Reaction products of Dihydro-3-(tetrapropenyl)furan-2,5 dione with propane-1,2,diol

Endpoint summary

Description of key information

Physico-chemical properties of 2-(tetrapropenyl)succinic acid, monoester with propane-1,2-diol (CAS Number 52305-09-6; EC Number 257-836-6) and the results of in vitro and in vivo studies conducted with the substance have been used to determine, as far as possible, a toxicokinetic profile for 2-(tetrapropenyl)succinic acid, monoester with propane-1,2-diol.

Key value for chemical safety assessment

Bioaccumulation potential:

high bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

25

Absorption rate - inhalation (%):

100

Additional information

The substance2-(tetrapropenyl)succinic acid, monoester with propane-1,2-diolis a yellow liquid and as it is defined as a UVCB no molecular formula or molecular weight is specified. Its melting point could not be detected but a glass transition was observed at -18 °C; onset of boiling occurs at 173 °C with decomposition. Its density is 1.0482 g/cm³at 20 °C with a vapour pressure of 5.790×10 ^-3Pa at 20°C or 6.479×10^-3Pa at 25°C.

Determination of the partition coefficient of 2-(tetrapropenyl)succinic acid, monoester with propane-1,2-diol was hindered by technical issues relating to the substance but the substance was predicted to be hydrophobic with log Kow of 4.8504, 5.1671 and 10.9361 for the acid, monoester and diester, respectively.

The mean water solubility is low at 55.09 µg/mL and 13.43 µg/mL for the acid and monester respectively. For the diester solubility was estimated to be very low at 0.2 µg/mL. The surface tension of the test material was 34.65 mN/m and was therefore considered to be surface active.

Oral absorption

In an acute oral toxicity study, the acute median lethal dose (LD₅₀) of 2-(tetrapropenyl)succinic acid, monoester with propane-1,2-diol was found to be in the range of 300 to 2000 mg/kg body weight. At 300 mg/kg only limited signs of toxicity (hunched posture) were observed within the first 4 hours of dosing, but no abnormalities were observed at necropsy and the animals gained weight as expected. One animal was dosed at 2000 mg/kg and was subsequently killedin extremis one day after dosing due to adverse clinical signs of toxicity and loss of body weight. Observations at necropsy included dark liver, dark kidneys, gaseous stomach and haemorrhage of the gastric mucosa and non-glandular epithelium of the stomach.

Repeated dose toxicity of 2-(tetrapropenyl)succinic acid, monoester with propane-1,2-diol in rats was examined in an initial 14-day oral gavage range-finder study and a subsequent 28-day oral gavage OECD 407 study. In the 14-day range-finder study male and female rats were dosed with 2-(tetrapropenyl)succinic acid, monoester with propane-1,2-diol at 100, 300, 500 or 1000 mg/kg bw/day. Animals dosed at 500 or 1000 mg/kg bw/day were killed in extremis on Day 5 or Day 2 of dosing, respectively, due to the severity of signs observed. These included (but were not limited to) decreased activity, piloerection and/or hunched posture and necropsy examination revealed findings in the stomach (distended appearance, abnormal contents and thickening/irregular surface of the non-glandular mucosa) and intestinal tract (distention and abnormal contents and/or colour). Treatment of animals with 100 or 300 mg/kg bw/day was well-tolerated and there were no deaths. There was no clear effect of treatment on organ weights. Macroscopic changes in the stomach (thickening and/or depressions on the non-glandular mucosa) were limited to some animals dosed at 300 mg/kg bw/day. 

In the 28-day OECD 407 study male and female rats were dosed daily with 2-(tetrapropenyl)succinic acid, monoester with propane-1,2-diol at 30, 100 or 300 mg/kg bw/day. Recovery from any effects was evaluated during a 2-week recovery period. The only findings of note were histopathological changes in the stomach indicative of site of contact effects, which were not present after 2 weeks recovery, indicating full recovery. The NOAEL for local effects was defined as 100 mg/kg bw/day for males (based on histopathology findings at 300 mg/kg bw/day) and 300 mg/kg bw/day for females. The NOAEL for systemic effects was defined as 300 mg/kg bw/day for males and females. The lowest effect dose in the target organ (identified as the GI tract) was defined as 300 mg/kg bw/day.

