material applied are removed and the resulting skin reactions are evaluated by the method of Draize. A second reading is made 48 hours later (72 hours after application).

 

Rhubafurane caused moderate skin irritation. The dermal effects observed after 24 hours generally consisted of slight or well-defined erythema and/or very slight edema. Very slight ischemia, focal haemorrhages and slight edema were noted at one intact and one abraded site. After 72 hours slight to distinct scaliness was observed at five intact and three abraded sites while two abraded sites by then showed slight incrustation.

However, to use this study for classification purposes although deviations in its study protocol from the OECDTG 404 were observed, it is feasible to use such data for classification by calculating the mean values for erythema and oedema on the basis of only the 24 and 72 hours time points. Calculation of mean scores are restricted to the results obtained from intact skin. 

The mean scores calculated for each animal tested within 2 scoring times (24 and 72 h) were 3.5/1/1.5/1.5/1/1 for erythema and 1.5/0.5/1/0.5/0.5/0.5 for oedema.

 

Under the test conditions, the test material is not classified as irritant to the skin according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) and the GHS. This study is considered as acceptable and satisfies the requirement for skin irritation endpoint.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Reference 1

Endpoint:

eye irritation: in vitro / ex vivo

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

an in vitro eye irritation study does not need to be conducted because adequate data from an in vivo eye irritation study are available

Justification for type of information:

In accordance with section 1.1 (Use of existing data) of Annex XI to the REACH Regulation, the in-vitro eye irritation study (required in section 8.2) does not need to be conducted as a reliable in-vivo study is available and provides sound conclusive evidence that the substance is non-irritating.

Reference 2

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

June 1981

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Remarks:

Techniques published by the FDA of the United States (Fed. Reg. 28 (119), 5582, 1963) and Draize and Kelley (Drug. Cosmet. Industr. 71 (1952) 36) are followed.

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

Deviations to the OECD guideline 405: No 1 hour and 14-day observation period and 6 animals used instead of 3

Principles of method if other than guideline:

Techniques published by the FDA of the United States (Fed. Reg. 28 (119), 5582, 1963) and Draize and Kelley (Drug. Cosmet. Industr. 71 (1952) 36) are followed.

GLP compliance:

no

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

Not reported

Vehicle:

unchanged (no vehicle)

Controls:

yes, concurrent no treatment

Amount / concentration applied:

0.1 mL

Duration of treatment / exposure:

After administration, the upper and lower eye lid were carefully closed and subsequently held together for at least one second before releasing, to prevent loss of material.

Observation period (in vivo):

24, 48, 72 hours and 7 days after the instillation.

Number of animals or in vitro replicates:

6

Details on study design:

Six New Zealand White albino rabbits are used for each test substance. The animals are caged individually and receive no hay or other extraneous material that might enter the eyes.
The eyes of the animals are examined before testing and only those animals without observable eye defects are used. One tenth of a milliliter of the test substance is allowed to fall on the everted lower lid of one eye of each rabbit; the upper and lower eye lid are then carefully closed and subsequently held together for at least one second before releasing, to prevent loss of material. The other eye, remaining untreated, serves as a control.
The eyes are not washed following instillation and the animals are released immediately.
The eyes are examined at 24, 48, 72 hours and 7 days after instillation of the test material.
An animal is considered as giving a positive reaction if there is, at any of the readings, discernible opacity of the cornea (other than a slight dulling of the normal lustre), or ulceration of the cornea, or inflammation of the iris (other than a slight deepening of the folds (rugae) or a slight circumcorneal injection), or if such substance produces in the conjunctivae (palpebral and bulbar, excluding the cornea and iris) an obvious swelling with partial eversion of the lids, or a diffuse deep-crimson red with individual vessels not easily discernible. The FDA-scoring is used.
The test is considered positive if four or more of the animals in the test group of six rabbits exhibit a positive reaction. If one animal exhibits a positive reaction, the test is regarded as negative.
If two or three animals exhibit a positive reaction, the test is repeated, using a different group of six animals. The second test is considered as positive if three or more of the animals exhibit a positive reaction. If only one or two animals in the second test exhibit a positive reaction, the test is again repeated with a different group of six animals. Should a third test be needed, the substance will be regarded as an irritant if two or more animals exhibit a positive response.

