Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw

Additional information

Acute Oral Toxicity

In an initial study utilizing an Irwin dose-range screen, groups of 4 male CD-1 mice were given single oral doses of 2,2,4-trimethyl-1,3-pentanediol (TMPD), at doses of either 0, 0.316, 1.0, 3.16, or 10.0 g/kg with a constant dose volume of 31.6 ml/kg. Detailed observation of the mice was performed at 30, 90, 150, and 300 minutes after dosing. All mice receiving 3.16 or 10.0 g/kg died. Before death they all showed signs of generalized depression. At a dose of 1.0 g/kg, all mice survived, and the same signs of CNS depression were noted, and these effects decreased in severity during the test day. There were no notable effects at the lowest dose of 0.316 g/kg. Based upon these data, an acute oral LD50 for TMPD in mice was determined statistically to be 1.8 g/kg.

Due to the steep slope of the dose-response curve for the acute toxicity of TMPD (ie, the dose that produced 100% lethality was only 3-fold greater than the dose that produced no lethality), a definitive study was performed. In this key study, an initial limit dose of 2,000 mg/kg was administered to one healthy female Sprague Dawley rat by oral gavage. Due to the absence of mortality in this animal, four additional females sequentially received the same dose level. Since these animals survived, no additional animals were tested. Females were selected for the test because they are frequently more sensitive to the toxicity of test compounds than males. All animals were observed for mmiality, signs of gross toxicity, and behavioral changes at least once daily for 14 days after dosing. Body weights were recorded prior to administration and again on Days 7 and 14 (termination) following dosing. Necropsies were performed on all animals at terminal sacrifice. All animals survived test substance administration and gained body weight during the study. Following administration, three animals exhibited ana-genital staining, hypoactivity, reduced fecal volume, hunched posture, gasping, irregular respiration and/or facial staining. However, the animals recovered by Day 3 and along with the remaining two animals were active and healthy. Under the conditions of this study, the acute oral LD50 of 2,2,4-trimethyl-1,3-pentanediol is greater than 2,000 milligrams per kilogram of body weight in female rats.

The acute oral toxicity of 2,2,4-trimethyl-1,3-pentanediol also was evaluated in four additional supporting studies conducted by methods that predate Good Laboratory Practices and regulatory guidelines but conducted according to acceptable scientific methodology in effect at the time of the study. In two of the studies, groups of 2 rats/group received single doses of approximately 200, 400, 800, 1600 or 3200 mg/kg bw of the test material as a 40% solution either in a 2:1 ethanol:water vehicle or SDA 3-A alcohol administered by oral gavage. In both high-dose groups, one of two animals died before study termination. Abnormal clinical signs indicated reversible effects on the central nervous system and included weakness, vasodilatation, ataxia, and prostration. All survivors recovered and gained weight over the 14-day observation period. The oral LD50 was approximately 3200 mg/kg bw in both of these studies. In two lesser studies, single rats and mice received up to 6400 mg/kg bw of the test substance as a 20% corn oil preparation. All rats receiving 1600, 3200 and 6400 mg/kg bw died within 1 hour of dosing. Abnormal clinical signs included clonic convulsions, gasping and unconsciousness. All surviving animals gained weight over the 14-day observation period. The test material was less toxic to mice when administered in a corn oil vehicle since the animal receiving a dose of 1600 mg/kg bw survived while the animal in the 3200 mg/kg bw dose group died within 20 minutes of dosing. Abnormal clinical signs in mice included weakness, ataxia, gasping and unconsciousness. The oral LD50s in these two supporting studies were 800 to <1600 mg/kg bw and 1600 to <3200 mg/kg bw for rats and mice, respectively. 

 

In addition to classification for acute lethality, 2,2,4-trimethyl-1,3-pentanediol has been evaluated for potential classification as an aspiration hazard. 2,2,4-Trimethyl-1,3-pentanediol does not meet the criteria for a Category I Aspiration Hazard according to UN GHS or EU CLP regulations, i.e., (a) a chemical known to be an aspiration hazard, or (b) a hydrocarbon with a kinematic viscosity of 20.5 mm2/s, measured at 40 ºC. 2,2,4-Trimethyl-1,3-pentanediol also does not belong to a class of chemicals specifically noted in the UN GHS regulations for Category 2, i.e., n-primary alcohol with 3-13 carbon atoms, isobutyl alcohol, and ketones with ≤13 carbon atoms. Category 2 of GHS also considers a number of physical properties in the evaluation of an aspiration hazard. 2,2,4 -Trimethyl-1,3-pentanediol is a chunk solid and unlikely to present an aspiration hazard.

