Registration Dossier

Administrative data

Description of key information

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 adverse effect observed (not irritating)

Additional information

Skin irritation

For the dermal irritation/corrosion endpoint, the key study was performed by Perstorp AB using NesterolTM, the trade name for isobutyric acid, monoester with 2,2,4 -trimethylpentane-1,3 -diol. This study was selected as key study because it is the most modern study available, which was performed under GLP. The supporting studies were peformed using TexanolTM Ester-Alcohol (the Eastman trade name for isobutyric acid, monoester with 2,2,4 -trimehtylpentane-1,3 -diol). The supporting studies, while relatively contemporary and GLP compliant were not performed according to guidelines.

In a dermal irritation study, three New Zealand White rabbits were each administered 0.5 mL of undiluted NesterolTM to the clipped skin of the back for four hours under semiocclusion. The animals were then observed for a total of 14 days for signs of primary irritation (erythema and edema). During the observation period, the test substance caused very slight to well-defined erythema in three animals accompanied by very slight edema in one animal. Dryness and sloughing of the skin was noted in two animals starting on day 6 or 7 to day 13 when the skin of all animals was perceived as normal. The conclusion of this study was that "NesterolTM does not require labelling with the risk phrase R38 "Irritating to skin" in accordance with EEC Council Directive 79/831/EEC, Annex VI, Part HCD) as described in Commission Directive 93/21/EEC."

The potential for isobutyric acid, monoester with 2,2,4 -trimethylpentane-1,3 -diol to cause skin corrosion/irritation is well understood. In a primary dermal irritation/corrosion study conducted according to an internal Eastman Kodak Company method, at most, only slight irritation was observed in five guinea pigs at any time during the 14-day observation period when 5.0, 10.0 or 20.0 mL/kg bw of the undiluted test material was applied to the clipped depilated abdomen under occlusive contact for 24 hours. In a follow-up study conducted by the same laboratory, neither primary irritation nor exacerbation of effects was observed when 0.5 mL of the undiluted test material was repeatedly applied to the clipped backs of five guinea pigs for a total of 9 exposures over an 11-day period. Based on these two studies, isobutyric acid, monoester with 2,2,4 -trimethylpentane-1,3 -diol is not classified as a primary skin irritant.

Eye Irritation

For the eye irritation/corrosion endpoint, the key study was performed by Product Safety Labs (PSL) using 2,2,4-trimethyl-1,3-pentanediol monoisobutyrate (hereinafter “test substance”) which was provided by Perstorp AB. This study was selected as a key study because it is the most modern study available, which was performed under GLP. Two additional supporting studies also were conducted. 

 

In a primary eye irritation study conducted by PSL, 3 female New Zealand Albino rabbits were pretreated by instillation of 2-3 drops of ocular anesthetic (Tetracaine Hydrochloride Ophthalmic Solution, 0.5%) into both the treated and control eye of each animal. One-tenth of a milliliter of undiluted test substance was then instilled into the conjunctival sac of the right eye of each rabbit by pulling the lower lid away from the eyeball. The upper and lower lids were then gently held together for about one second before releasing to minimize loss of the test substance. The other eye of each rabbit remained untreated with the test substance and served as a control.Ocular irritation was evaluated using a high-intensity white light at 1, 24, 48, and 72 hours and at 4 days post-instillation. A fluorescein dye evaluation procedure was used in the treated eye at 24 hours and as needed at subsequent scoring intervals to evaluate the extent of corneal damage or to verify reversal of effects. Individual scores were recorded for each animal. In addition to observations of the cornea, iris and conjunctivae, any other observed lesions were noted. The average score for all rabbits at each scoring period was calculated to aid in data interpretation. The time interval with the highest mean score (Maximum Mean Total Score - MMTS) for all rabbits was used to classify the test substance by the system of Kay and Calandra. The average individually-determined irritation scores for cornea, iris and conjunctiva (redness and chemosis) across 24, 48 and 72 hours were calculated for EC classification.There was no iritis observed in any treated eye during this study. One hour after test substance instillation, all three treated eyes exhibited ‘positive’ conjunctivitis. By 24 hours, corneal opacity also developed in two animals, that also was observed in both animals at 48 hours and in one animal at 72 hours. The overall incidence and severity of irritation decreased thereafter. All animals were free of ocular irritation by Day 4 (study termination). Based on the results of this study, the test substance was considered to be a mild ocular irritant that does not meet the criteria for GHS Toxicity and EC classification (Regulation No. 1272/2008), and therefore, no risk phrase for ocular irritation is required.

 

In a previous primary eye irritation study that was reported in 1995, 0.1 mL of test substance was instilled into the conjunctival sacs of 3 New Zealand Albino rabbits (2 males and 1 female). Animals were then observed for 7 days. Ocular reactions were recorded and descriptors (slight, moderate, strong, severe) were assigned for grading severity of ocular lesions. The eyes of all rabbits were examined with a handheld light. Signs of irritation were limited to corneal opacification without iridial inflammation and a diffuse crimson coloration of the conjunctiva with two rabbits having diffuse crimson coloration accompanied by considerable swelling with partial eversion of the eyelids. After 7 days, all eyes appeared normal.  The test substance is considered to be a reversible ocular irritant in this study. However, the stated conclusion of this study was that the test substance does not require labelling with the risk phrase "Irritating to eyes", in accordance with Council Directive 79/831/EEC, Annex VI, Part II(D) as described in Commission Directive 93/21/EEC.

