Amines, C12-14-tert-alkyl, mixed sec-Bu and iso-Bu phosphates

Endpoint summary

Description of key information

Oral absorption is likely for Amines, C12-14-tert-alkyl, mixed sec-Bu and iso-Bu phosphates (CAS 96690-34-5), whereas dermal and inhalation absorption potential is assumed to be low. Amines, C12-14-tert-alkyl, mixed sec-Bu and iso-Bu phosphates (CAS 96690-34-5) will probably be distributed in the body and excretion is expected via urine.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

Basic toxicokinetics

There are no studies available in which the toxicokinetic behaviour of Amines, C12-14-tert-alkyl, mixed sec-Bu and iso-Bu phosphates (CAS 96690-34-5) has been investigated.

Therefore, in accordance with Annex VIII, Column 1, Section 8.8.1, of Regulation (EC) No 1907/2006 and the Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2017), assessment of the toxicokinetic behaviour of Amines, C12-14-tert-alkyl, mixed sec-Bu and iso-Bu phosphates (CAS 96690-34-5) 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).

Amines, C12-14-tert-alkyl, mixed sec-Bu and iso-Bu phosphates (CAS 96690-34-5) is a liquid at 20 °C with a molecular weight ranging from 154.10 to 290.19 g/mol, a water solubility of 1322 mg/L, a vapour pressure of ≤ 54 Pa at 20 °C and a log Pow ranging from 0.69 to 5.63.

Absorption

Absorption is a function of the potential for a substance to diffuse across biological membranes. The most useful parameters providing information on this potential are the molecular weight, the octanol/water partition coefficient (log Pow) value and the water solubility. The log Pow value provides information on the relative solubility of the substance in water and lipids (ECHA, 2017).

Oral

Regarding oral/gastro-intestinal (GI) absorption, molecular weights below 500 are favourable for absorption, whereas molecular weights above 1000 do not favor absorption. Generally the smaller the molecule the more easily it may be taken up. Water-soluble substances will readily dissolve into the gastrointestinal fluids. Moderate log P values (between -1 and 4) are favourable for absorption by passive diffusion. Any lipophilic compound may be taken up by micellar solubilisation but this mechanism is of relevance for highly lipophilic compounds (log P > 4), and particularly those that are poorly soluble in water (1 mg/L or less) that would otherwise be poorly absorbed (ECHA, 2017).

Considering the physico-chemical properties of the test substance, the moderate water solubility (1322 mg/L), the low molecular weight (154.10 to 290.19 g/mol) and the log Pow value (ranging from 0.69 to 5.63) indicate that absorption after oral administration is very likely.

In addition, acute oral toxicity data resulted in a LD50 value > 300 and < 2000 mg/kg bw (Key, AOT, 2012). Mortality was observed and the most relevant clinical signs involved reduced spontaneous activity, moving the bedding, kyphosis, bradykinesia, piloerection, tremor and salivation in animals treated at 2000 mg/kg bw. These findings of the acute oral toxicity study are indicating systemic toxicity. If signs of systemic toxicity are present, then absorption has occurred (ECHA, 2017).

Overall, taking into account the physico-chemical properties and the available toxicological data of amines, C12-14-tert-alkyl, mixed sec-Bu and iso-Bu phosphates (CAS 96690-34-5) indicating systemic toxicity, the potential for oral absorption of the substance is very high.

Dermal

To partition from the stratum corneum into the epidermis, a substance must be sufficiently soluble in water. Moreover, a log Pow between 1 and 4 and low molecular weights are favourable for dermal absorption (ECHA, 2017). If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration (ECHA, 2017). An available in vivo study with amines, C12-14-tert-alkyl, mixed sec-Bu and iso-Bu phosphates (CAS 96690-34-5) revealed skin irritant properties (WoE, 1993). Moreover, the available in vitro corrosion study with Amines, C12-14-tert-alkyl, mixed sec-Bu and iso-Bu phosphates (CAS 96690-34-5) revealed a positive result (WoE, 2013).

However, taking into account the results of the available acute dermal toxicity study with Amines, C12-14-tert-alkyl, mixed sec-Bu and iso-Bu phosphates (CAS 96690-34-5), no mortality and no clinical signs of toxicity were observed up to the end of the 14-day observation period (Key, 2017). Only signs of dermal irritation were noted in this study. Therefore the LD50 was considered to be > 2000 mg/kg bw in rats.

Since in the acute oral toxicity study mortality and clinical signs (indicating systemic toxicity) occurred, but no mortality and no clinical signs of toxicity were observed in the acute dermal toxicity study, the dermal absorption potential of Amines, C12-14-tert-alkyl, mixed sec-Bu and iso-Bu phosphates (CAS 96690-34-5) was considered to be low. In addition, the physico-chemical properties support the assumption that the target substance might not partition from the stratum corneum into the epidermis.

