2-Butyne-1,4-diol, polymer with methyloxirane

Endpoint summary

Description of key information

Skin: WoE in vivo and in vitro tests: not irritating
Eye: WoE in vivo and in vitro tests: not irritating

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:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable study report which meets basic scientific principles with acceptable restrictions (limited documentation, e.g. no details about test substance)

Principles of method if other than guideline:

Skin irritation was tested using an internal standardized test method (BASF test).
White Vienna rabbits were used. Usually, two animals were treated for 1, 5, 15 minutes and for 20 hours using occlusive conditions. An application site of 2.5x2.5 cm was covered with the liquid test substance. After the application times (1, 5 and 15 min) the skin was washed with Lutrol solution (50%). The animals were observed for 8 days and skin changes were recorded daily. The report describes findings after 24 hours and at the end of the observation period (8 days). For a final evaluation, the findings after 48 and 72 hours from the raw data were taken into account.

GLP compliance:

no

Species:

rabbit

Strain:

Vienna White

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 3.45 kg (male 1), 2.64 kg (male 2)

ENVIRONMENTAL CONDITIONS
- not reported

Type of coverage:

occlusive

Preparation of test site:

shaved

Vehicle:

unchanged (no vehicle)

Controls:

other: untreated skin of the same animal

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): presumably 1 mL

Duration of treatment / exposure:

1 min, 5 min, 15 min and 20 hours

Observation period:

8 days

Number of animals:

2

Details on study design:

Since irritation data are recommended for a 4 h skin exposition, results of the available 20 h and the 15 min exposition will serve as approximation.

TEST SITE
- Area of exposure: The application site of 2.5 X 2.5 cm at the upper third of the back was covered with a cotton cloth loaded with the undiluted liquid (37°C; approx. 1 mL)

REMOVAL OF TEST SUBSTANCE
- Washing: washing was done in the 1 min, 5 min and 15 min test directly after exposure. Lutrol 50% (mild detergent) was used.
No washing was done after the 20 hours treatment.

SCORING
Descriptive scores of the raw data have been converted to Draize numerical scores.

Irritation parameter:

erythema score

Remarks:

(20-hour application)

Basis:

mean

Remarks:

out of 2 animals

Time point:

other: mean over 24, 48 and 72 h

Score:

0

Max. score:

4

Reversibility:

other: reversibility: not applicable

Remarks on result:

other: There are no data about 72 h. Due to not any irritating effects at 24 and 48 hour reading time point, the value for the 72 hour reading time point was extrapolated and considered to be 0.

Irritation parameter:

edema score

Remarks:

(20-hour application)

Basis:

mean

Remarks:

out of 2 animals

Time point:

other: mean over 24, 48 and 72 h

Score:

0

Max. score:

4

Reversibility:

other: reversibility: not applicable

Remarks on result:

other: There are no data about 72 h. Due to not any irritating effects at 24 and 48 hour reading time point, the value for the 72 hour reading time point was extrapolated and considered to be 0.

Irritant / corrosive response data:

After 20 hours treatment no irritant effects were determined at reading times of 24, 48 hours and the end of the observation period of 6 days.

Other effects:

No other effects observed.

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

CLP: not classified
EU: not classified

Executive summary:

Skin irritation was tested using an internal standardized test method (BASF test).

Two white Vienna rabbits were treated for 1, 5, 15 minutes and for 20 hours using occlusive conditions. A shaved application site of 2.5x2.5 cm was covered with the liquid test substance. After the application times (1, 5, 15 min and 20 hours) the skin was washed with Lutrol solution (50%). The animals were observed for 8 days and skin changes were recorded daily. The report describes findings after 24 hours and at the end of the observation period (8 days). For a final evaluation, the findings after 48 and 72 hours from the raw data were taken into account. There are no data about 72 h. Due to not any irritating effects at 24 and 48 hour reading time point, the value for the 72 hour reading time point was extrapolated and considered to be 0. After 20 hours treatment no irritant effects were determined at reading times of 24, 48 hours and the end of the observation period of 6 days.

According to the conditions of the test, the test substance has not to be classified as irritant to the skin.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

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:

other: Study comparable to guideline study (partly limited documentation, e.g. no details about the test substance; 50 µL instead of 100 µL test substance instilled; eye not washed out).

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

yes

Remarks:

(no details about the test substance; 50 µL instead of 100 µL test substance instilled.)

Principles of method if other than guideline:

Internal standardized test method (BASF-Test): 50 µL of the test substance were applied to the conjunctival sac of one eye in each of 2 animals. The animals were examined after 10 min, 1 and 3 h on the day of treatment and up to 8 days afterwards. Findings were recorded daily. The eyes were not washed out after 24 hours as specified in OECD Guideline 405.

