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Additional information

Justification for read-across approach

In order to fulfil the toxicological information requirements established in Annexes VII-X, Section 8, of Regulation (EC) No 1907/2006, data from acute toxicity via inhalation for Fatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7) and Fatty acids, C5-9, mixed esters with dipentaerythritol and pentaerythritol (CAS 85536-35-2); the subchronic oral repeated dose toxicity for pentanoic acid, mixed esters with pentaerythritol, isopentanoic and isononanoic acid (CAS No. 146289-36-3); the genetic toxicity information for pentaerythritol tetravalerate (CAS 15834-04-5) and Fatty acids, C5-10, esters with pentaerythritol (CAS 68424-31-7) and information for developmental toxicity for Fatty acids C8-10, mixed esteres with diPE, isooctanoic acid, PE and triPe (CAS 189200-42-8) and Trimethylolpropane Caprylate Caprate (CAS 11138-60-6) are used to predict the same endpoints for dipentaerythritol ester of nC5/iC9 acids in a read-across approach.

Following the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, a common functional group and the likelihood of common breakdown products via biological processes, which result in structurally similar chemicals and a constant pattern in the changing of the potency of the properties across the category, are the criteria for justifying substance similarity and ultimately the read-across approach itself.

Dipentaerythritol ester of nC5/iC9 acids and all target substances are characterised by ester bond(s) between a polyol with a neopentane backbone and one or more carboxylic (fatty) acid moieties comprise saturated linear and/or branched chains of 5 to 10 C-atoms length. For the purpose of justification of the read-across approach, available information on the toxicokinetic behaviour of the source and target substances are discussed in parallel in order to assess similarities, in particular regarding metabolism as relevant biological process resulting in structurally similar chemicals. A constant pattern in the changing of the potency of the properties between the source and the target substances consists in a lack of potency within the group.

A detailed justification for the read-across approach is provided in the technical dossier (see IUCLID Section 13) as well as in the Chemical Safety Report.

Toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Dipentaerythritol ester of nC5/iC9 acids has been investigated.

Therefore, in accordance with Annex VIII, Column 1, 8.8.1, of Regulation (EC) No 1907/2006, 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, 2008) and taking into account further available information on the chemical group of pentaerythritol esters.

Absorption

Oral

The substance Dipentaerythritol ester of nC5/iC9 acids is a complex mixture of hexaesters of dipentaerythritol (2,2,2',2'-Tetrakis(hydroxymethyl)-3,3'-oxydipropan-1-ol) with a mixture of n-pentanoic acid and 3,5,5-trimethylhexanoic acid. Dipentaerythritol is a hexa-alcohol containing 6 hydroxyl groups each of which may react independently with the fatty acids present in the reaction mixture. The molecular weight of the analysed main components of Dipentaerythritol ester of nC5/iC9 acids ranges from 983 to 1096 g/mol and therefore does not favour absorption. Dipentaerythritol ester of nC5/iC9 acids has a low water solubility (< 0.0775 mg/L, Lumsden, 2000) and a high log Pow > 6.2 (Lumsden, 2000). The absorption of the highly lipophilic substance may therefore be limited by the inability to dissolve into gastro intestinal (GI) fluids but may be enhanced by micellular solubilisation. However, large molecules with molecular weights in the 1000´s are normally considered too large to cross biological membranes; however small amounts of such substances may be transported into epithelial cells by pinocytosis or persorption (Aungst and Shen, 1986).

In the GI tract, metabolism prior to absorption via gut microflora or enzymes in the GI mucosa may occur. Fatty acid esters with glycerol (glycerides) are rapidly hydrolysed by ubiquitously expressed esterases and almost completely absorbed (Mattson und Volpenheim, 1968, 1972a). In contrast, molecules containing more than 3 ester bonds showed lower rates of enzymatic hydrolysis in the GIT (Mattson and Volpenhein, 1972a,b). For example, the in vitro hydrolysis rate of pentaerythritol ester was ~2000 times slower in comparison to glycerol esters (Mattson and Volpenhein, 1972a,b). This result is supported by in vivo studies in rats, showing incomplete absorption of the fatty acids of compounds containing more than 3 ester groups. This decrease became more pronounced as the number of ester groups increased, probably the result of different rates of hydrolysis in the intestinal lumen (Mattson und Volpenhein, 1972c). Further in vivo studies in rats showed that the hexaester of sorbitol is not absorbed (Mattson and Nolen, 1972). Thus, the hexaester of dipentaerythritol is not considered to be rapidly hydrolysed in the GIT by esterases and absorption of the whole substance has to be considered to be very low as described above. Furthermore, according to the “Lipinski Rule of Five” (Lipinski et al. 2001) a poor absorption of substances is more likely when more than one of the following conditions is fulfilled: there are more than 5 H-bond donors, 10 H-bond acceptors and the molecular weight is greater than 500 and the n-octanol/water partition coefficient is greater than 5. When applying the “Rule of Five”, Dipentaerythritol ester of nC5/iC9 does violate two of the described conditions and thus a low absorption after oral administration is expected.

