Registration Dossier

Administrative data

Description of key information

Repeated insult patch testing of human volunteers as well as a skin irritation/corrosion study in rabbits indicate a low potential for skin irritation or corrosion.  A guideline in vitro eye irritation study and a guideline eye irritation study in rabbits indicate a low potential for eye irritation.

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)

Additional information

Skin Irritation

The potential for dibutyl terephthalate to cause skin corrosion/irritation is well understood. Two key studies in humans conducted according to sound scientific principles and one supporting study in animals conducted according to OECD Guideline 404 were considered in the evaluation. In a study to evaluate the primary irritation potential of dibutyl terephthalate in humans, three (3) twenty-four (24) hour applications of the undiluted test material were made to the same site on the upper backs of 15 volunteers. The subjects were patched dermally under occlusive conditions on Days 1, 3 and 5. Scores of the test sites were made 24 or 48 hours after removal of the patches. Scores for all panelists were reported as “0” and the test material was considered to be not irritating under conditions used in this study. In a repeated insult patch test conducted in 208 volunteers by the same laboratory three months later and using the same lot number of test material, patches were applied three (3) times per week for three (3) weeks to the upper back under occluded contact for an exposure period of twenty-four (24) hours. Rest period consisted of 24 or 48 hours following patch application. All scores for response were graded as “0” except for a single individual in which response was graded as moderate on one occasion and slight on another. In a dermal irritation corrosion study in the rabbit, a single application of the undiluted test material was applied to shaved skin under occlusive contact for four (4) hours. There were no signs of edema or erythema in two of three test animals. A single animal displayed signs of minimal erythema at the 24, 48 and 72 observations which fully cleared by Day 7. The application conditions used in the two human studies were much more stringent than current testing guidelines for animal studies, i.e., 24-hour application versus 4-hour application and multiple applications versus single applications. Based on the observations made in the two human studies and the single animal study, dibutyl terephthalate is not classified as a primary skin irritant.    

  

Eye Irritation

The potential for dibutyl terephthalate to cause eye burns/irritation is well understood. The test material has been evaluated based on the physical properties of the substance, the results of dermal irritation studies in humans following repeated 24-hour contact with intact skin under occluded contact, the results of an in vivo eye irritation study conducted according to OECD Guideline 405, and the results of an in vitro IrritectionAssay. Prior to testing, the pH of the test material was measured to ascertain the potential for the test material to cause serious eye damage. A pH value of 7.347 for a 10% suspension of the test substance demonstrated that the test material was neither strongly acid not strongly alkaline. In addition, repeated 24-hour dermal contact with the undiluted test material caused no irritation in human subjects. The results of the in vitro IrritectionAssay suggested that the undiluted test substance may have the potential to produce, at most, minimal eye irritation. In an in vivo eye irritation study conducted according to regulatory guidelines, 0.1 mL of the undiluted test material was instilled into one eye of each of six rabbits. Three treated eyes were washed immediately with distilled water. There were no signs of corneal injury, iritis or chemosis during the observation period. Signs of irritation in both washed and unwashed eyes were limited to minimal redness of the conjunctivae (Grade 1). All unwashed and two of three washed eyes were normal by 48 hours. The remaining washed eye was normal at the 72-hour observation. Based on all available data, dibutyl terephthalate is not expected to cause eye burns or irritation.   

  

Respiratory Tract Irritation

Although no acute or repeated inhalation toxicity studies were available for review, the physical properties of dibutyl terephthalate along with results for eye irritation and repeated skin irritation studies can be used to evaluate the potential for the subject chemical to cause respiratory tract irritation. Dibutyl terephthalate is a liquid at room temperature, has a boiling point of 341.8 °C at 760 mmHg, and has an extremely low vapor pressure (0.0000784 mmHg) at room temperature. Based on the physical properties of dibutyl terephthalate, the potential for significant inhalation exposure is very limited. In addition, no signs of dermal irritation were observed in repeat-exposure studies in which human volunteers were exposed for up to nine 24-hour applications under occluded contact and application of undiluted dibutyl terephthalate to the rabbit eye caused, at most, slight irritation. Based on all available data, dibutyl terephthalate is not expected to cause respiratory tract irritation.  

Justification for classification or non-classification

There were no signs of edema or erythema in a human primary skin irritation study in which a group of fifteen adult volunteers received three (3) twenty-four (24) hour applications of the undiluted test material to the same site on the upper backs. Dibutyl terephthalate was applied under occlusive conditions on Days 1, 3 and 5. Scores of the test sites were made 24 or 48 hours after removal of the patches. Scores for all panelists were reported as “0” and the test material was considered to be not irritating under conditions used in this study. In a repeated insult patch test conducted in 208 volunteers in which patches were applied three (3) times per week for three (3) weeks to the upper back under occluded contact for an exposure period of twenty-four (24) hours, all scores for response were graded as “0” except for a single individual in which response was graded as moderate on one occasion and slight on another. Dibutyl terephthalate was considered to be non-irritating in this study. The test conditions used in these two human repeat exposure studies were significantly more severe, i.e., 24-hour exposure than current OECD guideline specifications for a skin irritation/corrosion study. In a dermal irritation corrosion study in the rabbit, a single application of the undiluted test material was applied to shaved skin under occlusive contact for four (4) hours. There were no signs of edema or erythema in two of three test animals. A single animal displayed signs of minimal erythema at the 24, 48 and 72 hour observations which fully cleared by Day 7. Prior to initiation of the dermal irritation study in rabbit, the pH of the test substance was measured and the value obtained (7.3) demonstrated that dibutyl terephthalate was neither strongly acid not strongly alkaline. Based on a weight-of-the-evidence assessment, dibutyl terephthalate is not classified for “Skin irritation/ corrosion” according to GHS. 

  

The only clinical sign of irritation in the eyes of six rabbits following instillation of 0.1 mL of the test material into the conjunctival sac of one eye per rabbit was slight redness (grade 1) in some animals at the 1, 24 and/or 48-hr observation points. Three of the six eyes were immediately flushed with water. All unwashed eyes (3) and two of three washed eyes were normal by 48-hr post-application while the remaining washed eye was normal by 72-hr. In addition, dibutyl terephthalate was not classified for either skin corrosivity or irritation following repeated 24-hr occluded contact with intact human skin and the pH (7.3) of the test material does not suggest a potential for corrosion or irritation. Based on a weight-of-the-evidence assessment, dibutyl terephthalate is not classified for “Serious Eye Damage/ Eye Irritation” according to GHS.

  

There were no acute or repeat exposure toxicity studies by which to evaluate the potential for dibutyl terephthalate to cause respiratory tract irritation. However, based on (1) the physical properties of dibutyl terephthalate, i.e., extremely low vapor pressure and pH of 7.3; (2) an absence of dermal irritation in repeat-exposure studies in which human volunteers were exposed for up to nine 24-hr applications under occluded contact; and (3) minimal irritation following application of undiluted dibutyl terephthalate to the rabbit eye, dibutyl terephthalate is not expected to cause respiratory tract irritation. Based on a weight-of-the-evidence assessment, there are no data to suggest that dibutyl terephthalate would meet the criteria for classification as a respiratory tract irritant according to the GHS guidelines.