GLP compliance:

no

Species:

rabbit

Strain:

Vienna White

Details on test animals or tissues and environmental conditions:

TEST ANIMALS
- Source: M. Gaukler, Offenbach, Germany
- Weight at study initiation: 2.66 kg (males); 3.12 kg (female)

Vehicle:

unchanged (no vehicle)

Controls:

other: The adjacent eye served as control treated with NaCl.

Amount / concentration applied:

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 50 µL
- Concentration: undiluted

Duration of treatment / exposure:

single application (not washed out)

Observation period (in vivo):

8 days

Number of animals or in vitro replicates:

2 (1 male and 1 female)

Details on study design:

APPLICATION
Single application to the conjunctival sac of the right eyelid.

REMOVAL OF TEST SUBSTANCE
- The test substance was not washed out.

READINGS:
- 24, 48, 72 hours and 8 days after instillation.

SCORING SYSTEM: Draize scoring system, as recommended by the OECD guideline 405

TOOL USED TO ASSESS SCORE: fluorescein (at the end of exposure period)

Irritation parameter:

cornea opacity score

Basis:

mean

Remarks:

out of 2 animals

Time point:

other: mean over 24, 48 and 72 h

Score:

0

Max. score:

4

Reversibility:

other: reversibility: not applicable

Irritation parameter:

iris score

Basis:

mean

Remarks:

out of 2 animals

Time point:

other: mean over 24, 48 and 72 h

Score:

0

Max. score:

2

Reversibility:

other: reversibility: not applicable

Irritation parameter:

conjunctivae score

Basis:

mean

Remarks:

out of 2 animals

Time point:

other: mean over 24, 48 and 72 h

Score:

1

Max. score:

3

Reversibility:

fully reversible within: 8 days

Irritation parameter:

chemosis score

Basis:

mean

Remarks:

out of 2 animals

Time point:

other: mean over 24, 48 and 72 h

Score:

0

Max. score:

4

Reversibility:

other: reversibility: not applicable

Irritant / corrosive response data:

The treatment led to conjunctivae redness with a score of 1 which persisted from 24 to 72 hours and was fully reversible within 8 days in 1/2 animals.

Other effects:

No other findings were observed.

Table 1. Results of eye irritation study.

Rabbit #	Time	conjunctivae		iris	cornea
		redness	swelling
1	1 h	1	0	0	0
	24 h	1	0	0	0
	48 h	1	0	0	0
	72 h	1	0	0	0
	8 d	0	0	0	0
	average over 24, 48 and 72 h	1.0	0.0	0.0	0.0
2	1	0	0	0	0
	24 h	0	0	0	0
	48 h	0	0	0	0
	72 h	0	0	0	0
	8 d	0	0	0	0
	average over 24, 48 and 72 h	0.0	0.0	0.0	0.0

 

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

CLP: not classified
DSD: not classified

Executive summary:

 The test was performed according to an internal standardized test method under the following conditions: 50 µL of the test substance were applied to the conjunctival sac of one eye in each of 2 white Vienna rabbits. The animals were examined after 10 min, 1 and 3 h on the day of treatment and up to 8 days afterwards. Findings were recorded daily. The treatment led to conjunctivae redness with a score of 1 which persisted from 24 to 72 hours and was fully reversible within 8 days. No other findings were observed. Based on this study, the test substance is not irritating and has not to be classified (BASF, 1972).

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Additional information

1.    Hypothesis fortheanalogue approach

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006 whereby substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.

 

	Target Substance	Source Substance No 1	Source Substance No 2
Name	2-Butyne-1,4-diol, comp. with methyloxirane	2-Butyne-1,4-diol, comp. with oxirane (Polyethylene glycol ether with 2-butyne-1,4-diol)	2-Propyn-1-ol, compd. with methyloxirane
CAS	61596-96-1	32167-31-0	38172-91-7
Skin irritation	Non-guideline-study: similar toOECD 404, in vivo, not irritating (BASF, 1976) (RL3)	OECD 439, in vitro, not irritating (BASF, 2011) (RL1)   Non-guideline-study: similar toOECD 404, in vivo, not irritating (BASF, 1972) (RL2)	OECD 404, not irritating (BASF 1987), approx. 50%
Eye irritation	Non-guideline-study: similar toOECD 405, in vivo, very slight effects (BASF, 1976) (RL3)	Non-guideline-study: similar toOECD 405, in vivo, not irritating (BASF, 1972) (RL 2)   Non-guideline-study: HET-CAM, in vitro, not irritating (BASF, 2002) (RL2)	OECD 405, severe irritating (BASF, 1987), approx. 50%