 

The test material also was evaluated in an eye irritation study conducted according to an internal Eastman Kodak Company method that was reported in 1984. The conditions of exposure to the test matnerial and number of animals exposed were similar to that for a guideline eye irritation

study but the study was not GLP-compliant. The data indicate that the only irritant response was slight to moderate transient irritation in 2/3 unwashed eyes and 0/3 washed eyes at the 24-hour examination following instillation of 0.1 mL of the test substance into the conjunctival sac of the eye. One of three unwashed eyes and all washed eyes appeared clinically normal throughout the study. No corneal or adnexal staining was evident in these eyes when tested with fluorescein dye at 24 hours. Of the two remaining unwashed eyes, signs of irritation were limited to moderate erythema of the conjunctivae and slight erythema of the lids at 24 hours. Corneal staining was observed for both eyes and adnexal staining was noted for one of the two unwashed eyes at the 24-hour examinations. All eyes appeared clinically normal at the 48-hour examinations.

Respiratory Tract Irritation

The potential for isobutyric acid, monoester with 2,2,4 -trimethylpentane-1,3 -diol to cause respiratory tract irritation is well understood. In a non-guideline acute inhalation study in which rats were exposed (whole body) to 2.73 mg/L or 3.55 mg/L of the test substance for 6 hours, no clinical signs suggestive of respiratory tract irritation were observed. The latter concentration could only be generated by heating the test material to 100°C.

Justification for classification or non-classification

Skin irritation

Two studies exist evaluating the potential of isobutyric acid, monoester with 2,2,4 -trimethylpentane-1,3 -diol to cause skin irritation. In the key study performed by Perstorp, the maximum erythema and oedema scores over the entire duration of the study were 2 and 1, respectively. Based on these scores, isobutyric acid, monoester with isobutyric acid, monoester with 2,2,4-trimethylpentane-1,3-diol did not meet the criteria for classification under EU CLP. In the supporting study performed by Eastman, at most only slight irritation was observed in a primary dermal irritation/corrosion study in which isobutyric acid, monoester with 2,2,4 -trimethylpentane-1,3 -diol was applied to the clipped depilated abdomens of groups of five guinea pigs at dose levels up to 20 mL/kg bw under occluded contact for 24 hours. The test conditions used in this study were significantly more severe, i.e., 24-hour exposure and much higher dose levels than current OECD guideline specifications for a skin irritation/corrosion study. In addition, neither primary irritation nor exacerbation of effects was observed when 0.5 mL of the undiluted test material was repeatedly applied to the clipped backs of five guinea pigs for a total of 9 exposures over an 11-day period. Based on a weight-of-the-evidence assessment, isobutyric acid, monoester with 2,2,4 -trimethylpentane-1,3 -diol may cause slight, transient skin irritation but is not classified for “Skin irritation/corrosion” according to EU CLP. The combined results of the Perstorp study and the two Eastman studies support the conclusion that isobutyric acid, monoester with 2,2,4 -trimethylpentane-1,3 -diol is not irritating.

 

Eye irritation

Three studies exist evaluating the potential of 2,2,4-trimethy-1,3-pentanediol monoisobutyrate to cause eye irritation. Based on the combined weight of evidence, 2,2,4 -trimethyl-1,3 -pentanediol monoisobutyrate should not be classified. At the time the studies were conducted, the conclusions of all studies were that the substance should not be classified. The 1995 study represents a contemporary GLP study, performed according to guideline, but it did not incorporate a washout phase. The 1984 study, while not done according to GLP or guideline, did incorporate a washout group. This suggests that the 1995 study would represent a more severe exposure scenario than the 1984 study, and would also not represent potential real-world exposures. While all eyes were clinically normal by 72 hours in the 1995 study, all clinical observations in the 1984 study were normal by 48 hours, suggesting a lower degree of irritancy. Additionally, the results of the 1995 study just met the criteria for more modern classification schemes (OECD GHS 2B), with only the corneal scores driving the results. However, in the 1984 study, the corneal scores in the unwashed eyes returned to normal within 48 hours, again supporting a conclusion of lower irritancy. To resolve these inconsistencies, a third study was conducted in 2011 by PSL using material produced by Perstorp AB. In the PSL study, although corneal opacity did persist in one animal for 72 hours, the combined scores for each animal were well below the threshold for classification as an ocular irritant (Regulation 1272/2008). Taken together, these three studies support the conclusion that 2,2,4 -trimethyl-1,3 -pentanediol monoisobutyrate is not irritating to the eye.

Respiratory tract irritation

There were no clinical signs indicative of respiratory tract irritation in rats following acute exposure to the highest airborne concentration ofisobutyric acid, monoester with 2,2,4-trimethylpentane-1,3-diol that could be generated by heating the test material to 100°C. In addition,isobutyric acid, monoester with 2,2,4-trimethylpentane-1,3-diol is not classified as a skin irritant according to EU CLP. Based on a weight-of-the evidence assessment, isobutyric acid, monoester with 2,2,4-trimethylpentane-1,3-diol is not classified for respiratory tract irritation according to EU CLP.