The available oral toxicity data of the test substance and a structurally related analogue substance are also considered for assessment of oral absorption.

No signs of systemic toxicity were observed in an acute oral toxicity test with Dipentaerythritol ester of nC5/iC9 acids, resulting in an LD50 value greater than 2000 mg/kg bw (Allen, 1999). Furthermore, available data on the subacute repeated dose toxicity via the oral route of Dipentaerythritol ester of nC5/iC9 acids showed no significant adverse effects in animals fed doses from 150 to 1000 mg/kg bw/day (Jones, 2000). These results suggest that Dipentaerythritol ester of nC5/iC9 acids are of low systemic toxicity, either due to a low toxicity potency or by a low absorption in combination with a low systemic toxicity.

The analogue substance pentanoic acid, mixed esters with pentaerythritol, isopentanoic and isononanoic acid (CAS No. 146289-36-3) showed systemic effects in the high-dose group (1000 mg/kg bw/day) in a 90-day repeated dose toxicity study (NOAEL = 300 mg/kg bw/day; Müller, 1998). Therefore, absorption of the intact parental compound or the respective metabolites occurred, resulting in a low order of systemic toxicity. The analogue substance is a tetraester, having a lower molecular weight in comparison with Dipentaerythritol ester of nC5/iC9 acids and possibly higher rates of hydrolysis to the respective fatty acids and the respective polyol pentaerythritol. The absorption of the analogue substance is therefore assumed to be higher than the absorption of Dipentaerythritol ester of nC5/iC9 acids.

In summary, the above discussed physico-chemical properties of Dipentaerythritol ester of n C5/iC9 acids and relevant literature data on further fatty acid esters with more than 4 ester bounds do not indicate rapid hydrolysis before absorption of Dipentaerythritol ester of n C5/iC9 acids to the respective fatty acids and the polyol dipentaerythritol. Furthermore, experimental acute and repeated dose data of Dipentaerythritol ester of n C5/iC9 acids give no indication of systemic absorption. Taking into account the physicochemical data of Dipentaerythritol ester of n C5/iC9 acids and oral toxicity data, a low absorption of the test material is assumed.

 

Inhalation

Based on the physicochemical properties of the main components, in a conservative approach, the absorption of Dipentaerythritol ester of n C5/iC9 acids via the lung is expected to be equal to the oral absorption.

The test material has a very low vapour pressure (5.4 x 10-15 Pa; Tremain, 2000). Due to the high molecular weight of the substance, absorption is driven by enzymatic hydrolysis of the ester to the respective metabolites and subsequent absorption. However, as discussed above, hydrolysis of fatty acid esters with more than 4 ester bounds is considered to be slow (Mattson und Volpenheim, 1968, 1972a). Therefore, inhalative absorption of Dipentaerythritol ester of n C5/iC9 acids is considered to be not higher than through the intestinal epithelium.

 

Dermal

On the basis of the following considerations, the dermal absorption of Dipentaerythritol ester of n C5/iC9 acids is considered to be very low. The molecular weight of the analysed main components of Dipentaerythritol ester of nC5/iC9 acids ranges from 983 to 1096 g/mol and therefore does not favour dermal uptake. The log Pow value of Dipentaerythritol ester of nC5/iC9 acids is > 6.2. A log Pow value above 6 will slow the rate of transfer between the stratum corneum and the epidermis and will limit absorption across the skin. For substances with a log Pow value in combination with a high molecular weight at these extremes, there is evidence in the literature that these substances can to a limited extent cross the skin (de Heer et al., 1999). The water solubility of Dipentaerythritol ester of nC5/iC9 acids is low (< 0.0775 mg/L), which reduces the partition from the stratum corneum into the epidermis and dermal uptake is likely to be low. Moreover, no toxicity was observed in the acute dermal toxicity test at a limit dose of 2000 mg/kg bw (Allen, 1999). No systemic effects or other evidence of absorption was observed in skin and eye irritation and skin sensitisation studies (Allen, 1999).

Taking the physiochemical parameters and the relevant toxicological test data together, the dermal absorption potential of the test substance is presumably very low.

Distribution and Accumulation

The concentration of a substance in blood or plasma and subsequently its distribution is dependent on the rates of absorption. As discussed above, absorption of Dipentaerythritol ester of nC5/iC9 acids is considered to be very low based in part on its physico-chemical characterisation as a poorly water-soluble substance with a high molecular weight. For a wide distribution, contrary physico-chemical properties are required as small water-soluble molecules are able of a wide distribution. In addition, as no signs of systemic toxicity were observed for Dipentaerythritol ester of nC5/iC9 acids in acute and repeated dose toxicity studies and only a low degree of systemic toxicity was observed for pentanoic acid, mixed esters with pentaerythritol, isopentanoic and isononanoic acid the distribution of Dipentaerythritol ester of nC5/iC9 acids is considered to be very low.