Irritation parameter:

chemosis score

Basis:

animal: #11 and #12

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 7 days

Remarks on result:

probability of mild irritation

Irritation parameter:

chemosis score

Basis:

animal: #10

Time point:

24/48/72 h

Score:

0.6

Max. score:

4

Reversibility:

fully reversible within: 7 days

Remarks on result:

probability of mild irritation

Irritation parameter:

chemosis score

Basis:

animal: #9

Time point:

24/48/72 h

Score:

0.6

Max. score:

4

Reversibility:

fully reversible within: 7 days

Remarks on result:

probability of mild irritation

Irritation parameter:

chemosis score

Basis:

animal: #7 and #8

Time point:

24/48/72 h

Score:

2

Max. score:

4

Reversibility:

fully reversible within: 7 days

Remarks on result:

probability of mild irritation

Irritation parameter:

conjunctivae score

Basis:

animal: #12

Time point:

24/48/72 h

Score:

1.3

Max. score:

3

Reversibility:

fully reversible within: 7 days

Remarks on result:

probability of mild irritation

Irritation parameter:

conjunctivae score

Basis:

animal: #11

Time point:

24/48/72 h

Score:

1.3

Max. score:

3

Reversibility:

fully reversible within: 72 hours

Remarks on result:

probability of mild irritation

Irritation parameter:

conjunctivae score

Basis:

animal: #10

Time point:

24/48/72 h

Score:

0.6

Max. score:

3

Reversibility:

fully reversible within: 72 hours

Remarks on result:

probability of weak irritation

Irritation parameter:

conjunctivae score

Basis:

animal: #9

Time point:

24/48/72 h

Score:

1

Max. score:

3

Reversibility:

fully reversible within: 7 days

Remarks on result:

probability of mild irritation

Irritation parameter:

conjunctivae score

Basis:

animal: #7 and #8

Time point:

24/48/72 h

Score:

1.6

Max. score:

3

Reversibility:

not fully reversible within: 7 days

Remarks on result:

positive indication of irritation

Irritation parameter:

iris score

Basis:

animal: #11 and #12

Time point:

24/48/72 h

Score:

0.3

Max. score:

2

Reversibility:

fully reversible within: 48 hours

Remarks on result:

probability of weak irritation

Irritation parameter:

iris score

Basis:

animal: #7

Time point:

24/48/72 h

Score:

0.3

Max. score:

2

Reversibility:

fully reversible within: 72 hours

Remarks on result:

probability of weak irritation

Irritation parameter:

iris score

Basis:

animal: #9 and #10

Time point:

24/48/72 h

Score:

0

Max. score:

2

Remarks on result:

no indication of irritation

Irritation parameter:

iris score

Basis:

animal: #8

Time point:

24/48/72 h

Score:

0.6

Max. score:

2

Reversibility:

fully reversible within: 72 hours

Remarks on result:

probability of weak irritation

Irritation parameter:

cornea opacity score

Basis:

animal: #7 and #8

Time point:

24/48/72 h

Score:

1

Max. score:

4

Reversibility:

fully reversible within: 7 days

Remarks on result:

probability of mild irritation

Irritation parameter:

cornea opacity score

Basis:

animal: #9, #10 and #11

Time point:

24/48/72 h

Score:

0

Max. score:

4

Remarks on result:

no indication of irritation

Irritation parameter:

cornea opacity score

Basis:

animal: #12

Time point:

24/48/72 h

Score:

0.6

Max. score:

4

Reversibility:

fully reversible within: 72 hours

Remarks on result:

probability of weak irritation

Irritant / corrosive response data:

The test product caused slight corneal opacity in three rabbits (No.7, 8 and 12), slight iritis in four rabbits (No.7, 8, 11 and 12) and slight or moderate redness and swelling of the conjunctivae in all animals. In the course of the seven-day observation period these lesions cleared up, except for slight redness of the conjucntivae, noted in two animals (No.7 and 8) at the seventh day.

Table 1: Individual Scores Awarded to the Occular Lesions Elicted by the Rhubafurane

Time point	Rabbit Number	Cornea	Iris	Conjunctivae
				Redness	swelling
After 24 hours	7	1	0	2	2
	8	1	1	2	2
	9	0	0	1	1
	10	0	0	1	1
	11	0	1	2	2
	12	1	1	2	2
After 48 hours	7	1	1	2	2
	8	1	1	2	2
	9	0	0	1	0
	10	0	0	1	1
	11	0	0	2	1
	12	1	0	1	1
After 72 hours	7	1	0	1	2
	8	1	0	1	2
	9	0	0	1	1
	10	0	0	0	0
	11	0	0	0	0
	12	0	0	1	0
After 7 days	7	0	0	1	0
	8	0	0	1	0
	9	0	0	0	0
	10	0	0	0	0
	11	0	0	0	0
	12	0	0	0	0

Interpretation of results:

GHS criteria not met

Conclusions:

Under the test conditions, the test item is not classified as irritant to the eyes according to the Regulation (EC) No. 1272/2008 (CLP) and to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS).

Executive summary:

In an eye irritation study performed according to an equivalent study following the OECD Guideline No. 405 protocol, New Zealand White albino rabbits are used for assess the eye irritant potential of the test material. 