 

Acute Dermal Toxicity

 

The acute dermal toxicity of 2,2,4-trimethyl-1,3-pentanediol was evaluated in several key and supporting studies conducted by methods that predate Good Laboratory Practices and regulatory guidelines but conducted according to acceptable scientific methodology in effect at the time of the study. In the first key study, a single dose of 250, 500 or 1000 mg/kg bw of the neat solid moistened with water was applied to the depilated backs of guinea pigs under occluded contact for 24 hours. No deaths or clinical signs were reported during the study. Two of the three animals gained weight during the study while the third animal lost weight (dose level not reported). Slight erythema, scarring along the edge of the patch area, sparse hair, and desquamation were present at study termination. In the second key study, a single dose of 250, 500 or 1000 mg/kg bw of the neat solid was applied to the depilated and abraded backs of guinea pigs under occluded contact for 24 hours. One animal died on Day 13 but since this was not the animal receiving the highest dose, the dermal LD50 was considered to be >1000 mg/kg bw. No clinical signs were reported and both surviving animals gained weight. Minimal irritant effects were present at the conclusion of the observation period. Based on the results of the key studies, the acute dermal LD50 was considered to be >1000 mg/kg bw. Three lesser studies provided support for the observations made in the key studies. In two of the supporting studies, no deaths were reported when up to 20 mL/kg bw of a 40% preparation of the test material in ethanol or 3A alcohol was applied to the clipped skin of guinea pigs under occlusive wrap for 24 hours. No clinical signs were reported, no animals lost weight during the study, and irritant effects were similar to those observed when animals were treated with the vehicle alone. Based on the density of the test material, the estimated dermal LD50 was >8.0 g/kg bw in both studies. In a third supporting study, no deaths or clinical signs were observed when up to 20 mL/kg bw of a 25% preparation of the test material in a 90:10 acetone:corn oil vehicle was applied to the clipped skin of guinea pigs under occluded contact for 24 hours and no animals lost weight during the study.  Signs of irritation at the application site were limited to very slight edema and very slight erythema. The estimated dermal LD50 in that supporting study was >5000 mg/kg bw. Based on the results of the three supporting studies, the dermal LD50 was considered to be at least 5000 mg/kg bw.

 

Acute Inhalation Toxicity

 

The acute inhalation toxicity of 2,2,4-trimethyl-1,3-pentanediol was evaluated in a key study conducted by methods that predate Good Laboratory Practices and regulatory guidelines but conducted according to acceptable scientific methodology in effect at the time of the study. Four rats were exposed (whole-body) to an atmosphere containing 4.5 mg/L of the test substance for a period of six hours. The calculated total dose respired was 2.8 g/kg bw. No mortality was observed during the study and all animals gained weight over the observation period. Treatment-related clinical signs were noted shortly after the start of exposure and were limited to piloerection, vasodilatation, lacrimation and nose rubbing. The acute inhalation LC50 was considered to be >4.5 mg/L.   

 

Justification for classification or non-classification

2,2,4-Trimethyl-1,3-pentanediol is not classified for acute toxicity by the dermal or inhalation routes according to Annex I of Directive 67/548/EEC. Based on an acute oral LD50 value of >2000 mg/kg for female Sprague Dawley rats in a key study, 2,2,4-trimethyl-1,3-pentanediol is considered to be hazard category 5 for acute toxicity by the oral route of exposure under EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 and the UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS).  This category carries the signal word and hazard statement "warning: may be harmful if swallowed", but does not warrant a hazard classification, and no hazard symbol is required.

Based on an acute dermal LD50 of >5000 mg/kg bw for guinea pigs, 2,2,4-trimethyl-1,3-pentanediol is not classified for acute lethality by the dermal route of exposure under EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 or the UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS). Based on a 6-hr acute inhalation LC 50 of >4.5 mg/L air, 2,2,4-trimethyl-1,3-pentanediol is not classified for acute lethality by the inhalation route according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 or the UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS). 

 

2,2,4-Trimethyl-1,3-pentanediol is not classified for target organ toxicity according to Annex I of Directive 67/548/EEC. Based on clinical signs indicating reversible effects on the central nervous system in rats in the key acute oral toxicity studies, 2,2,4-trimethyl-1,3-pentanediol is classified as Category 3 for Specific Target Organ Toxicity – Single Exposure according to EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 and UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS).

 

2,2,4-Trimethyl-1,3-pentanediol is not classified as an aspiration hazard according to Annex I of Directive 67/548/EEC or EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008. Based on a review of its physical properties, 2,2,4-trimethyl-1,3-pentanediol is not classified as an aspiration hazard according to UN Globally Harmonized System of Classification and Labelling of Chemicals (GHS).