4,4'-thiodiethylene hydrogen -2-octadecenylsuccinate

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Data waiving:

other justification

Justification for data waiving:

other:

Description of key information

In accordance with REACH Regulation Annex VIII, Section 8.8.1, column 1, an assessment of the toxicokinetic behaviour of the substance to the extent that can be derived from the relevant available information should be provided. An assessment based on existing data is provided in the discussion below.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

25

Absorption rate - inhalation (%):

100

Additional information

Basic toxicokinetics

There are no experimental studies available in which the toxicokinetic behaviour of the Substance has been assessed.

In accordance with Annex VIII, Column 1, section 8.8.1, of Regulation (EC) 1907/2006 and with Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, 2012), 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 physicochemical and toxicological properties according to the relevant Guidance (ECHA, 2012) and taking into account available information on the data generated on the Substance.

The Substance is a UVCB substance and has a molecular weight of823.26. The Substance is a brown waxy solid at 20 °C, has a water solubility of <1.43 mg/L at 22 °C and a vapour pressure of 1.92 x 10^-3± 6.66 x 10^-5Pa at 20 °C. Log Kow is considered to be significantly > 6.5 based on experimental data and QSAR estimates (Log Kow = 17 - 18.3).

Significance of Route of Exposure

Oral route:This is not considered a relevant route for occupational exposure or the general population. Slight exposure may occur via accidental hand-to-mouth contact, but this isn’t expected to contribute significantly to exposure.

Dermal route:This is considered the principle route for occupational exposure.

Inhalation route:Under conditions of normal handling and use, the registered substance will not be aerosolized. Additionally the Substance is considered to have a vapour pressure of 1 .92 x 10-3± 6.66 x 10^-5Pa at 20 °C, therefore is considered to have negligible volatility properties. Therefore there is no toxicokinetic assessment on the update via the inhalation route. Although it is considered that based on the use of the Substance there is negligible exposure a risk assessment will be conducted to demonstrate safety. With respect to inhalation absorption, in the absence of any quantitative data, and as a worst-case assumption, for risk assessment purposes absorption by inhalation of the Substance is assumed to be 100%.

 

Absorption

Oral

Absorption through the gastrointestinal (GI) tract can be anticipated based on the physical chemical characteristics of the Substance. A Substance that does not favour oral absorption have the following characteristics; molecular weight is close and above 1000, is not water soluble, is considered to be highly lipophilic (Log Kow >4) and considered to be able to ionize. 

EC 93882-40-7 is has a high molecular weight of ~823 g/mol, is considered to have a very low water solubility (<1.43 mg/L), a high Log Kow of > 6.5 and carboxyl (COOH) functional groups that are considered to be ionizable.  These characteristic indicate that the absorption of the Substance is predicted to be very low through the GI tract. 

 

The Substance is further supported by the results obtained from animal toxicity tests conducted. The available acute oral toxicity data provided an LD₅₀value > 10000 mg/kg bw. Some effects of treatment were noted; however these effects were considered to be local and considered not to be systemic. The subacute 28day repeat dose study demonstrated a low order of toxicity with a no-observable-adverse effect level (NOAEL) of 300 mg/kg/day. The study showed adaptive Liver effects (hypertrophy and clinical chemistry changes) and increases in adrenal gland weight after an oral 28-day repeat dose toxicity. Other effects noted were considered to be a local effect at the site of contact and/or secondary to treatment. Similar effects noted in the Reproduction Development Toxicity Screening (OECD 421) were also considered to be related to site of contact up a dose of 450 mg/kg day supporting the low inherent toxicity of the Substance.

 

Taken together, the physical chemical properties and the relatively low toxicity observed in the animal studies suggest that either low levels of the test substance were absorbed, and/or the test material has low inherent toxicity. The registered substance will exhibit limited absorption profile following oral exposure. Based on this information, it is clear that significant oral absorption is unlikely, but the exact extent cannot be determined, and so, in accordance with ECHA guidance, is assumed to be 50% for risk assessment purposes.

Dermal

Absorption through the skin is also governed by the similar physical chemical characteristic as oral absorption. A Substance does not favour absorption through the skin have the following characteristics; if the molecular weight is >500, has a water solubility of < 1mg/L and has a Log Kow <1 or >4. The physical characteristics of EC 93882-40-7 indicate that the Substance is considered to be very lipophilic and therefore absorption is predicted to be very low through the skin.