0.1 mL of undiluted test item was instilled into the right eye of 6 rabbits. The upper and lower eyelids were held together for about one second immediately after application, to prevent loss of the test item, and then released. The left eye remained untreated and served as control. The eyes were examined and the changes were observed at 24, 48, 72 h and 7 days after instillation of test item and graded according to the Draize method.
The eyes are not washed following instillation and the animals are released immediately

The test product caused slight corneal opacity in three rabbits (No.7, 8 and 12), slight iritis in four rabbits (No.7, 8, 11 and 12) and slight or moderate redness and swelling of the conjunctivae in all animals. In the course of the seven-day observation period these lesions cleared up, except for slight redness of the conjucntivae, noted in two animals (No.7 and 8) at the seventh day.

Mean individual scores at 24, 48 and 72 h after exposure for the 6 animals were 1 / 1 / 0 / 0 / 0 / 0.6 for cornea score; 0.3/ 0.6 / 0 / 0 / 0.3 / 0.3 for iris score; 1.6 / 1.6 / 1 / 0.6 / 1.3 / 1.3 for conjunctivae score and 2 / 2 / 0.6 / 0.6 / 1 / 1 for chemosis score.

Under the test conditions, the test item is not classified as irritant to the eyes according to the Regulation (EC) No. 1272/2008 (CLP) and to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin irritation:

A key study was identified (TNO, 1981).

In a dermal irritation study comparable to the OECD guideline 404, the primary irritation to the skin is measured by a patch-test technique on the abraded and intact skin of albino rabbits.

An amount of 0.5 mL of the test substance is brought on the intact or abraded skin of six healthy adult New Zealand White albino rabbits under a surgical patch fixed to the application site by means of adhesive tape.
After an exposure period of 24 hours the patches and the material applied are removed and the resulting skin reactions are evaluated by the method of Draize. A second reading is made 48 hours later (72 hours after application).

Rhubafurane caused moderate skin irritation. The dermal effects observed after 24 hours generally consisted of slight or well-defined erythema and/or very slight edema. Very slight ischemia, focal haemorrhages and slight edema were noted at one intact and one abraded site. After 72 hours slight to distinct scaliness was observed at five intact and three abraded sites while two abraded sites by then showed slight incrustation.

Although deviations from the OECDTG 404 were observed in the study protocol, it is however feasible to use such data for classification by calculating the mean values for erythema and oedema on the basis of only the 24 and 72 hours time points. Calculation of mean scores are restricted to the results obtained from intact skin. 

The mean scores calculated for each animal tested within 2 scoring times (24 and 72 h) were 3.5/1/1.5/1.5/1/1 for erythema and 1.5/0.5/1/0.5/0.5/0.5 for oedema.

Under the test conditions, the test material is not classified as irritant to the skin according to the Annex VI of the Regulation (EC) No. 1272/2008 (CLP) and the GHS. This study is considered as acceptable and satisfies the requirement for skin irritation endpoint.

 

Eye irritation:

A key study was identified (TNO, 1981).

In an eye irritation study performed according to an equivalent study following the OECD Guideline No. 405 protocol, New Zealand White albino rabbits are used for assess the eye irritant potential of the test material. 

0.1 mL of undiluted test item was instilled into the right eye of 6 rabbits. The upper and lower eyelids were held together for about one second immediately after application, to prevent loss of the test item, and then released. The left eye remained untreated and served as control. The eyes were examined and the changes were observed at 24, 48, 72 h and 7 days after instillation of test item and graded according to the Draize method.
The eyes are not washed following instillation and the animals are released immediately

The test product caused slight corneal opacity in three rabbits (No.7, 8 and 12), slight iritis in four rabbits (No.7, 8, 11 and 12) and slight or moderate redness and swelling of the conjunctivae in all animals. In the course of the seven-day observation period these lesions cleared up, except for slight redness of the conjucntivae, noted in two animals (No.7 and 8) at the seventh day.

Mean individual scores at 24, 48 and 72 h after exposure for the 6 animals were 1 / 1 / 0 / 0 / 0 / 0.6 for cornea score; 0.3/ 0.6 / 0 / 0 / 0.3 / 0.3 for iris score; 1.6 / 1.6 / 1 / 0.6 / 1.3 / 1.3 for conjunctivae score and 2 / 2 / 0.6 / 0.6 / 1 / 1 for chemosis score.

Under the test conditions, the test item is not classified as irritant to the eyes according to the Regulation (EC) No. 1272/2008 (CLP) and to the Globally Harmonized System of Classification and Labelling of Chemicals (GHS).

Justification for classification or non-classification

Harmonized classification:

The substance has no harmonized classification according to the Regulation (EC) No. 1272/2008 (CLP).

 

Self classification:

Based on the available data:

No additional self-classification is proposed regarding skin and eye irritation and the test substance is not classified according to the criteria of the Regulation EC No. 1272/2008 (CLP) and to the GHS.

- No data was available regarding respiratory irritation.