long chain alkyl thio carbamide metal complex

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Data waiving:

other justification

Justification for data waiving:

other:

Materials and methods

Objective of study:

other: Assessment of toxicokinetic behaviour

Applicant's summary and conclusion

Executive summary:

There are no experimental studies available on the absorption, distribution, metabolism and excretion for EC: 457-320-2. In accordance with REACH Annex VIII (section 8.8.1), an assessment of the toxicokinetic behaviour of the substance can be derived from the relevant available information. Therefore, in accordance with ECHA Endpoint Specific Guidance Document R7c, the available physical chemical properties and toxicological studies have been used to assess the toxicokinetic properties of the substance.

Absorption

Absorption is the process of a substance entering the body via diffusion across biological membranes. Molecular weight (average molecular weight of approximately 2224 g/mol), water solubility (< 0.31 mg/L) and n-octanol/water partition coefficient (log P > 5.1) are useful parameters to assess the absorption potential.

Oral

The substance has an average molecular weight of 2224 g/mol; substances with a molecular weight more than 1000 are considered to not favour oral/gastrointestinal absorption (ECHA, 2012). Furthermore, the low water solubility and high n-octanol/water partition coefficient (log P) also suggests limited absorption. However, if limited absorption does occur, the large Log P suggests preferential partitioning to lipid-rich tissues.

The acute oral study demonstrated a lack of toxicity with an LD50 > 2000 mg/kg bw (highest tested dose) with lack of effects seen; this may support the lack of absorption during acute exposure. There is a sub-acute (28-day) oral study on EC: 434-650-5 which is considered suitable for read-across based on its structural and chemical similarities. The 28-day oral toxicity study (OECD 407) has a NOAEL of 1000 mg/kg bw/day (highest tested dose), although, there were some histopathological findings suggesting that some absorption of the test substance occurred through the gastrointestinal tract and taken up in the mesenteric lymph nodes. An OECD 421 (reproductive and developmental screening study) is available on the test substance that can be used to assess the absorption behaviour. Adverse behaviour/CNS-related findings were seen in males and females when dosed 1000 mg/kg bw/day, and females at this dose also had a higher liver weight when compared to the control. This shows that absorption has occurred and partitioned preferentially to lipid-rich tissues.

Although the chemical properties of the test substance suggests limited absorption, the available data on the substance exhibits that some degree of absorption occurs after repeated exposure and the substance partitions to lipid-rich tissues. Therefore, based on the available information on the substance, the bioavailability of the substance in humans is likely after oral uptake.

Dermal

Dermal absorption occurs when substance gets to the epidermis and dermis when topically applied. Substances with a molecular weight less than 100 g/mol favour dermal absorption (ECHA, 2012). The average molecular weight of the test substance is 2224 g/mol which suggests that dermal absorption is less likely to occur. Furthermore, the low water solubility and high log P suggests that the ability to partition from the stratum corneum to the epidermis is likely to be low (ECHA, 2012). The substance is classified as a category 2 skin and a skin sensitiser category 1B. Irritant effects were seen in the acute dermal and sub-acute dermal studies but elicited no systemic toxicity. However, a lack of systemic toxicity cannot exclusively be explained by lack of absorption but may also be a result of low toxicological potential. The skin sensitization potential of the substance also indicates that some level of dermal absorption was occurring. Irritants may also enhance dermal absorption through damage to the skin surface.

Based on the available information, dermal uptake in humans is considered possible due to the irritant and sensitising nature of the substance. For hazard assessment purposes, as the molecular weight is more than 500 and the log Pow > 5, absorption via the dermal route is considered 10% in accordance with ECHA guidance R7c (ECHA, 2012).

Inhalation

There are no inhalation studies available. The vapour pressure is very low (3.4 x 10^-6Pa at 25°C) which indicates that under normal use and handling conditions the substance will not be available for inhalation as a vapour, and, therefore, respiratory absorption is not likely. However, the properties of the substance (high log P and low water solubility) suggests that if absorption did occur the compound would be taken up by micellular solubilisation.

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%.

Distribution

Distribution of a substance within the body depends on the physicochemical properties of the substance, particularly the molecular weight, the lipophilic character and the water solubility. In general, the smaller the molecule, the wider is the distribution. Highly lipophilic substances tend 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).

The low water solubility suggest that the substance is less likely to diffuse through aqueous channels and pores, meaning its diffusion rate will be low to certain tissues. As the log Kow is > 5.1, the test substance is likely to distribute preferentially to fatty tissues.

The available toxicology studies did not identify target organ toxicity, however the effects seen in the OECD 421 study suggest that some absorption and partitioning to lipid-rich tissues (the CNS) occurred at the highest dose of 1000 mg/kg bw/day. There was no evidence of bioaccumulation from the available repeat-dose toxicity studies, and no alteration of fat colour (the substance is a red viscous liquid) was observed. Moreover, the bioaccumulation study in fish demonstrates the low potential to bioaccumulate.

Metabolism

There is no experimental data on the metabolism of the substance. 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). Therefore, it is considered not impractical to predict the likely metabolites in the absence of experimental data.

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 (more than 300 g/mol) 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. Substances with strong polarity and high molecular weight are less likely to re-circulate. Although, depending on the metabolic changes that may have occurred, the compound that is finally excreted may have few or none of the physico-chemical characteristics of the parent compound (ECHA, 2012).

Based on the high molecular weight and low water solubility of the substance, excretion via the urine is less likely and biliary secretion is favoured. However, if the test substance is metabolised and undergoes conjugation, excretion via the urine is possible. Therefore, due to the unknown metabolic profile of the test substance both major routes of excretion are considered likely for the parent substance as well as for arising metabolites.

 

 

References

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