2,5-Furandione, dihydro-, mono-C15-20-alkenyl derivs.

Endpoint summary

Description of key information

A theoretical assessment is performed taking into account physico-chemical

information and the results of toxicity studies on 2,5-Furandione,

dihydro-, mono-C15-20-alkenyl derivs. As a conclusion, the absorption via oral,

inhalation and dermal route is expected to be low. In addition,

the potential for bioaccumulation is also regarded as low.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

10

Absorption rate - dermal (%):

10

Absorption rate - inhalation (%):

10

Additional information

Introduction

There are no studies available where the toxicokinetic behaviour of 2,5-Furandione, dihydro-, mono-C15-20-alkenyl derivs.was evaluated. Therefore a theoretical assessment is performed taking into account physico-chemical information and the results of toxicity studies on 2,5-Furandione, dihydro-, mono-C15-20-alkenyl derivs.

The compound of interest is a yellow viscous liquid, manufactured by a reaction of isomerized olefins with maleic anhydride. As the starting materials isomerized olefins are UVCB substances, their reaction product is also considered a UVCB. Based on the content of C15-C20 olefins in the starting material the main containing reaction products are assumed to be 2,5-Furandione, 3-(hexadecen-1-yl)dihydro- (CAS 32072-96-1), 2,5-Furandione, dihydro-3-(octadecen-1-yl)- (CAS 28777-98-2) and 2,5-Furandione, 3-(eicosen-1-yl)dihydro- (CAS 53520-67-5), respectively.

Table 1 Composition of 2,5-Furandione, dihydro-, mono-C15-20-alkenyl derivs. and main physic-chemical properties of components

	2,5-Furandione, dihydro-, mono-C15-20-alkenyl derivs.	2,5-Furandione, 3-(hexadecen-1-yl)dihydro-	2,5-Furandione, dihydro-3-(octadecen-1-yl)-	2,5-Furandione, 3-(eicosen-1-yl)dihydro-
CAS No.	68784-12-3	32072-96-1	28777-98-2	53520-67-5
Molecular weight	<500	322.49	350.55	378.60
Typical content %		ca. 50%	ca. 50%	ca. 5%
Partition Coefficient (log Kow)	Log Kow = 8.46 – 10.42 Read-across	Log Kow = 8.46 (1)	Log Kow = 9.44 (1)	Log Kow = 10.42 (1)
Water solubility	Unstable (0.017 mg/L)	0.0048767 mg/L (2)	0.00044701 mg/L (2)	0.000040711 mg/L (2)

(1)     Estimated by KOWWIN v1.68

(2)     Estimated by WATERNT v1.01

 

The substance 2,5-Furandione, dihydro-, mono-C15-20-alkenyl derivs. is a UVCB with an average molecular weight of < 500 g/mol. The substance is unstable in water as it dissociates with a half-life of 27 min at 70 °C in pure water and 80 min in water-THF (Lackinger 2010). Also, 97% hydrolysis was found after 14h at 37°C and pH 7.4 (AkzoNobel 2012). Due to the instability in water, any measurement of the partitioning coefficient is technically not feasible. The Log Pow was therefore derived from the calculated values of the containing components which were found to be in the range of 8.46 to 10.42 at 25°C.

The vapor pressure was found to be negligible(1E-06 Pa at 20°C).

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. In addition to molecular weight the most useful parameters providing information on this potential are the octanol/water partition coefficient (log Pow) value and the water solubility. These data of the substance 2,5-Furandione, dihydro-, mono-C15-20-alkenyl derivs. and of the listed individual components will be used to evaluate the toxicokinetic behaviour.

Oral

In general, a molecular weight < 500 is favourable for absorption via the biological membranes of the gastrointestinal tract (GI). For substances with log Pow >4 and low water solubility (< 1 mg/L) uptake via the GI tract is in general low, but some micellular solubilisation by bile salts in the gastro-intestinal tract may allow crossing of lipid biological membranes.
Based on the instability upon contact with water and the log Pow of 2,5-Furandione, dihydro-, mono-C15-20-alkenyl derivs. only some absorption of the substance is expected. The hydrolysis products may be slightly more water soluble, but are expected to have a high log Pow as well ( 6.74, as was calculated for a theoretical structure T16 H).
In the available repeated dose studies (OECD 422, OECD 408 and OECD 443) effects on liver and the gastrointestinal tract are reported that are related to test substance or its hydrolysis products, which confirms that some absorption must have occurred. In contrast, the acute and short-term oral studies in rats with 2,5-Furandione, dihydro-, mono-C15-20-alkenyl derivs. showed no substance related clinical signs and no mortality, leading to NOAEL values of 1000 mg/kg bw. The LD50 value was found to be >2000 mg/kg bw. These results are therefore considered indicative for limited absorption.