Skin irritant and corrosive chemical may damage the skin surface to enhance penetration. Additionally if the substance has been identified as a skin sensitiser then this may indicate uptake must have occurred, although it may only represented a small fraction of the dose applied. EC 93882-40-7 is not considered to be a skin irritant based on the in vitro data studies. The available acute dermal toxicity data provided an LD₅₀value > 3160 mg/kg bw, which showed local skin effects which could enhance absorption, however there were no signs of systemic toxicity further supporting the low order of toxicity of the Substance.  The Substance is considered to be a skin sensitiser therefore could indicating that some uptake had occurred.

Overall, the physical chemical characteristics and the sensitisation observation of the Substance indicate dermal update in human is considered possible. The data suggest poor percutaneous penetration and the Substance to have low inherent systemic toxicity. The registered Substance is likely to exhibit limited absorption profile following dermal exposure. In the absence of any quantitative data and in line with latest EC guidance on dermal absorption (EFSA Guidance, 2012), 25% dermal absorption will be used for risk assessment purposes.

 

Distribution and Accumulation

Distribution of a compound within the body depends on the physicochemical 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, it is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration, particularly in fatty tissues (ECHA, 2012). EC 93882-40-7 is has a high molecular weight, is considered to have a very low water solubility and a high Log Kow, therefore is considered to be highly lipophilic.

Highly lipophilic substances tend in general to concentrate in adipose tissue, and depending on the conditions of exposure may accumulate. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, it is generally the case that substances with high log Pow values have long biological half-lives (ECHA, 2012). Overall, the available information indicates the bioaccumulation of the Substance in adipose tissue cannot be excluded if absorbed.

 

Metabolism

The potential for non-enzymatic hydrolysis of EC 93882-40-7 could not be evaluated as a suitable and/or sensitive analytical test method could not be established to differentiate parent and transformation products. Therefore no study was conducted.

 

Biotransformation is one of the main factors, which influence the fate of a chemical in the body, its toxicity, and its rate and route of elimination. Traditionally biotransformation is divided into two main phases, phase I and phase II. Phase I, the so-called functionalisation phase, has a major impact on lipophilic molecules, rendering them more polar and more readily excretable. In phase II, often referred to as detoxicification, such functionalised moieties are subsequently conjugated with highly polar molecules before they are excreted. Both phases are catalysed by specific enzymes. Furthermore, it has been suggested that a phase III relates to the excretion of conjugates and involves plasma membrane transporters. Most chemicals are potentially susceptible to biotransformation of some sort, and all cells and tissues are potentially capable of biotransforming compounds. Generally, the liver and the entry portals of the body are the main biotransformation sites to be considered (ECHA, 2012).

 

There is no experimental data available on the metabolism of EC 93882-40-7. It is very difficult to predict the metabolic changes a substance may undergo on the basis of physico-chemical information alone. Although it is occasionally possible to look at the structure of a molecule and identify potential metabolites, it is by no means certain that these reactions will occur in vivo. It is even more difficult to predict the extent to which it will be metabolised along different pathways and what species differences may exist (ECHA, 2012).

 

A prediction of expected metabolites including the extent to which each metabolite will be metabolised is difficult in the absence of any experimental data. It should be noted that absorption and toxicity to the substance it considered to be low based on the discussion above.

 

Excretion

The major routes of excretion for substances from the systemic circulation are the urine and/or the faeces via bile and directly from the GI mucosa. Substances that are excreted in the urine tend to be water-soluble and of low molecular weight (below 300 g/mol in the rat, mostly anionic and cationic compounds) and generally, they are conjugated metabolites (e.g., glucuronides, sulphates, glycine conjugates) from Phase II biotransformation. Biliary excretion involves active secretion rather than passive diffusion. Substances that are excreted in the bile tend to have higher molecular weights or may be conjugated as glucuronides or glutathione derivatives. Substances in the bile pass through the intestines before they are excreted in the faeces and as a result may undergo enterohepatic recycling (ECHA, 2012).

Based on the molecular weight of the Substance and as the metabolic profile of EC 93882-40-7, both major routes of excretion are possible

References

ECHA (2012). Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

EFSA Panel on Plant Protection Products and their Residues (PPR); Guidance on Dermal Absorption. EFSA Journal 2012;10(4):2665),