Registration Dossier

Administrative data

Description of key information

A skin irritation study on butanediol diglycidyl ether in rabbits, which was performed according to test guidelines and in compliance with GLP, has demonstrated that the test compound is not a skin irritant. In other skin irritation studies, butanediol diglycidyl ether was reported as a moderate to severe irritant; however, these studies were conducted with a longer exposure period (usually 24 hours) with limited information provided and therefore, were considered unreliable. 
An eye irritation study on butanediol diglycidyl ether in rabbits, which was performed according to test guidelines and in compliance with GLP, has demonstrated that the test compound is an eye irritant. Similar results were reported in additional eye irritation studies conducted on butanediol diglycidyl ether in rabbits.

Key value for chemical safety assessment

Skin irritation / corrosion

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:
key study
Study period:
1988
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Well documented, according to accepted guidelines
Qualifier:
according to
Guideline:
OECD Guideline 405 (Acute Eye Irritation / Corrosion)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)
Deviations:
no
GLP compliance:
yes
Species:
rabbit
Strain:
New Zealand White
Details on test animals or tissues and environmental conditions:
TEST ANIMALS
- Source: Kleintierfarm Madoerin AG, CH 4414 Fuellinsdorf/Switzerland
- Age at study initiation: males: 14 weeks, female: 15 weeks
- Weight at study initiation: males: 2.0-2.9 kg, female: 2.6 kg
- Housing: Individually in stainless steel cages equipped with an automatic cleaning and drinking system
- Diet (e.g. ad libitum): Pelleted standard Kliba 341, Batch 37/88 and 38/88 rabbit maintenance diet ("Kliba", Klingentalmuehle AG, 4303 Kaiseraugst, Switzerland) ad libitum
- Water (e.g. ad libitum): Community tap water from Itingen, ad libitum
- Acclimation period: Four days under laboratory conditions after veterinary examination


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20±3°C
- Humidity (%): 40-70%
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12


Vehicle:
unchanged (no vehicle)
Controls:
not required
Amount / concentration applied:
TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.1 mL
Duration of treatment / exposure:
Single exposure
Observation period (in vivo):
The eyes of each animal were examined 1, 24, 48 and 72 hours, 7, 14 and 21 days after administration.

Number of animals or in vitro replicates:
3
Details on study design:
The eyes of the animals were observed 24 hours prior to test article administration. The test article (0.1 ml per animal) was placed in the conjunctival sac of the left eye of each animal after gently pulling the lower lid away from the eyeball. The lids were then gently held together for about one second to prevent loss of the test article. The right eye remained untreated and served as the reference control. The eyes of each animal were examined 1, 24,48 and 72 hours, 7, 14 and 21 days after administration. The irritation was assessed according to the OECD Guidelines for testing of Chemicals, Section 4, number 405 "Acute Eye Irritation/Corrosion adopted February 24, 1987. The corrosive properties of the test article and the staining of the treated eye were described and recorded. Eye examinations were made with a slit-lamp 30 SL/M (C. Zeiss AG, Zuerich/Switzerland) and a Varta Cliptrix diagnostic-lamp (A. Riegger, Basel/Switzerland).

