Propane-1,2-diol, propoxylated

Endpoint summary

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

86

Absorption rate - dermal (%):

40

Additional information

No data on toxicokinetic behavior of ‘propane-1,2-diol, propoxylated’ are available. 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.

One well-conducted and well-reported toxicokinetic study using oral route of exposure is available with two of the constituents and lower homologues of ‘propane-1,2-diol, propoxylated’ (a multi-constituent substance), mono- and tripropylene glycol, while two dermal penetration studies are available on mono- and dipropylene glycol. Regarding inhalation route of exposure, only for monopropylene glycol limited data are available. All three substances are usually present in the commercial ‘propane-1,2-diol, propoxylated’ at the following concentrations: 0-2% monopropylene glycol, 5 -75% dipropylene glycol and 20-75% tripropylene glycol. Therefore it is considered acceptable to derive the data on toxicokinetic behavior of ‘propane-1,2-diol, propoxylated’ by read-across from its constituents.

Oral route of exposure

One well-conducted and well-reported study with mono- and tripropylene 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-labile conjugates of mono-, di- and tripropylene glycol for both groups.

Absorption

Based on the average recovery of ca. 91% of the¹⁴C label tripropylene glycol 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. ‘propane-1,2-diol, propoxylated’ is expected to be similarly absorbed via oral exposure.

Distribution

Approximately 10% of the radiolabeled dose of tripropylene glycol 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. A similar distribution profile is expected for ‘propane-1,2-diol, propoxylated’.

Metabolism

Twenty-four hours after administration of a single oral dose of 40 mg/kg bw tripropylene glycol 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. Similarly, ‘propane-1,2-diol, propoxylated’ is expected to be highly metabolized to smaller glycols and CO₂.

Inhalation route of exposure

Only limited data addressing the absorption of monopropylene glycol by inhalation are available. Bau et al. (1971) reported that less than 5% of a technetium-labeled aerosol containing 10% monopropylene glycol in deionized water was taken up by human volunteers after inhalation for 1 hour in a mist tent. The authors measured the aerosol mass median diameter to be 4.8-5.4 microns, a size small enough to have enabled penetration to the deep lung. Ninety percent of the dose was found in the nasopharynx and it rapidly entered the stomach with very little entering the lungs. Monopropylene glycol was not directly measured, not allowing the determination of absorption through the nasal mucosa. However, the low dose rate from inhalation exposure and the small surface area would not lead to significant absorption of monopropylene glycol. Additionally, as ‘propane-1,2-diol, propoxylated’ has a significantly higher boiling point and lower vapor pressure than monopropylene glycol, under normal conditions of use the inhalation exposure potential of this substance is low and hence likelihood of absorption via inhalation is low.

Dermal route of exposure.

Two in vitro skin penetration studies (El du Pont de Nemours and Company, 2007a and 2007 b) with the structural homologues mono- and dipropylene glycol, using human cadaver skin and performed under infinite dose conditions, are 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 6 skin replicates representing 5 human subjects (monopropylene glycol) or7 skin replicates representing 4 human subjects (dipropylene glycol). By the conclusion of the 24-hour exposure interval, only a negligible portion of the applied dose of neat substances (0.14% and 0.075% for mono- and dipropylene glycol, respectively) had penetrated through the skin into the receptor fluid. In general, the test substance was detected in receptor fluid within about an hour of application (lag time ~6 hours for mono- and 1 hour and 3 minutes for dipropylene glycol, respectively). Steady-state penetration was determined to be 95.4 μg/cm²/h (r²≥ 0.999) and 39.3 μg/cm²/h (r²≥ 0.999) for mono- and dipropylene glycols, respectively. These values represent the maximum flux for neat substances. 

Based on the slope at steady-state and the concentration of the substance in the applied solution, taken as its density, the permeability coefficient for neat mono- and dipropylene glycols were calculated to be 9.21×10^-5cm/h and 3.85×10^-5cm/h. For ‘propane-1,2-diol, propoxylated’, a similar rate of dermal uptake is expected.

Applicability of the obtained results for ‘propane-1,2-diol, propoxylated’

Based on the structural similarity of the substances (critically all contain the same functional groups) it is expected that the consistent results on toxicokinetics obtained for tripropylene glycol and monopropylene glycol are representative of all five glycols. Thus, it can be expected that all five glycols are rapidly absorbed upon oral administration and all five will be rapidly dispersed in body water, with some concentration at sites of metabolism and elimination (liver and kidney). Available data indicates that uptake of dipropylene glycol by the dermal route is insignificant and uptake by the inhalation route is not considered to be relevant due to the very low vapour pressure of dipropylene glycol. Uptake by these routes of higher molecular weight members of the series is even less likely.

The metabolic breakdown path appears to be:

PentaPG→TetraPG→TPG→DPG→MPG→CO₂

Where:

PentaPG = pentapropylene glycol

TetraPG =tetrapropylene glycol

TPG = tripropylene glycol

DPG = dipropylene glycol.

MPG = monopropylene glycol

This supports the conclusion that data for monopropylene glycol, dipropylene glycol and tripropylene glycol will be relevant for the higher weight members of the series and also for each other because of the common breakdown pathway. Therefore, interpolation and extrapolation between members of the series and application to 'propane-1,2 -diol, propoxylated' is justified to satisfy REACH mammalian toxicity and ecotoxicity endpoint requirements. It can therefore be expected that all substances constituting ‘propane-1,2-diol, propoxylated’ shall be rapidly absorbed upon oral administration. The value of 86% oral absorption, obtained for tripropylene glycol, is considered to be acceptable to be used for DNEL derivation in case of ‘propane-1,2-diol, propoxylated’, as tripropylene glycol is one of the major constituents of ‘propane-1,2-diol, propoxylated’. The distribution of higher homologues is also expected to occur primarily to liver and kidneys. It is feasible to assume that metabolism of higher homologues will also occur via the stepwise formation of the lower oligomers, as it is observed for tripropylene glycol, which then undergo further oxidation to CO2.

For dermal route of exposure, a value of 40% for dermal absorption has been chosen by expert judgment to be used for DNEL derivation for ‘propane-1,2-diol, propoxylated’. This value has been chosen as an average value between the percentage of dermal absorption obtained in the studies with mono- and dipropylene glycol and the maximal oral absorption (corresponding to 86%), and is considered to represent a worst-case approach.