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Description of key information

Introduction

Physico-chemical properties of Coolact 10 (chemical name: 3-[[5-methyl-2-(1-methylethyl)-cyclohexyl]oxy]propane-1,2-diol; EC Number: 289-296-2; CAS Number: 87061-04-9) and the results of in vitro and in vivo studies conducted with the substance have been used to determine, as far as possible, a toxicokinetic profile for the substance.

Physicochemical properties

Coolact 10 (3-[[5-methyl-2-(1-methylethyl)cyclohexyl]oxy]propane-1,2-diol) is a multi-constituent substance (organic) with a molecular formula of C13H26O3and molecular weight of ca.230.34 g/mol. It is comprised of roughly equal proportions of 1,2-propanediol, 3-[[1R,2S,5R)-5- methyl-2-(1-methylethyl)cyclohexyl]oxy]-,(2S)- and 1,2-propanediol,3-[[1R,2S,5R)-5-methyl-2-(1-methylethyl)cyclohexyl]oxy]-,2R)-. Coolact 10 is a clear colourless liquid at room temperature with a freezing point of -19.7°C and a boiling point of 299°C. Its specific gravity and vapour pressure at 20°C are 0.9997 and approximately 78 Pa, respectively. The partition coefficient (log Pow) is 3.5 at 30°C, pH 7.2 and it is soluble in water at 2.27 g/L at 20.0 ± 0.5°C.

Absorption

Oral absorption

In acute oral toxicity studies, the acute median lethal dose (LD50) of Coolact 10 was >2000 mg/kg body weight. In the most recent study (OECD 420 compliant) no signs of toxicity were observed at 2000 mg/kg, however 1/6 female animals died on day 2; there were no male deaths. There were no treatment-related necropsy findings in either males or females (including the decedent).

In a 28-day repeated dose oral (dietary) toxicity study (equivalent to OECD 407) Coolact 10 was tolerated up to a dose of 5000 mg/kg diet in male and female rats, with no deaths and few clinical signs observed. There were effects on some clinical chemistry parameters in both sexes across all or the majority of dose groups. In addition, gross and anatomic pathology revealed treatment-related changes in the liver at all dose levels and consequently the LOAEL was considered to be 250 mg/kg bw/day (dietary concentrations were adjusted during the study to maintain a constant intake in mg/kg bw/day)

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In a dose-finding pre-natal developmental toxicity study in rats (gavage administration from gestation Day 6 to Day 15) Coolact 10 was administered at doses ranging from 125 to 3000 mg/kg bw/day. Three animals dosed at 3000 mg/kg bw/day died between gestation Days 8 and 11. Although no gross lesions were observed at necropsy the deaths were attributed to the test substance treatment. Clinical signs at the maximum dose included decreased activity, abnormal breathing, staining in anogenital and/body surface; postdose increased salivation and material around the nose, mouth and/or eyes were also observed. Treatment-related reductions in body weight were observed throughout the study at 3000 mg/kg bw/day, however, no treatment related differences from the control group were observed during necropsy and liver weights were comparable among the groups. Overall, there were no treatment-related adverse effects on development of pups. In the main study (equivalent to OECD 414 and conducted at 100, 500 and 1500 mg/kg bw/day) 2/30 dams administered Coolact 10 at 1500 mg/kg bw/day died prior to scheduled necropsy. At this high dose (which exceeds the regulatory accepted limit dose of 1000 mg/kg bw/day) clinical signs included anogenital and/or body surface staining, red or brown material around the nose, mouth and/or eyes; and/or staining around mouth. There were some dose related effects on body weight gain accompanied by significantly decreased treatment related reductions in food consumptions during the treatment period for the high dose group dams. At necropsy, absolute and relative liver weights were increased significantly in the 1500 mg/kg bw/day group in comparison to the control group. This increase was attributed to the test substance. No relevant indications of the developmental toxicity were observed in any group and the NOAEL for developmental effects was set at 1500 mg/kg bw/day accordingly; the maternal NOAEL was set at 500 mg/kg bw/day.

The available in vivo data, indicate that oral absorption of 2-(tetrapropenyl)succinic acid, monoester with propane-1,2-diol does occur and this is supported by the physico-chemical properties of Coolact 10. It is sufficiently small (MW ca 230 g/mmol) and soluble in water (albeit at a moderate level) and therefore is likely to dissolve in the gastrointestinal fluid; its moderate log Pow favours absorption by passive diffusion. Therefore, in the absence of any other information, for the purposes of human DNEL setting, 50% oral absorption is assumed for risk assessment purposes.

Dermal absorption

No in vivo toxicity data following dermal application are available. Coolact 10 is a skin irritant (in vitro skin irritation study compliant with OECD 439), although in vivo data with formulations of Coolact 10 (10% formulation tested in rabbits, 50% formulation tested in guinea pigs and 5% formulation tested in humans) show no skin irritation. It is a liquid and its solubility in water would suggest a moderate absorption from the stratum corneum into the epidermis, furthermore its log Pow also favours dermal absorption. Therefore, in the absence of any other information, for the purposes of human DNEL setting, 50% dermal absorption, the same extent of oral absorption, is assumed for risk assessment purposes.

Inhalation absorption

No inhalation toxicity data are available for Coolact 10 as human exposure via the inhalation route is expected not to occur. The low vapour pressure and high boiling point of the substance indicate that creation of vapours of the substance are unlikely. However, the moderate log Pow would favour absorption directly across the respiratory tract epithelium by passive diffusion. In the absence of any quantitative data, absorption by inhalation is assumed to be 100%.

Distribution, Metabolism and Elimination

No information is available to describe the distribution, metabolism or elimination of the material.

The relatively low molecular weight and the moderate water solubility of Coolact 10 would suggest that wide diffusion could occur through aqueous channels and pores. In addition, its moderate log Pow may enable distribution across lipid membranes, with possibly a slightly higher intracellular than extracellular concentrations, especially in fatty tissues. 

No information is available on the fate of any absorbed material and in vitro genotoxicity studies showed little quantitative difference in toxicity between exposures in the absence of exogenous metabolism and those in the presence of exogenous metabolism (using rat liver S9 fraction).

Bioaccumulation is considered unlikely to occur.

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential
Absorption rate - oral (%):
50
Absorption rate - dermal (%):
50
Absorption rate - inhalation (%):
100

Additional information