 

Lack of data for a given endpoint is indicated by “--“

 

2.    Analogue approach justification

The above mentioned substances are considered to be similar on the basis of structural similarity resulting in similar properties and/or activities. The available endpoint information of the source substances are used to predict the respective endpoints2-Butyne-1,4-diol, comp. with methyloxirane (CAS 61596-96-1). A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Since only less reliableskin and eye irritation studies are available for the target substance2-Butyne-1,4-diol, comp. with methyloxirane (CAS 61596-96-1), a read-across from the structurally related source substancePolyethylene glycol ether with 2-butyne-1,4-diol (CAS 32167-31-0) wasusedin accordance to Regulation (EC) No. 1907/2006 Annex XI, 1.5.

 

 

3.    Results

Skin

Non-OECD-Guideline studies

a)    Target substance(CAS 61596-96-1)

Before OECD Guideline 404 was established, skin irritation was tested using an internal method (BASF test). 2 white vienna rabbits were treated for 1, 5 and 15 minutes and for 20 hours using occlusive conditions. An application site of 2.5 x 2.5 cm was covered with the liquid test substance and effects on skin were observed after 4h, 1,4,6 and 7 days after patch removal. Directly after patch removal, there were effects visible for erythema 0.75 for animal 1 and 0.25 for animal 2. There were no effects 24h after patch removal and no corrosion at any time. Based on this study, the test substance could be classified as non-irritating (BASF, 1976).

b)    Source substance No 1(CAS 32167-31-0)

Skin irritation was tested using an internal standardized test method (BASF test).Two white Vienna rabbits were treated for 1, 5, 15 minutes and for 20 hours using occlusive conditions. A shaved application site of 2.5x2.5 cm was covered with the liquid test substance. After the application times (1, 5, 15 min and 20 hours) the skin was washed with Lutrol solution (50%). The animals were observed for 8 days and skin changes were recorded daily. The report describes findings after 24 hours and at the end of the observation period (8 days). For final evaluation average values were used. As there are no reading for and no irritation happened at 24h and 48h, the value for the 72 hour reading time point was extrapolated and considered to be 0. Hence the average values for Erythema and Edema were 0, further no treatment specific observations are found at the end of the observation period, the test substance has not to be classified as irritant to the skin (BASF, 1972).

OECD-Guideline studies

c)    Source substance No 1(CAS 32167-31-0)

The potential the test substance to cause dermal irritation was assessed by a single topical application of 30μL of the test substance to a reconstructed three dimensional human epidermis model (EpiDerm™) according to OECD No 439. Three EpiDerm™ tissue samples were incubated with the test substance for 1 hour followed by a 42-hours post-incubation period. Tissue destruction was determined by measuring the metabolic activity of the tissue after exposure/ post-incubation using a colorimetric test. The reduction of mitochondrial dehydrogenase activity, measured by reduced formazan production after incubation with a tetrazolium salt (MTT) was chosen as endpoint. The formazan production of the test substance treated epidermal tissues is compared to that of negative control tissues.

The test substance was not able to reduce MTT directly and the mean viability of the test-substance treated tissues determined after an exposure period of 1 hour with about 42 hours post-incubation was 116%.

 

Therefore, the test itemdoes not show a skin irritation potentialin the EpiDerm™ skin irritation test under the test conditions chosen (BASF, 2011)

 

d)    Source substance No 2 (CAS 38172-91-7)

According to OECD 404, skin irritation was tested without GLP compliance. The applicant site of 2.5 x 2.5cm of 3 white Vienna rabbits was exposed for 4h to undiluted (but a.i. approx. 50%) test item using semiocclusiv conditions and washed with Lutrol and Lutrol/water (1:1) followed by a 72 hours observation period with readings after 30 min and 60 min after the removal of the test patches and 24 h, 48 h and 72 h after the beginning of application. Untreated skin sites of the same animal were used as negative control. No signs of irritation or corrosion were observed at any time. Based on this study, the test substance could be classified as non-irritating (BASF, 1987).