As absorption of the parent substance Dipentaerythritol ester of nC5/iC9 acids is considered to be very low, a potential for bioaccumulation is low, as well.

 

Metabolism and Excretion

As described above considering the physicochemical properties of the test material and oral toxicity data a very low absorption of the intact parent compound is assumed.

The hydrolysis of esterified alcohols with more than 3 ester groups is assumed to be slow as discussed above. This is supported by in vivo studies in rats, in which a decrease in absorption was observed with increasing esterification. For example, pentaerythritol tetraoleate ester had an absorption rate of 64% and 90% (25% and 10% of dietary fat), whereas the hexaester of sorbitol was not absorbed (Mattson and Nolen, 1972). As Dipentaerythritol ester of nC5/iC9 acids is a hexaester as well, the absorption rate is expected to be low.

Assuming a previous stepwise hydrolysis by esterases and gastrointestinal lipases to the fatty acids and the polyol dipentaerythritol, absorption of the products of hydrolysis may occur. QSAR calculations of the main component Dipentaerythritol ester of nC5 using the OECD QSAR ToolBox 2.3.0. have shown metabolites using simulators of liver, skin and microbial simulators. The simulation results in 17, 3 and 54 metabolites (liver, skin, microbial simulator), respectively.

Possible metabolites after the hydrolysis of the ester are medium chain fatty acids (MCFA), which are ubiquitous substrates for energy production within physiological pathways. The most significant oxidation pathway of fatty acids is beta-oxidation in the mitochondria. Even numbered fatty acids are degradaded via beta-oxidation to carbon dioxide and acetyl-CoA, under the release of biochemical energy. In contrast, the metabolism of the uneven C5 and iC9 fatty acids results in carbon dioxide and an activated C3-unit. This C3-unit undergoes a conversion into succinyl-CoA before entering the citric acid cycle (Stryer, 1996). The ultimate excretion products are carbon dioxide and water. The resulting polyol component from the ester hydrolysis, dipentaerythritol is very polar (log Pow = -1.8; OECD SIDS, 2009). A metabolism and excretion study in mice of the structural analogue pentaerythritol has shown that the polyol itself was absorbed rapidly and excreted unchanged via the urine and feces (Dicarlo et al., 1965).

In summary, the hexaester of dipentaerythritol is not considered to be rapidly hydrolysed in the GIT by esterases and gastrointestinal lipases and absorption of the whole substance has to be considered to be very low as described above. After a slow hydrolysis, the possible breakdown products are MCFA and the polyol dipentaerythritol, with the ultimate excretion products carbon dioxide and water from the MCFA and a rapid excretion of the polyol component with the urine and feces.

Furthermore, studies on genotoxicity with the test material and an analogue substance were negative; thus no evidence of a reactivity of Dipentaerythritol ester of n C5/iC9 acids is given under the test conditions.

 

References:

Aungst B. and Shen D.D., 1986: Gastrointestinal absorption of toxic agents. In Rozman K.K. and Hanninen O. Gastrointestinal Toxicology. Elsevier, New York 

De Heer, C., Wilschut, A., Stevenson, H., and Hakkert, B. C. Guidance document on the estimation of dermal absorption according to a tiered approach: an update. V98.1237. 1999. Zeist, NL, TNO

DiCarolo J., Hartigan J.M., Coutinho C.B., Phillips G.E., 1965 Absorption, distribution and excretion of pentaerythritol and pentaerythritol tetranitrate by mice. Proc Soc Exp Biol Med 118:311-5.

Lipinski C.A., Lombardo F., Dominy B.W. and Feeney P.J., 2001: Experimental and computational approaches to estimate solubility and permeability in drug discovery and development settings. Adv Drug Del Rev 46: 3–26.

Mattson F.H. and Volpenhein R.A., 1972a: Hydrolysis of fully esterified alcohols containing from one to eight hydroxyl groups by the lipolytic enzymes of rat pancreatic juice. J Lip Res 13, 325-328

Mattson F.H. and Volpenhein R.A., 1972b: Digestion in vitro of erythritol esters by rat pancreatic juice enzymes. J Lip Res 13, 777-782

Mattson F.H. and Volpenhein R.A., 1972c: Rate and extent of absorption of the fatty acids of fully esterified glycerol, erythritol, xylitol, and sucrose as measured in thoracic duct cannulated rats. J Nutr 102, 1177-1180

Mattson F.H. and Nolen, 1972: Absorbability by Rats of Compounds Containing from One to Eight Ester Groups. J Nutr, 102(9):1171-5.

Stryer, L. 1996. Biochemistry. Fourth edition. Spektrum Akad. Verl.