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Description of key information

Based on the physicochemical properties of Kerocom FM38, only limited amounts of the parent substance will become systemically available following oral exposure. It cannot be ruled out that hydrolysis reactions lead to the formation of a polar product and the respective fatty acid which due to their favourable physicochemical properties may be readily absorbed by the walls of the GI tract. Also the substance intrinsic skin irritation potential may facilitate a certain uptake of the chemical through damaged skin parts. 
However, apart from a certain skin sensibilisation potential, the absence of any systemic effects in the comprehensive toxicological investigation, indicates that no toxicologically relevant concentrations reach the systemic circulation.
Consequently, following oral intake the majority of the chemical is expected to be excreted with the faeces. If certain amounts of the hydrolysis products will become bioavailable, they will undergo further biotransformation processes before being excreted with the urine or will be consumed by catabolic reactions commonly observed for fatty acids.
Based on the physicochemical properties and the calculated BCF values neither the parent molecule nor its hydrolysis products are considered to be bioaccumulative.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

1 Physico-Chemical Data on Kerocom FM38

 

The aliphatic compound Kerocom FM38 (CAS name: Fatty acids, C8-18 and C18-unsaturated, reaction products with diethanolamine and propylene oxide) appears as a clear, amber coloured liquid of low viscosity at standard ambient temperature and pressure.

Due to the mixture with varying aliphatic chain length the molecular weight will be found in the range of approximately 231 to 824 g/mol.

At standard ambient pressure, the melting point is 2°C while the boiling point was determined to be 99.5°C.

Due to the chemicals amphiphilic properties the water solubility could not be determined. Placed in water, the chemical formsemulsions which partly separate in two phases with different homogeneity.Also the log Pow could not be determined, because of the chemicals surface activity. However, due the long hydrophobic tails and its miscibility with n-octanol (> 1000 g/L at 20°C) the chemical is expected to partition towards the organic solvent.Depending on the length of the carbon chain, a BCF value in the range of 4.931 to 294.4 L/kg wet-weight was calculated using EPIWIN. The substance has a relatively low vapour pressure which was determined to be1.1 hPa at 20°C.

2         Toxicokinetic analysis ofKerocom FM38

 

Absorption

 

Oral route:

The fact that the surface active and amphiphilic chemical forms emulsions once in contact with aqueous solutions will limit the possibility of systemic absorption via passive diffusion through the walls of the gastrointestinal(GI) tract. However, absorption properties may be enhanced following micellular solubilisation by bile salts. Also small amounts of the substance may be transported into the epithelial cells by pinocytosis or persorption.

Moreover, due to the acidic nature of the stomach fluid, possible hydrolysis of the amide group must be taken into consideration. If hydrolysis reactions occur, the polar part of the molecule may be cleaved from the aliphatic tail by the formation of an additional hydroxyl amine end group and a carboxylic acid end group respectively. The resulting fatty acid will be readily absorbed via the GI tract in the same manner as similar dietary fatty acids. The reduced molecular weight (< 200 g/mol) and the expected high water solubility ofthe potentially occurring polar cleavage product could lead to systemic absorption by passing through aqueous pores or membranes with bulk transport of water.

With regards to toxicological data, in an acute oral systemic toxicity study in rats (OECD 423), the LD50 value was determined to be higher than 2000 mg/kg bw. Here no adverse effects were observed which indicated that the substance and its potential hydrolysis product have a limited potential to cause acute systemic toxicity following a single oral administration.

Similarly, besides local irritation and inflammatory effects on the forestomach which are most likely caused by the surface active properties of the molecule, no signs of systemic toxicity were observed in a subacute 28-day repeated dose toxicity on rats (OECD 407). Consequently, the respective NOAELfor systemic toxicity was determined to be 1000 mg/kg bw/day (limit dose) while the NOAEL for local effects was determined to be 300 mg/kg bw/day. As the forestomach of rats lacks the protective lining present in the GI tract of humans, this finding may not be of direct relevance to humans.

These aforementioned results are also comparable to the findings obtained from a reproduction/developmental toxicity screening test in rats (OECD 421) were Kerocom FM38 did not cause any signs of systemic toxicity to neither the parent animals nor the offspring.

Also, no genotoxic and no systemic toxic effects were observed in anin vivomouse micronucleus assay in bone marrow cells of mice (OECD 474). 

Nevertheless, for the potential hydrolytic cleavage products some absorption is likely to occur due to the physicochemical properties of the polar product and due to common GI absorption processes for fatty acids.

