Esterification products of dihydrofuran-2,5-dione, C16-24 (even numbered) alkenyl with propane-1,2,3-triol and propane-1,2,3-triol oligomers

Endpoint summary

Description of key information

Minimal absorption via oral, dermal or inhalation routes of exposure is expected based on the experimental data and the physico-chemical properties of the substance. Distribution will be through blood to tissues and organs although absorption will be minimal. Metabolism and elimination are predicted to be rapid. The substance will not bioaccumulate.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

The toxicokinetic profile of EC 940-875-4 was predicted using the physical chemical properties of the substance, the data obtained from acute and repeated-dose toxicity studies, as well as information gained from genotoxicity assays.

 

Physico-chemical properties

 

EC 940-875-4 is a UVCB with an average molecular weight of approximately 1418 to 1433. The substance is poorly water soluble, estimated to be 1.43 x 10^-9g/L, with a very high estimated octanol/water partition coefficient, log P_ow16.06, (which is >4, the bioaccumulation limit), and a low vapour pressure (2.1 x 10^-3Pa @ 25^oC, extrapolated). The substance has surface-active properties (surface tension value of 53.5 mH/m at 21±0.5°C) and can also form an emulsion in water. A computer prediction of the hydrolytic properties of the substance suggests that hydrolysis is very slow (half-life of 77 days at pH8 and 2 years at pH7).

 

Absorption

 

Oral Route

The physical chemical properties described above indicate that EC 940-875-4 has a molecular size (MW1418-1433) greater than that which may be expected to be easily absorbed within the mammalian gastrointestinal tract, should that material be ingested. Being highly lipophilic but with a Log P_ow>11 (est. log P_ow= 16.06), EC 940-875-4 may be expected not to cross gastrointestinal epithelial barriers, and the high MW may also significantly restrict absorption, at least of a major proportion of this UVCB. The substance has surface-active properties and the possibility exists that it may participate in micelle transport into the hepatic portal system along with other lipophilic substances (e.g., dietary fats). However, an acute oral gavage toxicity study identified no evidence of toxicity (LD50 >2000 mg/kg bw). A 28-day repeat dose study using the oral route gave a NOAEL of 1000 mg/kg bw/day. In the acute study the only clinical signs that were observed were hunched posture and lethargy at 2000 mg/kg, but such symptoms are frequently observed as a side-effect of the dosing procedure and are not conclusive as evidence of absorption. No such clinical signs were observed in the 28-day study in animals dosed with 1000 mg/kg for 28 days. The lack of adverse findings following oral dosing may be due to limited gastrointestinal absorption of the test material after dosing, or a very low index of inherent toxicity for this substance, and/or its metabolite(s). There is some evidence that the substance is not likely to hydrolyse readily, so the possibility that smaller sub-units of the substance will be absorbed is low.

 

Dermal Route

Regarding the dermal absorption of EC 940-875-4, its rate of uptake into the stratum corneum and its rate of transfer between the stratum corneum and the epidermis are likely to be very slow considering both the high MW (1418-1433) and the estimated log P_ow16.06. Moreover, it is assumed that the dermal uptake of EC 940-875-4 is also limited based on its low water solubility^1,2. These assumptions were supported by the absence of observed systemic effects following dermal application of EC 940-875-4 in the acute dermal toxicity study at 2000 mg/kg. The substance did cause very slight erythema and very slight oedema in the dermal toxicity study, and also reversible well-defined erythema and slight oedema in a skin irritation study in rabbits. In a sensitisation study in mice (LLNA) the substance was concluded to be a sensitiser because there was an increase in stimulation index at dose levels of 5, 10 and 25% in dimethyl formamide. However, the LLNA assay has been shown to be highly prone to false positive results when used with substances that are surface active. Therefore, this result is considered not to be evidence of absorption via the dermal route.

 

Inhalation Route

The potential for inhalation toxicity was not studied directly in a toxicology study using the inhalation route. However, the low vapour pressure of EC 940-875-4 (2.1 x 10^-3Pa @ 25^oC, extrapolated) indicates a very low propensity to enter atmospheric air in a respirable form. Thus, respiratory absorption under normal use and handling of this material is expected to be inconsequential. The substance is used as an emulsifierand as a consequence there is a potential for exposure via the production of aerosols. In this case the absorption across the respiratory epithelium is likely to be very low, because of the physicochemical properties discussed previously. For route-to-route extrapolation purposes (oral-to-inhalation extrapolation), it is proposed to include a default factor of 2, i.e. the absorption percentage by oral route is half that of the inhalation absorption as suggested on page 19 of Guidance Document, Chapter R.8.

 

Distribution

 

Systemic distribution of EC 940-875-4 can be predicted from the physical chemical properties of this substance. The relatively high log P_owand poor water solubility suggests that this substance, upon systemic absorption, may be transported through the circulatory system as micelles or in association with a carrier molecule such as a lipoprotein or other macromolecule. The lipophilic character, high Log P_owand the high MW of EC 940-875-4 suggests that a major proportion of the substance will not readily traverse cellular barriers or distribute into fatty tissues. There is no evidenceof cumulative toxicity, such as significant systemic toxicity and/or histopathological changes, or increasing severity of clinical observations from the repeated dose study, as might be manifested if there was an accumulation of EC 940-875-4 or metabolites in body tissues.

 

Metabolism

 

EC 940-875-4 is a UVCB. Like most xenobiotics, EC 940-875-4 may be expected to undergo phase I oxidation/reduction, esterase-catalyzed hydrolysis and subsequent Phase II conjugation. Acute and repeated-dose toxicity testing provided no evidence that EC 940-875-4 was metabolized into toxic metabolites. Data from studies on bacterial mutagenicity, mammalian cell mutagenicity and chromosomal aberration in mammalian cells, in which EC 940-875-4 was subjected to rat hepatic microsomal enzyme systems, did not show any evidence of genotoxic activity from the substance or its potential metabolites. The in vitro toxicity of EC 940-875-4 was slightly reduced in the presence of metabolic enzymes. This may indicate that the potential metabolites may be less toxic than the substance itself or simply that the presence of protein may bind the substance such that the toxicity is reduced.

 

Excretion

 

The structural characteristics of EC 940-875-4 suggest that this molecule may readily undergo phase I and phase II metabolic transformation. The resulting metabolic by-products are expected to undergo routine renal and or biliary excretion.

 

References:

1. Derivation of assessment factors for human health risk assessment. ECETOC Technical Report No. 86. ISBN-0773-6347-86, Brussels, February 2003, page 13, paragraph 1.

2. Guidance document on dermal absorption. European Commission Sanco/222/2000 rev. 7. Page 7, paragraph 2.