Registration Dossier

Administrative data

Description of key information

Skin Irritation: Not irritating, based on a weight of evidence.
Eye Irritation: Not irritating, based on a weight of evidence.

Key value for chemical safety assessment

Skin irritation / corrosion

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Skin Irritation

The potential for the registered substance to cause skin irritation has been addressed using the weight of evidence approach consisting of four in vivo studies. The first two studies were performed using the registered substance, whereas the other two were performed with structural analogues.

 

In the first study (Anon., 1957) the potential of the test material cause skin irritation was assessed in an acute exposure dermal irritation study using rabbits. The study pre-dates GLP and the standard guidelines; nevertheless, data are well reported and the experiment was conducted in accordance with generally accepted scientific principles. Accordinly the study was assigned a reliability score of 2 in line with Klimisch (1997). During the study the depilated trunk of 11 rabbits was exposed to large doses of the test material for a period of 24 hours in an occlusive fashion. A single rabbit was treated with a dose of 8 mL/kg bw; 10 rabbits were treated with a dose of 16 mL/kg bw. The Draize scale for scoring erythema and edema was used to grade the irritant response of the skin. The maximum possible score for erythema and edema is 4, giving a maximum total of 8 per rabbit. The irritation observed at the higher level of treatment was mild to moderate, with a maximum score of 3. However the irritation was transient and was completely reversed in 4 to 7 days. Therefore under the conditions of this study the test material is considered to be unclassified.

In the second study (Anon., 1957) the potential of the test material to cause skin irritation was assessed in a primary skin irritation test, with repeated exposure over 3 consecutive weeks. The study pre-dates GLP and the standard guidelines; nevertheless, data are well reported and the experiment was conducted in accordance with generally accepted scientific principles. Accordinly the study was assigned a reliability score of 2 in line with Klimisch (1997). During the study 1 mL of test material was applied to the intact and abraded skin of 10 depilated rabbits, and contact maintained for 6 hour per day. The skin was examined and assessed in accordance with the Draize scale for erythema and edema for 14 days after the final treatment. The maximum possible score for erythema and edema is 4, giving a maximum total per rabbit of 8. The skin of all 10 animals remained entirely normal throughout the experiment, with the exception of slight erythema, which was noted in most of the treated animals (6/10 intact skin, 9/10 abraded skin). The rabbits’ behaviour and appearance was unaffected, and all animals survived and gained bodyweight. Under the conditions of this study the test material is not a primary irritant and requires no classification according to EU criteria.

 

The third study (Birch, 1973) reports the dermal irritation potential of the read-across substance, 6,6'-di-tert-butyl-4,4'-thiodi-m-cresol . The potential to cause skin irritation was assessed in the New Zealand Albino rabbit. The study pre-dates GLP and the standard guidelines; nevertheless, data are well summarised and the experiment was conducted in accordance with generally accepted scientific principles. Therefore the study was assigned a reliability score of 2 in line with Klimisch (1997). 500 mg of the test material was applied as a finely ground powder moistened with water to the intact and abraded skin of 6 test animals, with exposure lasting for 24 hours. The animals were observed for 7 days. Slight erythema was evident for the 72 hours following exposure. However these effects were completely reversed after 7 days. No edema was seen. Based on these findings, no classification is required in accordance with EU criteria under the conditions of this study.

The fourth study (Birch, 1974) reports the dermal irritation potential of the read-across substance, 6,6'-di-tert-butyl-4,4'-butylidenedi-m-cresol. The potential to cause skin irritation was assessed in the New Zealand Albino rabbit. The study pre-dates GLP and the standard guidelines; nevertheless, data are well summarised and the experiment was conducted in accordance with generally accepted scientific principles. Therefore the study was assigned a reliability score of 2 in line with Klimisch (1997). 500 mg of the test material was applied as a finely ground powder moistened with water to the intact and abraded skin of 6 test animals, with exposure lasting for 24 hours. The animals were observed for 7 days. No erythema or edema was seen. As a result of this, no classification is required in accordance with EU criteria under the conditions of this study.