2-(tetrapropenyl)succinic acid, monoester with propane-1,2-diol was tested in an OECD 421 (reproductive and developmental toxicity screen) study in rats at doses of 30, 100 or 300 mg/kg bw/day, via oral gavage. The oral administration of the test material was well tolerated with no adverse effect of treatment apparent with respect to the parents, offspring or mating performance.

The available in vivo data, suggests that oral absorption of 2-(tetrapropenyl)succinic acid, monoester with propane-1,2-diol is limited. This is supported by the physico-chemical properties of the substance; the substance has low to very low solubility in water and log Kow values >4 indicating it to be hydrophobic. However, as the substance is an ester, hydrolysis in the acid environment of the stomach could occur and the physico-chemical properties of such hydrolysis products may be significantly different to the parent substance. Therefore, given the findings in the toxicity studies, the potential for increased absorption due to the use of corn oil as the vehicle and in the absence of any other information, for the purposes of human DNEL setting, 100% oral absorption is assumed for risk assessment purposes.

Dermal absorption

An acute dermal toxicity study (OECD 402) has been conducted with 2-(tetrapropenyl)succinic acid, monoester with propane-1,2-diol. After a single 24-hour application at 2000 mg/kg there were no deaths or signs of systemic toxicity associated with the test material. Signs of dermal irritation were observed, however, animals generally showed expected body weight gains and no abnormalities were noted at necropsy. No signs of corrosion were noted. The acute dermal median lethal dose (LD50) of the test item in the Wistar strain rat was found to be greater than 2000 mg/kg body weight.

In an in vitro skin corrosion study 2-(tetrapropenyl)succinic acid, monoester with propane-1,2-diol was shown to be not corrosive to skin but in an in vitro skin irritation test the test substance was concluded to be a skin irritant. Furthermore it was concluded to cause severe eye damage in an in vitro (BCOP) eye irritation study. Finally the substance was concluded to not be a skin sensitizer in an in vivo skin sensitisation study in guinea pigs. 

Substances with high water solubility and partition coefficients >0 are expected to be highly absorbed, with optimum absorption occurring for substances with water solubility of 100-10000 µg/mL and log P values of -1-4. 2-(tetrapropenyl)succinic acid, monoester with propane-1,2-diol has low water solubility and is highly lipophilic (4.8-10.9) it is therefore predicted to be low to moderately absorbed into the stratum corneum but then continued transfer through the epidermis is expected to be low. This assessment is supported by the toxicity data which demonstrate no systemic toxicity or skin sensitisation following dermal administration of 2-(tetrapropenyl)succinic acid, monoester with propane-1,2-diol but that site of contact irritation does occur.

Therefore, it can be concluded that absorption via the dermal route is unlikely and for the purposes of DNEL setting, dermal absorption is estimated at 25% according to the 2017 EFSA guidance on dermal absorption.

Inhalation absorption

No inhalation toxicity data are available for 2-(tetrapropenyl)succinic acid, monoester with propane-1,2-diol as human exposure via the inhalation route is expected not to occur. The low vapour pressure and high boiling point of the substance indicate that creation of vapours of the substance are unlikely and the high partition coefficients would not favour absorption should exposure to vapours occur. However, as the substance is highly lipophilic (log Kow>4) there is the potential that inhalation of any liquid could result in absorption directly across the respiratory tract epithelium.

In the absence of any quantitative data, absorption by inhalation is assumed to be 100%.

Distribution, Metabolism and Elimination

No information is available to describe the distribution, metabolism or elimination of the material.

The low water solubility and highly lipophilic nature of the substance would suggest that diffusion across lipid membranes could occur facilitating distribution should absorption occur and this in turn could lead to accumulation over the exposure period.

No information is available on the fate of the possibly absorbed material however, in vitro genotoxicity studies showed little quantitative difference in toxicity between exposures in the absence of exogenous metabolism and those in the presence of exogenous metabolism (using rat liver S9 fraction), suggesting metabolism via liver enzymes may not occur.

 

Conclusions

Based on in vitro and in vivo data from studies performed with 2-(tetrapropenyl)succinic acid, monoester with propane-1,2-diol, oral absorption is estimated at 100%, inhalation absorption is estimated at 100% and dermal absorption is estimated at 25%. 

The potential for bioaccumulation is considered high.