Dermal

As is the case for oral absorption, dermal absorption depends also on molecular size, water solubility and log Pow. With an average molecular size of < 500 g/mol and the instability upon contact with water, the absorption of the substance 2,5-Furandione, dihydro-, mono-C15-20-alkenyl derivs. is anticipated to be low. In addition, for the main components the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis due to the log Pow >5.0 (ECHA, 2017).
This is supported by the results of the acute dermal study with of the substance 2,5-Furandione, dihydro-, mono-C15-20-alkenyl derivs. show that neither systemic effects nor mortality was noted after application of 2000 mg/kg bw. Nevertheless, the substance was found to be a skin sensitizer, a property that can only become apparent when some absorption via the skin is anticipated. Therefore it is concluded that there are indications for limited absorption. This is in line with the outcome of permeability model calculations on the components, which suggest also a low absorption potential. Together the results indicate a limited dermal absorption of 2,5-Furandione, dihydro-, mono-C15-20-alkenyl derivs., and 10% dermal absorption will be used in risk assessment (default value).

Table 2 Calculated dermal absorption of components of 2,5-Furandione, dihydro-, mono-C15-20-alkenyl derivs.

		2,5-Furandione, 3-(hexadecen-1-yl)dihydro-	2,5-Furandione, dihydro-3-(octadecen-1-yl)-	2,5-Furandione, 3-(eicosen-1-yl)dihydro-
DERMWIN (US EPA)	Dermal Absorption (mg/cm²/h)	1.07E-04	6.98E-06	9.35E-06
	Absorption Potential	10%	10%	10%
Ten Berge (2009)	Dermal Absorption (mg/cm²/h)	6.48E-07	1.32E-08	5.12E-09
	Absorption Potential	10%	10%	10%
Danish (Q)SAR	Dermal Absorption (mg/cm²/event)	0.00004	0.00002	0.00001
	Absorption Potential	10%	10%	10%

Inhalation

Respiratory absorption is expected to be low due to the logPow and hydrolysis in water (set at 10% as default value). However, uptake by inhalation of the substance 2,5-Furandione, dihydro-, mono-C15-20-alkenyl derivs. is not expected, as the substance is a viscous liquid with a very low vapor pressure. Although the substance is used in solution and inhalation via aerosols might occur, the uses during the whole life cycle are not expected to release vapours or aerosols/mists containing respirable and/or inhalable droplets. Therefore exposure and concomitant uptake via inhalation can be excluded.

Metabolism

When any of the constituents would become bioavailable (bioavailability is expected to be very low in view of the low uptake), it is expected that the part of the constituents that is actually taken up, may be metabolized to some extent. It is considered that hydrolysis of 2,5-Furandione, dihydro-, mono-C15-20-alkenyl derivs. upon contact with body fluids is the earliest step in metabolism. The resulting alkenylated succinic acid is similar to (rare) naturally occurring fatty acids, alkylitaconates, which are known to be degraded in the liver (Adler et al., 1957). It is expected that the metabolic breakdown of alkenylated succinic acid occurs by binding of CoA and subsequent release of Acetyl-CoA, which is used in many metabolic steps (e.g. fatty acid synthesis) or degradation in the citric acid cycle. The other resulting molecule is an unsaturated fatty acid, for which the ß-oxidation is likely to be the major fate in mammals. Fatty acids are oxidized in mitochondria by a sequence of reactions in which the fatty alkyl chain is shortened two carbon atoms at a time. 
However, in view of the complexity of the UVCB substance no further predictions of metabolism are included.

Excretion 

The main route of excretion after oral administration is expected to be via the faeces without becoming systemically available. No bioaccumulation of the substance is expected.

Conclusion

The uptake of 2,5-Furandione, dihydro-, mono-C15-20-alkenyl derivs. via the oral, dermal and inhalation route is expected to be limited which is in line with the hazard assessment showing  treatment related effects.

 

References

Adler, J. Shu-Fang Wang, AND Henry A. Lardy (1957): The metabolism of itaconic acid by liver mito¬chon-dria. . J Biol Chem. 1957 Dec;229(2):865-79. Available from:www.jbc.org/content/229/2/865.full.pdf

Danish (Q)SAR Database (2014), Danish EPA. Available at: http://qsar.food.dtu.dk/

ECHA Guidance on Information Requirements and Chemical Safety Assessment Chapter R.7c: Endpoint specific guidance Version 3.0, June 2017

Ten Berge, W. (2009): A simple dermal absorption model: derivation and application. Chemosphere. 2009 Jun;75(11):1440-5.

US EPA, 2012. Estimation Programs Interface Suite™ for Microsoft® Windows, v 4.11. United States Environmental Protection Agency, Washington, DC, USA.