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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, inhalative 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 ofreaction of isomerized olefins with maleic anhydride.As the starting material isomerized olefins are UVCB substances, their reaction product is also considered a UVCB. Based on the content of C15-C20 olefins in the source 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 of2,5-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. 58%

ca. 39%

ca. 0.1%

Partition Coefficient (log Kow)

Log Kow = 7.32 – 10.42 Read-across

Log Kow = 8.46 (2)

LogKow = 8.59 (4)

Log Kow = 9.44 (2) (4)

 

Log Kow = 10.42 (2) (4)

Water solubility

unstable

0.0048767 mg/L (3)

0.0004 mg/L (4)

0.00044701 mg/L (3)

0.0001 mg/L (4)

0.000040711 mg/L (3) 0.00001 mg/L (4)

(1)     Estimated by KOWWIN v1.68

(2)     Estimated by WATERNT v1.01

(3)     Danish (Q)SAR Database Report

 

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. Also, 97% hydrolysis was found after 14h at 20°C. The calculated values of the containing compounds were found to be in the range of 0.1892 - 0.00001 mg/L. Due to unstable property in water, any measurement of the partitioning coefficient is technically not feasible. The LogPow was therefore derived from the calculated values of the containing compounds which were found to be in the range of 7.32 to 10.27 at 25°C.

The vapor pressure was found to be negligible.

 

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 (logPow) 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 behavior.

 

Oral

In general, a molecular weight < 500 is favorable 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 logPow of 2,5-Furandione, dihydro-, mono-C15-20-alkenyl derivs. only some absorption of the substance is expected. However, in the in the available long-term studies, e.g. OECD 422 and OECD 414 effects on treated animals are reported that are related to test substance, which confirms that some absorption must have occurred.

In contrast, theacute oral studies in rats with 2,5-Furandione, dihydro-, mono-C15-20-alkenyl derivs. showed no substance related clinical signs and no mortality. The LD50 values was consequently 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 logPow. 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 logPow >5.0 (ECHA, 2012).

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 compounds, 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 compounds 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 vapors 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 test 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 only low toxicity.

 

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/

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.