Oxydipropanol

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

86

Absorption rate - dermal (%):

40

Absorption rate - inhalation (%):

100

Additional information

Oral route of exposure

No basic toxicokinetics studies on dipropylene glycol 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 as in vitro tests, QSARs, grouping and read-across.

A well-conducted and well-reported study on two structurally related substances, tripropylene glycol and 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, 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. A large fraction (21%) of the¹⁴C-tripropylene glycol dose was catabolized all the way to¹⁴CO₂, indicating considerable breakdown of tripropylene glycol. Little is known about the further metabolism of tripropylene glycol, but at least part of it probably enters into intermediary metabolism via monopropylene glycol formation, as does monopropylene glycol itself, as about a quarter is excreted as CO₂24 h after administration. Overall, the data indicate tripropylene glycol is readily biotransformed to dipropylene glycol and monopropylene glycol which is then 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.             

Applicability of the obtained results for dipropylene glycol

Based on the structural similarity of the substances and their comparable physico-chemical properties (all substances are viscous liquids with a low vapour pressure, relative density of ca. 1, miscible with water, with log Pow varying from -1.07 for propylene glycol to -0.379 for tripropylene glycol), it is expected that the results on toxicokinetics obtained for tripropylene glycol and monopropylene glycol are going to be largely applicable for dipropylene glycol. Thus, it can be expected that dipropylene glycol is rapidly absorbed upon oral administration; based on its lower molecular weight compared to tripropylene glycol it is expected that its absorption will also amount to at least 86%. This value will also be used in the risk assessment for the DNEL derivation. The distribution of dipropylene glycol is expected to occur primarily to liver and kidneys, which is in agreement with the results of repeated dose toxicity studies (see Section 7.5 for further details). As tripropylene glycol, dipropylene glycol is expected to be extensively metabolized to monopropylene glycol, which then undergoes further oxidation to CO₂. A full justification for read across within the propylene glycol series is contained in a separate document attached to chapter 13 of the lead registrants IUCLID dossier.

Inhalation route of exposure

No toxicokinetic studies on dipropylene glycol were available for assessment. In the absence of data, the inhalation adsorption rate is assumed to be 100% to represent the worst case and to follow the ECHA guidance on information requirements and chemical safety assessment.

Dermal route of exposure

An in vitro skin penetration study (El du Pont de Nemours and Company, 2007; Fasano et al, 2011), using human cadaver skin, performed in accordance with OECD guideline 428, was available for assessment. A nominal dose of 1200 µL/cm²of 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 = 1hour 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).

Based on the slope at steady-state (39.3 µg/cm²/h) and the concentration of DPG in the applied solution, taken as its density (1,020,000 µg/cm³), the permeability coefficient 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.