Fatty acids, tall-oil, 1-methyl-1,2-ethanediyl esters

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Rationale for reliability incl. deficiencies:

other: No studies are available on the toxicokinetics, metabolism and distribution of WS400145. Predictions were made based on physical-chemical properties and information on metabolism studies with similar substances.

Reason / purpose for cross-reference:

read-across: supporting information

Conclusions:

Interpretation of results: no bioaccumulation potential

Executive summary:

 The test material, WS400145, is a UVCB substance composed of mono- and diesters of propylene glycol (PG) with tall oil fatty acids. The molecular weight ranges approx. from 335 Da to 605 Da. The water solubility is very low, approx. 0.1 mg/l. The substance is lipophilic with an octanol / water partition coefficient log P_ow> 6.

Oral absorption and metabolism

In an acute oral toxicity study in rats no effects were observed at the limit dose of 2000 mg/kg body weight. In a subacute oral toxicity test in rats with reproduction and developmental toxicity screening no effects were observed in parental animals after repeated dosing at 1000 mg/kg body weight/day. Dosing also had no effects on reproduction and developmental endpoints. However, complete absorption of WS400145 after oral dosing is very likely.

Long et al (1958) reported results on absorption and metabolism of propylene glycol distearate in rats. In 1970 a report was published by King et al on the metabolism of stearoyl propylene glycol hydrogen succinate. For both substances in vitro hydrolysis by digestive enzymes, i.e. steapsin and pancreatin, was demonstrated to release fatty acids and PG. In in vivo studies in rats it was confirmed that hydrolysis of the PG esters in the digestive tract is the first step in their degradation. The free fatty acids are absorbed in the digestive tract and metabolised in the same way as fatty acids released from triglycerides. PG was also absorbed and almost completely degraded to CO₂in rats.

These metabolism studies demonstrate that mono- and diesters of PG with fatty acids are hydrolysed and metabolised in a manner similar to triglycerides.

Propylene glycol esters of fatty acids are an approved food additive composed of mono- and diesters of saturated and unsaturated fatty acids derived from edible oils and fats (E 477, Regulation (EC) 1333/2008). The fatty acids used in the manufacture of WS400145 are derived from tall oil the composition of which is not significantly different from other (edible) plant oils. Therefore, it is concluded that WS400145 is hydrolysed in the gastrointestinal tract as it was demonstrated for specific PG esters by Long et al and King et al. The fatty acids and PG are then metabolised by known pathways identical to metabolism of the food additive E 477.

Dermal absorption

After topical administration to intact skin, the transfer of WS400145 from the stratum corneum to the lower epidermis and dermis is expected to be very limited due to the high octanol/water partition coefficient [ECHA 2014]. In the in vitro skin irritation and in vivo eye irritation studies no irritation was observed. In the skin sensitization test in mice no irritation was observed at concentrations <25%. At 50% concentration slight thickening of the ear was observed indicating some irrtation.

Absorption by inhalation

Inhalation of any vapour from WS400145 is an unlikely route of human exposure, because the substance has a very low vapour pressure (7 x 10E-4 Pa at 25°C) and decomposes before boiling [ECHA 2014]. Exposure of humans to an inhalable aerosol of WS400145 may be unlikely, because it is a viscous liquid probably limiting its availability as an inhalable aerosol.

 

References:

ECHA 2014, Chapter R.7c: Endpoint specific guidance.

King W.R., Michael W.R., Coots R.H. (1970): Metabolism of stearoyl propylene glycol hydrogen succinate. Toxicol Appl Pharmacol 17, 519-528.

Long C.L., Domingues F.J., Studer V., Lowry J.R., Zeitlin B.R., Baldwin R.R., Thiessen R (1958): Studies on absorption and metabolism of propylene glycol distearate. Arch Biochem Biophys 77, 428-439.

Regulation (EC) 1333/2008 on food additives.

 

Description of key information

Toxicokinetic data on WS400145 are not available. However, studies on metabolism of very similar propylene glycol fatty acid esters were published demonstrating rapid metabolism by hydrolysis of the ester linkages to release free fatty acids and propylene glycol (for read-across justification document see Section 13).

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The test material, WS400145, is a UVCB substance composed of mono- and diesters of propylene glycol (PG) with tall oil fatty acids. The molecular weight ranges approx. from 335 Da to 605 Da. The water solubility is very low, approx. 0.1 mg/l. The substance is lipophilic with an octanol / water partition coefficient log P_ow> 6.

Oral absorption and metabolism

In an acute oral toxicity study in rats no effects were observed at the limit dose of 2000 mg/kg body weight. In a subacute oral toxicity test in rats with reproduction and developmental toxicity screening no effects were observed in parental animals after repeated dosing at 1000 mg/kg body weight/day. Dosing also had no effects on reproduction and developmental endpoints. However, complete absorption of WS400145 after oral dosing is very likely.

Long et al (1958) reported results on absorption and metabolism of propylene glycol distearate in rats. In 1970 a report was published by King et al on the metabolism of stearoyl propylene glycol hydrogen succinate. For both substancesin vitrohydrolysis by digestive enzymes, i.e. steapsin and pancreatin, was demonstrated to release fatty acids and PG. Inin vivostudies in rats it was confirmed that hydrolysis of the PG esters in the digestive tract is the first step in their degradation. The free fatty acids are absorbed in the digestive tract and metabolised in the same way as fatty acids released from triglycerides. PG was also absorbed and almost completely degraded to CO₂in rats.

These metabolism studies demonstrate that mono- and diesters of PG with fatty acids are hydrolysed and metabolised in a manner similar to triglycerides.

Propylene glycol esters of fatty acids are an approved food additive composed of mono- and diesters of saturated and unsaturated fatty acids derived from edible oils and fats (E 477, Regulation (EC) 1333/2008). The fatty acids used in the manufacture of WS400145 are derived from tall oil the composition of which is not significantly different from other (edible) plant oils. Therefore, it is concluded that WS400145 is hydrolysed in the gastrointestinal tract as it was demonstrated for specific PG esters by Long et al and King et al. The fatty acids and PG are then metabolised by known pathways identical to metabolism of the food additive E 477.

Dermal absorption

After topical administration to intact skin, the transfer of WS400145 from the stratum corneum to the lower epidermis and dermis is expected to be very limited due to the high octanol/water partition coefficient [ECHA 2014]. In the in vitro skin irritation and in vivo eye irritation studies no irritation was observed. In the skin sensitization test in mice no irritation was observed at concentrations<25%. At 50% concentration slight thickening of the ear was observed indicating some irrtation.

Absorption by in halation

Inhalation of any vapour from WS400145 is an unlikely route of human exposure, because the substance has a very low vapour pressure (7 x 10E-4 Pa at 25°C) [ECHA 2014]. Exposure of humans to an inhalable aerosol of WS400145 may be unlikely, because it is a viscous liquid probably limiting its availability as an inhalable aerosol.

 

References:

ECHA 2014, Chapter R.7c: Endpoint specific guidance.

King W.R., Michael W.R., Coots R.H. (1970): Metabolism of stearoyl propylene glycol hydrogen succinate. Toxicol Appl Pharmacol 17, 519-528.

Long C.L., Domingues F.J., Studer V., Lowry J.R., Zeitlin B.R., Baldwin R.R., Thiessen R (1958): Studies on absorption and metabolism of propylene glycol distearate. Arch Biochem Biophys 77, 428-439.

Regulation (EC) 1333/2008 on food additives.