The following numerical scoring system was used to grade the eye lesions: see attached tables.
Irritation parameter:
cornea opacity score
Basis:
animal #1
Time point:
other: 24, 48, and 72 hours
Score:
1.33
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: score at 21 days was 3
Irritation parameter:
iris score
Basis:
animal #1
Time point:
other: 24, 48, and 72 hours
Score:
0.67
Max. score:
2
Reversibility:
not reversible
Remarks on result:
other: score at 21 days was 1
Irritation parameter:
chemosis score
Basis:
animal #1
Time point:
other: 24, 48, and 72 hours
Score:
3
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: score at 21 days was 1
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #1
Time point:
other: 24, 48, and 72 hours
Score:
2
Max. score:
3
Reversibility:
not reversible
Remarks on result:
other: score at 21 days was 2
Irritation parameter:
cornea opacity score
Basis:
animal #2
Time point:
other: 24, 48, and 72 hours
Score:
1
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: score at 21 days was 1
Irritation parameter:
iris score
Basis:
animal #2
Time point:
other: 24, 48, and 72 hours
Score:
1
Max. score:
2
Reversibility:
fully reversible within: 7 days
Irritation parameter:
chemosis score
Basis:
animal #2
Time point:
other: 24, 48, and 72 hours
Score:
2
Max. score:
4
Reversibility:
fully reversible within: 7 days
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #2
Time point:
other: 24, 48, and 72 hours
Score:
2
Max. score:
3
Reversibility:
fully reversible within: 7 days
Irritation parameter:
cornea opacity score
Basis:
animal #3
Time point:
other: 24, 48, and 72 hours
Score:
1.33
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: score at 21 days was 4
Irritation parameter:
iris score
Basis:
animal #3
Time point:
other: 24, 48, and 72 hours
Score:
0.67
Max. score:
2
Reversibility:
not reversible
Remarks on result:
other: score at 21 days was 1
Irritation parameter:
chemosis score
Basis:
animal #3
Time point:
other: 24, 48, and 72 hours
Score:
2
Max. score:
4
Reversibility:
not reversible
Remarks on result:
other: score at 21 days was 1
Irritation parameter:
conjunctivae score
Remarks:
redness
Basis:
animal #3
Time point:
other: 24, 48, and 72 hours
Score:
2.67
Max. score:
3
Reversibility:
not reversible
Remarks on result:
other: score at 21 days was 2
Irritant / corrosive response data:
see attached table entitled eye irritation scores
Interpretation of results:
Category 1 (irreversible effects on the eye)
Remarks:
Migrated information Criteria used for interpretation of results: other: CLP (EC 1272/2008)
Endpoint conclusion
Endpoint conclusion:
adverse effect observed (irritating)

Additional information

Skin Irritation/Corrosion

The skin irritation potential of butanediol diglycidyl ether was evaluated in rabbits in a GLP-compliant study performed according to OECD Guidelines for the Testing of Chemicals No. 404 (Ullmann, 1988). In this study, New Zealand White rabbits were exposed to a single application of 0.5 mL of undiluted butanediol diglycidyl ether on the shaved dorsal under semi-occlusive conditions for a period of 4 hours. The skin reaction was assessed at 1, 24, 48, and 72 hours after the removal of the dressing, gauze patch, and test article. Skin reactions were scored according to a prescribed numerical system. Local signs (mean scores at 1, 24, 48, and 72 hours) consisted of grade 0.25 erythema and grade 0.00 edema. Based on the results, butanediol diglycidyl ether was reported to cause a primary irritation score of 0.00 when applied undiluted to intact rabbit skin. In the area of application, no staining of the treated skin by pigment or coloring of the test article was observed and no corrosive effect had occurred on the skin at any interval assessed. Butanediol diglycidyl ether is not classified as a skin irritant according to CLP (EC 1272/2008) criteria.

Several other skin irritation studies were conducted on butanediol diglycidyl ether. Results from the majority of these studies indicated that butanediol diglycidyl ether is a moderate to severe irritant; however, the exposure period was reported to be 24 hours (with or without repeated exposure), which is a longer exposure time than the recommended 4 hours as per OECD guidelines. As CLP classification should be based on the OECD TG 404, hazard assessment and classification was not determined. Details on these studies are presented below.

Seifert (1982) conducted a study following the procedure described in the Appraisal of the Safety of Chemicals and Foods, Drugs and Cosmetics (1959) of the U.S. Association of Food and Drug Officials (AFDO). The test article (TK 10352/d) was applied to 6 New Zealand White rabbits per sex under occlusive conditions for 24 hours and then the procedure was repeated for a total of 5 consecutive days (the fifth dressing was removed 8 hours following the application). Observations were recorded at 24 hours and on Days 8, 9, and 10. A primary reaction score of 6.3, a mean reaction score of 7.1, and a final reaction score of 8.0 were reported. After treatment there was no tendency of recovery during the observation period. Based on the results, TK 10352/d was reported to cause extreme irritation when applied to intact and abraded rabbit skin. Seifert (1982) repeated this procedure with test article TK 10352 using 3 rabbits/sex. The animals showed a primary reaction score of 5.2, a mean reaction score of 6.9, and a final reaction score of 8.0. TK 10352 was reported to cause extreme irritation when applied to intact and abraded rabbit skin.