Inhalation

The vapour pressure indicates if a substance may be available for inhalation as a vapour. As a general guide, highly volatile substances are those with a vapour pressure greater than 25 kPa. Substances with low volatility have a vapour pressure of less than 0.5 kPa (or a boiling point above 150 °C) (ECHA, 2017).

Inhalation potential of Amines, C12-14-tert-alkyl, mixed sec-Bu and iso-Bu phosphates (CAS 96690-34-5) is considered as negligible since the test substance is of low volatility (≤ 54 Pa), therefore the absorption potential via inhalation is also considered to be low.

Distribution and accumulation

Distribution of a compound within the body depends on the rates of the absorption and the physico-chemical properties of the substance; especially the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. If the molecule is lipophilic (log P >0), it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues (ECHA, 2017).

Amines, C12-14-tert-alkyl, mixed sec-Bu and iso-Bu phosphates (CAS 96690-34-5) has a low molecular weight and a moderate water solubility. Based on the physico-chemical properties and the high oral absorption potential, distribution within the body can be considered as very likely. In particular after oral absorption, it is expected that, Amines, C12-14-tert-alkyl, mixed sec-Bu and iso-Bu phosphates (CAS 96690-34-5) will enter the blood circulating system through which it will be distributed within the body. However based on the log Pow value, it is likely that the test substance might distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues.

Metabolism

No data are available regarding metabolism. Prediction of compound metabolism based on physicochemical data is very difficult. Structure information gives some but no certain clue on reactions occurring in vivo. The potential metabolites following enzymatic metabolism were predicted using the QSAR OECD toolbox (v4.1, OECD, 2017). For the prediction of the potential metabolites of the target substance Amines, C12-14-tert-alkyl, mixed sec-Bu and iso-Bu phosphates (CAS 96690-34-5) the constituents with the following SMILES codes:CC(C)(N)CCCCCCCCC, CC(C)(N)CCCCCCCCCC, CC(C)(N)CCCCCCCCCCC, CCC(C)OP(O)(=O)OC(C)CC and CCC(C)OP(O)(=O)OCC(C)C were used. This QSAR tool predicts which metabolites may result from enzymatic activity in the liver and in the skin, and by intestinal bacteria in the gastrointestinal tract. For the amine constituents (CC(C)(N)CCCCCCCCC, CC(C)(N)CCCCCCCCCC and CC(C)(N)CCCCCCCCCCC), 24 hepatic and 2 dermal metabolites were predicted, respectively. Primarily, hydroxylation of the aliphatic side chain and oxidation of the hydroxyl groups to aldehyde, ketone or carboxyl-groups, and/or hydroxylation of the amino group are the predicted metabolites which may occur in the liver, respectively. In the skin, hydroxylation of the amino group and oxidation of the hydroxyl group to a nitroso group was predicted. For the constituents with the SMILES codes CCC(C)OP(O)(=O)OC(C)CC and CCC(C)OP(O)(=O)OCC(C)C 11 hepatic and 3 dermal metabolites were predicted for the sec-Bu phosphates and 22 hepatic and 4 dermal metabolites were predicted for the iso-Bu phosphates, respectively. Primarily, hydroxylation and oxidation of the carbon side chain or cleavage of the carbon side chain are the predicted metabolites which may occur in the liver for both constituents. In the skin, hydroxylation of the aliphatic side chain was predicted. All these predicted metabolites can be regarded as phase I metabolites which are a common prerequisite for the phase II reactions or conjugation reactions, which transfer functional groups to the phase I metabolites to increase the water solubility and the excretion of the xenobiotic. Phase II metabolism by e.g. uridine 5′-diphospho(UDP)-glucuronosyltransferases (UGT) and sulfotransferases typically generate excretable hydrophilic metabolites by transferring activated glucuronic acid and sulfate-moiety to hydroxyl groups of the substrates, respectively (Aktories, 2005).

Besides the predicted liver and skin metabolites using the QSAR OECD toolbox (v4.1, OECD, 2017), up to 50 metabolites for the amine constituents and 11 metabolites for the sec-Bu and iso-Bu phosphates were predicted to result from all kinds of microbiological metabolism for the target substance. Most of the metabolites were found to be a consequence of the degradation of the molecule.

Excretion

Characteristics favourable for urinary excretion are low molecular weight (below 300 in the rat), good water solubility, and ionization of the molecule at the pH of urine. In contrast, molecules that are excreted in the bile have a high molecular weight (ECHA, 2017). Taken these aspects into account, urinary excretion of the parent substance, the dissociation products and the possible sulfate conjugate is very likely.

References

Aktories K., Förstermann U., Hofmann F. and Starke K. (2005): Allgemeine und spezielle Pharmakologie und Toxikologie. 9. Auflage, Urban & Fischer Verlag

ECHA (2017). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance. Version 3.0, June 2017

QSAR OECD toolbox (v4.1, OECD, 2017), prediction performed on 16 Mar 2018