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See also attached Toxicokinetic expert document

Toxicokinetic evaluation of “Soybean oil, epoxidized, methyl ester, reaction products with propylene glycol” (CAS 96690-51-6) based on existing data

 

REACH indicates that an “assessment of the toxicokinetic behaviour of the substance to the extent that can be derived from the relevant available information” should be performed at Annex VIII level.

 

General information

“Soybean oil, epoxidized, methyl ester, reaction products with propylene glycol” is considered a UVCB (substance of Unknown or Variable composition, Complex reaction product or Biological material). The constituents identified in this UVCB are summarised in table 1.

 

Table 1 “Soybean oil, epoxidized, methyl ester, reaction products with propylene glycol” constituents

Name-Constituent

CAS Number-Constituent

EC Number-Constituent

Concentration

range %

Fatty acids C16-C18, Me esters

-

-

10-20

Fatty acids, C18-unsatd., epoxidized, ME esters

-

-

10-35

Monomers of C18-unsatd. fatty acids, epoxidized, ME esters with propyleneglycol

-

-

25-50

Oligomers of C18-unsatd. fatty acids, epoxidized, ME esters with propyleneglycol

-

-

10-55

ADME data

Absorption, distribution, metabolism and excretion data on “Soybean oil, epoxidized, methyl ester, reaction products with propylene glycol” itself are not available and therefore the toxicokinetic assessment is based on the available toxicology data.

 

Information from physico chemical studies

An overview of the relevant physicochemical parameters for “Soybean oil, epoxidized, methyl ester, reaction products with propylene glycol” is provided below:

 

Table 2 physicochemical parameters

 

“Soybean oil, epoxidized, methyl ester, reaction products with propylene glycol”

Physical state

Liquid

Structure

UVCB

Molecular weight (g/mol)

270-1700

Log Kow

3.7 - 6.2 at pH 7 and 35°C

Water solubility (mg/L)

495.2 (for total compound [soybean oil, reaction mass])

Vapour pressure (Pa)

3.3 (at 20°C)

34 (at 50°C)

Absorption

Oral: The mortality and clinical effects observed after oral administration of “Soybean oil, epoxidized, methyl ester, reaction products with propylene glycol” in an OECD TG 401 study in rats, suggest that absorption takes place via the oral route. The molecular weight range of this UVCB is very wide, the molecules with a molecular weight below 500 are likely to be absorbed via the oral/GI tract. Uptake through aqueous pores or carriage of such molecules across membranes with the bulk passage of water in the GI tract can be expected. The larger molecules between 500 and 1000 g/mol may be absorbed, to a lesser extent. The constituents with molecular weights above 1000 do not favour absorption. Furthermore uptake by passive diffusion is likely based on the moderate log Kow values of “Soybean oil, epoxidized, methyl ester, reaction products with propylene glycol”. The oral absorption of the more highly lipophilic constituents of this UVCB (log Kow > 4) may be more dependent on micellar solubilisation.

Dermal: Based on the water solubility and log P value of the substance low to moderate absorption of at least a part of its constituents could be expected (ECHA guidance, 7.12, Table R.7.12-3). However, the molecular weight range of this UVCB is very wide, the molecules with a molecular weight <500 are likely to be absorbed dermally. The constituents having a molecular weight >500 may be too large to be absorbed through the skin. In an OECD TG 402 dermal toxicity study no acute dermal toxicity was observed in rabbits exposed to 8.856 g/kg bw.

 

Inhalation: The lipophilicity of the constituents (log Kow >4), and a moderate water solubility indicate that uptake of the substance via the lungs may occur partly by micellar solubilisation. However, the relevance of this route of absorption is limited due to the low vapour pressure of the substance. Nevertheless, the physico-chemical properties of the substance would facilitate absorption directly across the respiratory tract epithelium in case the substance is inhaled or following aspiration.

Distribution

Based its wide molecular weight range, the distribution of “Soybean oil, epoxidized, methyl ester, reaction products with propylene glycol” is expected to vary for the different constituents. For the smaller molecules wider distribution is expected. As the LogKow range indicates lipophilicity of the molecules in the substance, the intracellular concentration is expected to be higher than the extracellular concentration (Particularly in fatty tissues).

 

Metabolism

No information on metabolism can be derived from the physicochemical data that is available for “Soybean oil, epoxidized, methyl ester, reaction products with propylene glycol”. However, the (unsaturated) fatty acids in the substance are expected to be able to be metabolised via the beta-oxidation and TCA pathway. Furthermore, some information is available from a publication by Mattson et al. (1) in which the enzymatic hydrolysis of fully esterified alcohols containing from one to eight hydroxyl groups was studied. They report that nonspecific lipase; an enzyme present in pancreatic juice, can hydrolyse compounds containing more than three but less than six ester groups. A comparable metabolic process is expected play a role in the metabolism of “Soybean oil, epoxidized, methyl ester, reaction products with propylene glycol”.

Elimination

No substance specific information regarding elimination is available. Furthermore, evaluation of systemic effects (acute toxicity and repeated dose toxicity) does not indicate any effects that could be linked to the route of excretion.

Accumulation

There is low potential for the more highly lipophilic constituents of this UVCB (log P >4) to accumulate in individuals that are frequently exposed (e.g. daily at work) to these substances. Due to the high Log Kow values, a build-up of this substance within the body could only occur if the interval between exposures is less than 4 times the whole body half-life of the substance.

Table 4 Key information from the Reach dossier relevant for toxicokinetic assessment

 

“Soybean oil, epoxidized, methyl ester, reaction products with propylene glycol”

Irritation / corrosivity

OECD TG 439: not irritant

OECD TG 438: not irritant

Oral toxicity data

OECD TG 401: LD50 > 29,52 g/kg bw

Dermal toxicity data

OECD TG 402: LD50 > 8.856 g/kg bw

Skin sensitisation data

OECD TG 429: not sensitising

Repeated dose toxicity

OECD TG 407: NOAEL 1000 mg/kg bw/day in males and females. (highest dose) (read across from Fatty acids, C16-C18 and C18-unsatd., ME esters, epoxidized)

Reproductive toxicity

OECD TG 414: NOAEL 1000 mg/kg bw/day (highest dose) (read across from Fatty acids, C16-C18 and C18-unsatd., ME esters, epoxidized)


Conclusion

Oral uptake is expected based on information from the available test information (acute oral toxicity) and the range of physico chemical parameters. Dermal absorption would be possible for at least a part of its constituents, based on physico-chemical information. Based its wide molecular weight range, the distribution is expected to vary for the different constituents. The absorption values for hazard assessment would be 100% for the inhalation route, 50% for the oral route and 50% for the dermal route, respectively. However, based on the results of an oral repeated dose toxicity study (OECD TG 407 / GLP rat) performed with the read across UVCB Fatty acids, C16-C18 and C18-unsatd., ME esters, epoxidized the NOAEL (No Observed Adverse Effect Level) for general toxicity was considered to be 1000 mg/kg bw/day. No adverse effects were observed  at limit dose level, therefore no hazard assessment was performed.

 

References

(1) Hydrolysis of fully esterified alcohols containing from one to eight hydroxyl groups by the lipolytic enzymes of rat pancreatic juice. Mattson, F.H. and Volpenhain, R.A. 1972. J Lipid Res.; 13(3):325-8.

 

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

See also attached Toxicokinetic expert document