 

Slight to moderate irritation was observed in several of the studies, however these reactions were slight and in most cases fully reversible and were therefore below the limits of classification. Based on the observations made in the dermal irritation studies conducted using the substance to be registered and those from structurally similar substances, it can be concluded that the registered substance is not a dermal irritant.

Eye Irritation

The potential for the registered substance to cause eye irritation has been addressed using an in vitro study, which was performed on the substance to be registered, and a further two in vivo studies which were performed with structural analogues.

In the in vitro study (Verspeek-Rip, 2012) the corrosion and irritancy potential of the test material was investigated using the Bovine Corneal Opacity and Permeability Assay (BCOP) under GLP conditions and in accordance with the standardised guidelines OECD 437 and EU Method B.47. Accordingly the study was assigned a reliability score of 1 in line with Klimisch (1997).

In the first experiment, the test material was applied in a pure form on to the top of the corneas (enough to cover the cornea). However due to the consistency of the test material, the test was repeated and in the second experiment the test material was applied via a gauze patch of approximately 2 cm² directly on top of the corneas. For both experiments, negative and positive controls were run concurrently. The negative control was physiological saline and the positive control was benzalkonium chloride. The test material did not induce ocular irritation through both endpoints in both experiments, resulting in mean in vitro irritancy scores of -1.1 and 0.6 after 10 minutes of treatment. The test material did not cause severe irritation or corrosive in the Bovine Corneal Opacity and Permeability test under the experimental conditions in this study in accordance with EU criteria.

 

In the two in vivo studies (Birch 1973 and Birch 1974) the potential to cause eye irritation of the structural analogues was assessed (6,6'-di-tert-butyl-4,4'-thiodi-m-cresol and 6,6'-di-tert-butyl-4,4'-butylidenedi-m-cresol, respectively). The study pre-dates GLP and the standard guidelines; nevertheless, data is well summarised and the experiment is conducted in accordance with generally accepted scientific principles. Accordingly both studies were assigned a reliability score of 2 in accordance with Klimisch (1997).

In Birch (1973) the potential of the structural analogue (6,6'-di-tert-butyl-4,4'-thiodi-m-cresol) to cause eye irritation was assessed in the New Zealand Albino rabbit. 100 mg of the test material was applied as a finely ground powder to the eyes of 6 test animals, with exposure lasting for 24 hours. The animals were observed for 7 days. Moderate erythema and discharge were evident for the 24 hours following installation. However these effects were markedly improved by 48 hours and completely reversed after 72 based on these findings, no classification is required in accordance with EU criteria under the conditions of this study.

In Birch (1974) the potential of the test material (6,6'-di-tert-butyl-4,4'-butylidenedi-m-cresol) to cause eye irritation was assessed in the New Zealand Albino rabbit.100 mg of the test material was applied as a finely ground powder to the eyes of 6 test animals, with exposure lasting for 24 hours. The animals were observed for 7 days. Slight to moderate erythema and discharge were evident for the 24 hours following installation. However these effects were markedly improved by 48 hours and completely reversed after 72 hours. As a result of this, no classification is required in accordance with EU criteria under the conditions of this study.

 

Based on the in vitro data provided on the target substance, together with information from in vivo studies on structural analogues it can be concluded that the registration substance is not an eye irritant.


Justification for selection of skin irritation / corrosion endpoint:
One single study could not be selected since this endpoint has been addressed using a weight of evidence approach.

Justification for selection of eye irritation endpoint:
One single study could not be selected since this endpoint has been addressed using a weight of evidence approach.

Justification for classification or non-classification

Skin Irritation

According to the criteria outlined in Regulation (EC) No. 1272/2008 and Directive 67/548/EEC, this substance does not meet the criteria for classification as a skin irritant.

Eye Irritation

According to the criteria outlined in Regulation (EC) No. 1272/2008 and Directive 67/548/EEC, this substance does not meet the criteria for classification as an eye irritant.