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Description of key information

Introduction


There are no studies available where the toxicokinetic behaviour of 2-Oxetanone, 3-C14-16-alkyl-4-C15-17-alkylidene derivs. (alkyl ketene dimer, AKD) was evaluated. Therefore, in accordance with Annex VIII, Column 1, Item 8.8.1, of Regulation (EC) No 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), assessment of the toxicokinetic behaviour of the substance is conducted to the extent that can be derived from the relevant available information. This comprises a qualitative assessment of the available substance specific data on physico-chemical and toxicological properties according to Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017).The substance is a waxy solid, manufactured as the dimerisation product of linear C16:0 and C18:0 fatty acid chlorides with aliphatic amines by intermolecular lactone ring condensation. The substance is a mixture of alkyl ketene dimers with two long-chain alkyl groups (AKDs).


As the starting materials are UVCB substances, their reaction product also is considered a UVCB. The composition of fatty acids is indicated in the table below.


 


Table 1 Composition of 2-Oxetanone, 3-C14-16-alkyl-4-C15-17-alkylidene derivs.


 






































C16-16 ketene dimer



0%-35%



C16-18 ketene dimer



5%-55%



C18-18 ketene dimer



10%-95%



Sum of other alkyl ketene dimers



 0% -10 %



Fatty ketones



0%-8%



Unreacted fatty acids



0%-7%



Fatty anhydrides



0%-5%



Oligomers of AKD



0%-15%



 


The substance 2-Oxetanone, 3-C14-16-alkyl-4-C15-17-alkylidene derivs. is a UVCB with an average molecular weight of < 500 g/mol. The substance exhibits a very low water solubility of 5E-07 mg/L (based on calculation with Waternt (1.01) a representative structure C16-16),   and the partition coefficient logPow was calculated to be 14.2 (Kowwin 1.68).


The vapor pressure was calculated to be negligible (calculated as 4E-08 Pa with MPBPVP 1.43).


Studies on hydrolysis (Marton, 1990, Hercules European Test Laboratories, 2003) show that alkyl ketene dimers are expected to hydrolyze readily under neutral and alkaline conditions and are assumed to be stable to hydrolysis at acidic pH values.


 


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 (ECHA 2017). These data of the AKD will be used to evaluate the toxicokinetic behavior together with the ability of this substance to hydrolyze under basic conditions to ketones and fatty acids.


 


Oral


In general, a molecular weight < 500 is favorable for absorption via the biological membranes of the gastrointestinal tract (GI) (ECHA 2017). 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 solubilization by bile salts in the gastro-intestinal tract may allow crossing of lipid biological membranes.


Based on the limited water solubility and the logPow of AKD only some absorption of the substance as such is expected. When entering the GI tract the low stomach pH is not expected to be of influence on the break-down of the molecules, but when entering the intestines with much higher pH values, hydrolysis is expected and then the main components to be absorbed would be the hydrolysis products, the fatty acids and the ketones.


In the repeated dose studies (90-day and repeated dose-reproduction study) generic inflammation of diverse organs was found at doses of 65 mg/kg bw and above. These studies were performed with corn-oil as vehicle. In the more recently performed EOGRTS very limited indications of inflammation were seen and the NOAEL for parental and developmental toxicity was 250 mg/kg bw, the highest dose tested. This recent study used an aqueous vehicle.


It cannot be excluded that the vehicle has influenced uptake via the oral route.


Based on these findings it is concluded that absorption will be limited mainly to the hydrolysis products. It is expected that these products are easily metabolized and excreted (see below).


 


Dermal


As is the case for oral absorption, dermal absorption depends also on molecular size, water solubility and logPow (ECHA 2017). With an average molecular size of < 500 g/mol and a low water solubility, the absorption of the AKD is anticipated to be low. Hydrolysis at the application site is not expected to be main factor, due to the limited amount of water present at the surface of the skin. The substance is not irritating or corrosive, properties that could enhance dermal absorption.


Therefore it is concluded that there are indications for limited absorption and dermal absorption will be set at 10% (default value).


 


Inhalation


 


Based on the logPow and water solubility respiratory absorption is expected to be low (set at 10% as default value). However, uptake by inhalation of AKD is not expected, as the substance is a waxy solid 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


It is expected that the hydrolysis products become bioavailable. The fatty acids  will be metabolized by ß-oxidation. 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.


Ketones can be reduced to secondary alcohols by alcohol dehydrogenase in presence of NADH or by carbonyl reductase in presence of NADPH.  


 


R-CO-R' + NADH + H+ ----------- >  R-CHOH-R' + NAD+


R-CO-R' + NADPH + H+ + ----------- >  R-CHOH-R' + NADP+


Subsequently the alcohols are conjugated with glucuronic acid and excreted (WHO FOOD ADDITIVES SERIES: 50 Aliphatic Secondary Alcohols, Ketones and Related Esters).


 


Excretion 


The main route of excretion after oral administration for the hydrolysis products is expected to be via the urine.


No bioaccumulation of the test substance is expected.


Conclusion


The uptake of AKD via the oral route is expected to be related to uptake of the hydrolysis products. Dermal and inhalation absorption is expected to be limited.


 


 

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential
Absorption rate - oral (%):
10
Absorption rate - dermal (%):
10
Absorption rate - inhalation (%):
10

Additional information