 

Another skin irritation study was conducted according to the guidelines from the EPA OPP 81-5 (Acute Dermal Irritation) (Kobel, 1981). The test article TK 10352/d was applied to 3 New Zealand White rabbits/sex under occlusive conditions for 24 hours with an observation period of up to 14 days. The calculated primary irritation index was reported to be 4.3. The effects observed were not fully reversible within 14 days. The authors concluded that the test article TK 10352/d was reported to cause a marked irritation when applied to intact and abraded rabbit skin.

 

A skin irritation study was conducted on TK 10352 according to the guideline outlined by the U.S. Food and Drug Administration (FDA) in the Federal Register (September 17, 1964) Section 191.11 (Davies and Kynoch, 1973). The test article was applied under occlusive conditions to 6 rabbits for 24 hours and observations were recorded at 24 and 72 hours. The primary irritation index score was reported to be 4.3 in intact and abraded rabbit skin. The authors concluded that the test article is considered to be a moderate irritant to rabbit skin.

 

Similar to the studies conducted by Seifert (1982), Sachsse and Ullmann (1976) conducted a skin irritation study according to the procedure from the Appraisal of the Safety of Chemicals and Foods, Drugs and Cosmetics (1959) of the U.S. AFDO. Six Russian breed rabbits (3 animals/sex) were exposed to the test article for 24 hours (occlusive conditions not specified) and observed for a period of up to 72 hours following the application. The primary irritation index was reported to be 6.2 in intact skin and positive effects observed were not fully reversible within the observation period, indicating that the test article is a severe irritant to the rabbit skin.

 

Limited information on the study design was available in a skin irritation study conducted by Edwards and Schwebel (1969). No guidelines were followed. The test article was applied to rabbits under occlusive conditions (no further details available). The results indicated that there were marked edema and deep necrosis of the covered abraded area of the abdomen after 24 hours, and therefore, no further applications were applied to this area. A marked heavy eschar formed in three days and persisted for ten days. A deep scar was expected in this area. The covered unabraded area of the abdomen showed a severe hyperemia after 24 hours that resolved in 7 days. The uncovered area of the ear showed a moderate hyperemia in 24 hours that resolved in 3 days. Thus, the concentrated test material was capable of producing skin burns; however, the results of this study report are considered to be unreliable due to significant methodological deficiencies.

 

Eye Irritation

An eye irritation study on butanediol diglycidyl ether has been conducted in accordance with OECD Guidelines for the Testing of Chemicals No. 405 and in compliance with GLP (Ullmann, 1988). In this study, 0.1 mL of undiluted butanediol diglycidyl ether was instilled into the conjunctival sac of the left eye of each of 3 New Zealand White rabbits. Ocular changes were assessed and recorded at 1, 24, 48, and 72 hours and 7, 14, and 21 days after administration. Scoring was performed according to guideline methods. The mean cumulative scores (24, 48, and 72 hours) for the cornea, iris, and conjunctivae (redness and chemosis) for all animals were 5.67, 6.67, and 7.33, respectively. Based on the results, butanediol diglycidyl ether was reported to cause a primary irritation score of 5.92. No staining of the cornea and conjunctivae of the treated eyes by pigment or coloring of the test article was observed. Corneal opacity with different intensity was observed in all animals within 1 hour to 21 days after test article application. According to CLP classification (EC 1272/2008), butanediol diglycidyl ether is classified as a Category I eye irritant (irreversible effects on the eye).

