[(methylethylene)bis(oxy)]dipropanol

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - dermal (%):

86

Additional information

Oral route of exposure

One well-conducted and well-reported study on tripropylene glycol and its structural homologue monopropylene glycol was available for assessment (Dow Chemical Company, 1995). In this study, two groups of 5 male rats were administered a single oral dose of either radiolabeled (¹⁴C) tripropylene glycol or non-radiolabeled monopropylene glycol by gavage in water at target concentrations 40 mg/kg bw and 50 mg/kg bw, respectively. The excreta were collected for ca. 24 hours post-dosing. After sacrifice 24 hours post-dosing the remaining radioactivity in tissues was determined for the first group and urine was analyzed for free and acid-abile conjugates of mono-, di- and tripropylene glycol for both groups.

Absorption

Based on the average recovery of ca. 91% of the¹⁴C label administered from excreta, CO₂, skin, tissues and carcass after ca. 24 hours post-dosing sacrifice, it was concluded that tripropylene glycol is rapidly adsorbed if administered by gavage. The absorption of tripropylene glycol via oral route was calculated to amount to at least 86%, based on 5% of the administered dose recovered in faeces.

Distribution

Approximately 10% of the radiolabeled dose was recovered in tissues and carcass, with the liver and kidney having the greatest amount of radiolabel per gram of tissue 24 hours after dosing (ca. 0.2 and 0.1%, respectively). The¹⁴C concentration in blood was approximately 6.4 and 2.8 -fold lower than in liver and kidney, respectively.

Metabolism

Twenty-four hours after administration of a single oral dose of 40 mg/kg bw to male rats, 53% of the administered dose was eliminated in the urine. Only 5.8% of the dose was recovered as unmetabolized parent compound in the urine, while 7.2% was recovered as acid-labile conjugates of tripropylene glycol, 5.1% and 3.3% as free and acid-labile conjugates of dipropylene glycol and 3.3% and 0.6% as free and acid-labile conjugates of monopropylene glycol, respectively. Unidentified metabolites in the urine accounted for approximately 26% of the dose. A large fraction (21%) of the¹⁴C- tripropylene glycol dose was catabolized all the way to¹⁴CO₂, indicating considerable complete breakdown of tripropylene glycol. A lesser fraction was recovered in the feces (5%) and tissues (10%). The cage wash yielded 3%. The unidentified metabolism of tripropylene glycol most likely stems from entry of oxidized metabolites, such as pyruvate and lactate, both documented metabolites of monopropylene glycol, into intermediary metabolism via monopropylene glycol formation. Monopropylene glycol itself, is excreted as CO₂at about 25% of administered dose 24 h after administration. Overall, the data indicate tripropylene glycol is readily biotransformed to dipropylene glycol and monopropylene glycol which are then either conjugated or further oxidized to CO₂. The data of the animals administered monopropylene glycol indicate that approximately 11% of the monopropylene glycol administered was recovered in the urine as free monopropylene glycol with < 1% of the dose recovered as acid-labile conjugates.

 

Inhalation route of exposure

No toxicokinetic studies on tripropylene glycol using inhalatory route of exposure were available for assessment. However, based on a very low vapour pressure of tripropylene glycol (0.26 Pa), this route of exposure is not considered to be relevant for human toxicological risk assessment.

 

Dermal route of exposure.

No toxicokinetic studies on tripropylene glycol using dermal route of exposure were available for assessment. However, Article 13 of the REACH legislation states that, in case no appropriate animal studies are available for assessment, information should be generated whenever possible by means other than vertebrate animal tests,i. e.applying alternative methods such asin vitrotests, QSARs, grouping and read-across.

Anin vitroskin penetration study (El du Pont de Nemours and Company, 2007; Fasano et al, 2011) with the structural homologue dipropylene glycol, using human cadaver skin and performed under infinite dose conditions, was available for assessment. A nominal dose of 1200 µL/cm²(ca. 1.2 g/cm²) of the neat substance was applied for 24 hours under occlusive conditions to 7 skin replicates representing 4 human subjects. By the conclusion of the 24-hour exposure interval, only a negligible portion of the applied dose of neat dipropylene glycol (0.075%) had penetrated through the skin into the receptor fluid. In general, dipropylene glycol was detected in receptor fluid within about an hour of application (lag time = 1 hour and 3 minutes; 1.05 hours); steady-state penetration, which was represented by no less than 10 data points, was determined to be 39.3 µg/cm²/h (r²=0.999). This represents the maximum flux for neat dipropylene glycol.

Based on the slope at steady-state (39.3 µg/cm²/h) and the concentration of dipropylene glycol in the applied solution, taken as its density (1,020,000 µg/cm³), the permeability coefficient for neat dipropylene glycol was calculated to be 3.85×10^-5cm/h.

Based on the results of the study, a value of 40% for dermal absorption has been chosen by expert judgment to be used in the risk assessment and DNEL derivation. This value has been chosen as an average value between the percentage of dermal absorption obtained in the study and the maximal oral absorption (corresponding to 86%), and is considered to represent a worst-case approach.