Constitutional isomers of penta-O-allyl-β-D-fructofuranosylα-D-glucopyranoside; Constitutional isomers of hexa-O-allyl-β-D-fructofuranosylα-D-glucopyranoside; Constitutional isomers of hepta-O-allyl-β-D-fructofuransoylα-D-glucopyranoside

Endpoint summary

Additional information

The toxicokinetic profile of EC 419-640-0 (Constitutional isomers of penta-O-allyl-β-D-fructofuranosylα-D-glucopyranoside; Constitutional isomers of hexa-O-allyl-β-D-fructofuranosylα-D-glucopyranoside; Constitutional isomers of hepta-O-allyl-β-D-fructofuransoylα-D-glucopyranoside)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 419-640-0 is a UVCB with a molecular weight range of 56.06 to 662.3, however, the three identified low molecular weight components constitute a tiny fraction of the substance (typically <0.01%), whereas the six identified component that constitute >99% of the substance all have a MW >500. The substance is straw coloured liquid and is water soluble but the value is dependent on the loading rate, estimated to be 0.283 g/L to 4.1E-03 g/L.

The substance is reported to contain some moderately soluble components which aided the dissolution of the less soluble components. However, the method used to determine water solubility was the shake flask method, which is not the preferred method for surface active substances and would have promoted micelle formation. The true water solubility value is considered to be considerably less than 4.1E-03.

The octanol/water partition coefficient used in the CSA is log Pow 5.17, (which is >4, the bioaccumulation limit). However, the study determined the overall weighted partition coefficient of the test item to be 1.48 E05 with an overall weighted log10 Pow of 5.17. The test item had a weighted partition coefficient range of 1.32 to 1.07E08 and weighted log10 Pow range of 0.12 to 8.03 (OECD 117 and EU Method A.8). Consequently, the true value for the Log Pow may be >8.0.

 The substance has a low vapour pressure (2.4 E-03 Pa @ 38oC) and has surface-active properties (surface tension value of 48.0 mN/m at 21±0.5°C). An abiotic degradation test of the hydrolytic properties of the substance suggests that hydrolysis is very slow (half-life of >1 year at pH 4, 7 and 9).

 Absorption

Oral Route

The physical chemical properties described above indicate that EC 419-640-0 has a molecular size (MW 56.06 to 662.3, but >99.99% with a MW >500) greater than that which may be expected to be easily absorbed within the mammalian gastrointestinal tract, should that material be ingested. Being lipophilic with a Log Powlikely to be >8.0, EC 419-640-0 may be expected not to easily cross gastrointestinal epithelial barriers. The relatively high MW of the majority of the substance may 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) and an acute oral gavage toxicity study identified evidence of toxicity (LD50 in the range of 300 to 2000 mg/kg bw). A combined repeat dose and reproductive toxicity study using the oral route gave a NOAEL of 400 mg/kg bw/day. In the acute study severe clinical signs and premature death was observed in the single animal dosed at 2000 mg/kg; no clinical signs were observed at 300 mg/kg. In the repeat dose study clinical signs and premature deaths were observed in animals dosed with 750 mg/kg but the NOAEL was 400 mg/kg.

Dermal Route

Regarding the dermal absorption of EC 419-640-0, 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 MW range (56.06 to 662.3, predominantly >500) and the high log Pow. Moreover, it is assumed that the dermal uptake of EC 419-640-0 is also limited based on its low water solubility1,2. These assumptions were supported by the absence of observed systemic effects following dermal application of EC 419-640-0 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, but no erythema in a skin irritation study in rabbits. In a sensitisation study in mice (LLNA) the substance was concluded not to be a sensitiser. Therefore, these results are considered to be evidence of non-absorption via the dermal route.In this case it is considered appropriate to modify the default absorption rate from 10% to 1% when extrapolating from the oral to 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 419-640-0 (2.4 x 10-3Pa @ 38oC) 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 intermediate in the preparation of polymer compoundsand as a consequence there is little 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 419-640-0 can be predicted from the physical chemical properties of this substance. The moderately high log Powand 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 Powand the high MW of EC 419-640-0 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 increasing severity of clinical observations from the repeated dose study, as might be manifested if there was an accumulation of EC 419-640-0 or metabolites in body tissues.

 Metabolism

EC 419-640-0 is a UVCB (Constitutional isomers of penta-O-allyl-β-D-fructofuranosylα-D-glucopyranoside; Constitutional isomers of hexa-O-allyl-β-D-fructofuranosylα-D-glucopyranoside; Constitutional isomers of hepta-O-allyl-β-D-fructofuransoylα-D-glucopyranoside). Like most xenobiotics, EC 419-640-0 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 419-640-0 was metabolized into toxic metabolites because of the steep dose-response relationship (no effects at 400 mg/kg and severe effects at 750 mg/kg). Data from studies on bacterial mutagenicity, mammalian cell mutagenicity and chromosomal aberration in mammalian cells, in which EC 419-640-0 was subjected to rat hepatic microsomal enzyme systems, did show evidence of genotoxic activity in strains TA1535 and TA100 in the Ames bacterial mutagenicity assay, but not in the mammalian cell gene mutation assay or the mouse micronucleus test. Thein vitromutagenicity of EC 419-640-0 was not significantly different in the presence or absence of metabolic enzymes, which suggests no involvement of metabolism in this activity.It is suspected that the activity in the Ames test was caused by the trace of allyl alcohol which is known to be mutagenic to these strains of bacteria.

Excretion

 The structural characteristics of EC 419-640-0 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:

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.

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