 

Another eye irritation study on butanediol diglycidyl ether was conducted in New Zealand White rabbits (Kobel, 1981). The treated eyes of 3 of the 6 rabbits were flushed with physiological saline 30 seconds after treatment with undiluted test substance. Ocular changes were assessed and recorded at 24, 48, and 72 hours and 7, 14, and 21 days after administration. Scoring was reported to be conducted as per the OECD guideline. The mean irritation scores for the cornea, iris, and conjunctiva of the unrinsed eyes varied between 44 and approximately 80. No tendency of reversibility was observed. According to CLP classification (EC 1272/2008), butanediol diglycidyl ether is classified as a Category I eye irritant (irreversible effects on the eye).

 

Sachsse (1972) conducted a study, which adopted the methodology described in the Appraisal of the Safety of Chemicals in Foods, Drugs and Cosmetics (1959) of the U.S. AFDO. The treated eyes of 3 of the 6 animals were flushed with lukewarm water 30 seconds after treatment with undiluted test substance. The reactions were recorded at 24 hours and after 2, 3, 4, and 7 days following treatment. Scoring was reported to be conducted as per the OECD guideline. The primary irritation index was reported to be 40 for the cornea, 6.3 for the iris, and 15.3 for the conjunctivae. The test article was considered to be a severe irritant to rabbit eyes. CLP classification was not conducted as the observation period did not extend beyond 7 days and effects were still noted; however, CLP classification would be at least a Category 2 (causes serious eye irritation) and possibly a Category 1 (causes serious eye damage).

 

An eye irritation study, which followed the procedures outlined by the FDA in the Federal Register (September 17, 1964, §191.12) was conducted in 1 rabbit (Davies and Kynoch, 1973). One hour after instillation of the undiluted test article TK 10352, the cornea was opaque and there was considerable swelling of the conjunctivae with partial eversion of the eyelids. The reactions gradually increased until 3 quarters of the eye was opaque with the iris invisible. The animal was sacrificed at 14 days due to the severity of the response. The authors concluded that TK 10352 is markedly irritating to the eye mucosa. Within the limitations of the abbreviated test procedure, TK 10352 is considered to be an eye irritant according to the definition in the Federal Register (1964). According to CLP classification (EC 1272/2008), butanediol diglycidyl ether is classified as a Category I eye irritant (irreversible effects on the eye). It should be noted that the results of this study report are considered to be unreliable due to significant methodological deficiencies.

 

Limited information on the study design was available in an eye irritation study conducted by Edwards and Schwebel (1969). The test article butanediol diglycidyl ether produced no obvious pain when instilled directly into the eye, but immediate severe conjunctival swelling and redness were reported and persisted for 10 days. Cornea opacity with edema and necrosis also were observed for 10 days. After 10 days, the iris was unresponsive and appeared to be involved in synechia. The authors concluded that the concentrated test material is capable of producing possible permanent eye damage; however, the results of this study report are considered to be unreliable due to significant methodological deficiencies. The authors also stated that this is a cursory range finding study. This study report does not provide enough information to allow for CLP classification.


Justification for selection of eye irritation endpoint:
GLP study conducted according to international guideline.

Effects on eye irritation: highly irritating

Justification for classification or non-classification

Skin Corrosion / Irritation: According to Title I, Article 4, paragraph 3 of Regulation (EC) No 1272/2008, “if a substance is subject to harmonised classification and labelling in accordance with Title V through an entry in Part 3 of Annex VI, that substance shall be classified in accordance with that entry, and a classification of that substance in accordance with Title II shall not be performed for the hazard classes or differentiations covered by that entry.” According to Part 3 of Annex VI, the substance meets the criteria for category 2 classification as a skin irritant.

 

Serious Eye Damage / Eye Irritation: According to the Guidance on the Application of the CLP Criteria (ECHA Reference ECHA-09-G-02-EN), the in vivo test in rabbits according to OECD TG 405 is the standard test for hazard assessment and classification. The results of the in vivo test in rabbits according to OECD TG 405 indicate that the effects on the cornea, iris, and conjunctiva had not fully reversed within an observation period of 21 days in more than one animal. As a results, the substance meets the criteria for category 1 (irreversible eye effects) classification according to Regulation (EC) No 1272/2008, Annex I section 3.3.