 

 

Dermal route:

Based on the lipophilic properties associated with the aliphatic hydrocarbon chain, uptake into the outer stratum corneum is expected to be high. However, the low water solubility will hinder the transfer from the stratum corneum to the epidermis and this, in turn, will drastically limit the amount available for percutaneous absorption. These assumptions based on the physicochemical properties are further supported by the results achieved from an acute dermal toxicity study with Kerocom FM38 performed on rats (402). During this study, no systemic effects were observed and the LD50 was determined to be > 2000 mg/kg bw (limit dose). However, in this study indications of a certain skin irritation potential of the chemical were observed. A further in vivo test on rabbit skin (OECD 404) confirmed a slight irritation potential of the chemical. These results need to be evaluated carefully due to the fact that if a chemical causes local skin damage, direct absorption into the systemic circulation through the broken skin may be possible. In this regards the positive immunological response observed in a Murine Local Lymph Node Assay (LLNA) (OECD 429) provides evidence that at least a small amount of the substance becomes systemic available following epicutaneous administration. Overall, although the results from sensitisation testing show that the chemical or certain reaction products become bioavailable following dermal application, the physicochemical properties of the chemical and the results obtained in the acute dermal toxicity test do not suggest that toxicological relevant amounts are absorbed with regards to systemic toxicity.

 

Inhalation route:

Considering the low vapour pressure, the resulting low volatility and the results obtained in the acute oral, inhalation and dermal toxicity testing, it is unlikely that concerning amounts of the substance will reach the systemic circulation via the inhalation route when handled at room temperature.

 

 

Distribution

 

With regards to the physicochemical properties and the results achieved from the comprehensive toxicity testing, it appears that the bioavailability of Kerocom FM38 as such is limited. Nevertheless, due to hydrolysis reactions polar products and fatty acids may be formed in the stomach which, in turn, could reach the systemic circulation. Due to the enhanced water solubility of the polar hydrolysis product, it is expected that this will distributed within the body via the blood stream. Also fatty acids that reach the systemic circulation will be distributed with the blood stream in a similar manner as expected for other naturally occurring fatty acids.

Possible uptake into the body tissues remains unclear as the presented toxicological data indicates that no target organ was identifiable due to of the lack of any systemic effects. Based on the BCF values of the chemical and the potential hydrolysis products there is a negligible potential to bioaccumulate in the human body.

 

 

Metabolism


Because it is unlikely that Kerocom FM38 itself will be absorbed into the interior part of the body cells, the substance will hardly come in contact with intracellular metabolising enzymes.

However, if the polar hydrolysis product is formed and absorbed into the systemic circulation, further Phase I biotransformation reactions aiming to further increase the products hydrophilicity may occur. However, there is no empirical evidence for metabolic activation since thein vitromutagenicity assays showed no positive results in the presence and absence of S9 mix. Furthermore, Phase II conjugation reactions are likely to occur which covalently link an endogenous substrate to the hydrolysis product itself or to its Phase I metabolites in order to ultimately facilitate excretion.

The fatty acids products will be metabolised within the body via common physiological fatty acid metabolism pathways.

 

 

Excretion

 

Again, due to the amphiphilic nature of Kerocom FM38, it is expected that only minimal amounts will be absorbed following exposure. More specifically, after oral intake it is likely that the majority of the chemical will not be absorbed through the walls of the gastrointestinal tract but may be readily excreted via the faeces. However, in case the polar hydrolysis product is formed and reaches the systemic circulation, it is most likely that this or its final metabolites are excreted via the urine. The absorbed fatty acids will undergo catabolic processes commonly observed in the body.

 

 

3         Summary

 

Based on the physicochemical properties of Kerocom FM38, only limited amounts of the parent substance will become systemically available following oral exposure. It cannot be ruled out that hydrolysis reactions lead to the formation of a polar product and the respective fatty acid which due to their favourable physicochemical properties may be readily absorbed by the walls of the GI tract. Also the substance intrinsic skin irritation potential may facilitate a certain uptake of the chemical through damaged skin parts.

However, apart from a certain skin sensibilisation potential, the absence of any systemic effects in the comprehensive toxicological investigation, indicates that no toxicologically relevant concentrations reach the systemic circulation.

Consequently, following oral intake the majority of the chemical is expected to be excreted with the faeces. If certain amounts of the hydrolysis products will become bioavailable, they will undergo further biotransformation processes before being excreted with the urine or will be consumed by catabolic reactions commonly observed for fatty acids.

Based on the physicochemical properties and the calculated BCF values neither the parent molecule nor its hydrolysis products are considered to be bioaccumulative.

 
 
4        References

 

ECHA (2008), Guidance on information requirements and chemical safety assessment, Chapter R.7c: Endpoint specific guidance.

 

Marquardt H., Schäfer S. (2004). Toxicology. Academic Press,,, 2nd Edition 688-689.

 

Mutschler E., Schäfer-Korting M. (2001) Arzneimittelwirkungen. Lehrbuch der Pharmakologie und Toxikologie. Wissenschaftliche Verlagsgesellschaft, Stuttgart.

 

Rozman K.K., Klaassen C.D. (1996) Absorption, Distribution, and Excretion of Toxicants. In Klaassen C.D. (ed.) Cassarett and Doull's Toxicology: The Basic Science of Poisons. McGraw-Hill, New York.

 

Bonse G., Metzler M. (1978) Biotransformation organischer Fremdsubstanzen. Thieme Verlag, Stuttgart.