 

 

Eye

Non-OECD-Guideline study

a)    Target substance(CAS 61596-96-1)

The test substance was tested in a non-guideline study with 2 white vienna rabbits. Therefore, 50µl of the test substance were applied to the conjunctival sac of one eye of 2 animals. The saline-treated adjacent eye served as a control. The animals were observed 8 days whereupon changes were recorded on day 1,2,5,7 and 8. Questionable redness in raw data at 24h and 48h were converted into the presently used numerical grading system, resulting in a scoring of 0 for conjunctiva after 24 & 48 hours as an average of both animals. No records were described after 72hours. At the end of the Observation period after 8 days, no effects were observed. Based on this study, the test substance is not irritating (BASF, 1976).

b)    Source substance No 1(CAS 32167-31-0)

 

1.  The test was performed according to an internal standardized test method under the following conditions: 50 µL of the test substance were applied to the conjunctival sac of one eye in each of 2 white Vienna rabbits. The animals were examined after 10 min, 1 and 3 h on the day of treatment and up to 8 days afterwards. Findings were recorded daily. The treatment led to conjunctivae redness with a score of 1 which persisted from 24 to 72 hours and was fully reversible within 8 days. No other findings were observed. Based on this study, the test substance is not irritating and has not to be classified (BASF, 1972).

 

2.  An in vitro HET-CAM was performed to analyze the irritating potential of the test substance(CAS 32167-31-0). Since the time until the appearance of any type of effect with the undiluted test substance was generally >100 seconds, no irritating potential can be addressed to the test substance (BASF, 2002).

 

OECD-Guideline studies

c)    Source substance No 2 (CAS 38172-91-7) 

A single application of 0.1 ml of the unchanged test substance was given into the conjunctiva sac of the right eyelid of 3 white vienna rabbits without GLP compliance according to OECD 405. Eye effects were documented 1 h, 24 h, 48 h, 72 h, 8 days, 15 days and 21 days after the application and the untreated eyes were used as negative control. One male animal showed not reversible effects after day 21, while the second male did not show any of these effects at any time point. The female developed loss of corneal tissue and contracted pupils only 48 hours after application of the test substance. These effects were fully reversible. Based on irreversible effects in one animal, the test substance holds the risk of serious eye damage. (BASF, 1987)

 

 

4.    Key study assignment:

 

Skin:

There are few information according skin irritation available. For the target substance (CAS 61596-96-1) the available study (BASF, 1976), is not so well documented and thus judged as less reliable, especially as the study is not more critical than the studies conducted with the source substances (CAS 32167-31-0 and38172-91-7).Therefore all studies were used in a weight of evidence approach.

 

Eye:

There are few information according eye irritation available. For the target substance (CAS 61596-96-1) the available study (BASF, 1976), is not so well documented and thus judged as less reliable, especially as the study is not more critical than the study conducted with the source substance No 1 (CAS 32167-31-0). But further there is a study available for the source substance No 2 showing severely irritating effects. Nevertheless this result is from the as most distanced read across, which is a additional a smaller molecule. Therefore as no eye irritating effects are observed for the substance itself and the more closer read across molecule the irritation observed for source substance No 2 is judge as worst case and more related to the size of the molecule. All results were integrated in the dossier but based on a WOE the more closer related homologues and the substance itself are rated as more reliable for assessing these endpoint.

 

5.    Conclusion

 

Skin:

In summary, one less reliable skin irritation studies from2-Butyne-1,4-diol, comp. with methyloxirane (CAS 61596-96-1) isavailable which points to no skin irritation. Two otherreliable skin irritation studies from source substance (read across substance) Polyethylene glycol ether with 2-butyne-1,4-diol (CAS 32167-31-0) showed no skin irritation in vivo and in vitro and further one in vivo study with the source substance 2-Propyn-1-ol, compd. with methyloxirane was also negative. As all results were negative the target substance is not skin irritating.

 

Eye:

In summary, three eye irritation studies from the target substance2-Butyne-1,4-diol, comp. with methyloxirane (CAS 61596-96-1) and the source substance Polyethylene glycol ether with 2-butyne-1,4-diol (CAS 32167-31-0) areavailable, which points to slight (BASF, 1976) respectively no eye irritation (BASF, 1972 and BASF, 2002). Nevertheless, from the more distanced read across source substance no 2 evidence for severe irritation are available. As this molecule is much smaller than the target or the source substance no 1 and further three studies did not show any concerns for eye irritation the result from source substance No 2 is judge as worst case and related to the molecular weight. In summary based on a weight of evidence from all results the target substance is assumed to be not irritating to eye.

 

In conclusion, it is not warranted to classify the target substance as skin or eye irritant.

Justification for selection of skin irritation / corrosion endpoint:
Most relevant and reliable study. Weight of evidence approach.

Justification for selection of eye irritation endpoint:
Most relevant and reliable study. Weight of evidence approach.

Justification for classification or non-classification

Based on the above information, a classification of the target substance as skin or eye irritant according to Regulation (EC) 1272/2008 or Directive 67/548/EEC is not justified.

- GHS: no classification

- DSD: no classification