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Description of key information

Short description of key information on bioaccumulation potential result: 
1) scientific statement: Toxicokinetic statement (Chemservice 2012)
2) Prediction - Toxtree, (Chemservice 2011)
Short description of key information on absorption rate:
scientific statement: Toxicokinetic statement (Chemservice 2012)

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information

1,1'-dithiobis[hexahydro-2H-azepin-2-one] was evaluated regarding its toxicokinetic behaviour. Due to its physico-chemical properties it is reasonable to assume, that the substance is well absorbed after oral exposure. In addition, it is assumed to be poorly absorbed after exposure via inhalation and to be only absorbed to a certain extent into the stratum corneum and into the epidermis. The substance is expected to be distributed throughout the body, reaching also the inner cell compartments, due to its lipophilicity. The substance is not expected to bear accumulative potential after repeated exposures. 1,1'-dithiobis[hexahydro-2H-azepin-2-one] is expected to be extensively metabolised via the Cytochrome P450 group of metabolizing enzymes and subsequently eliminated via the bile as glucuronic acid conjugates or unchanged via the urine.

Discussion on bioaccumulation potential result:

Absorption:

In general, absorption of a chemical is possible, if the substance crosses biological membranes. This process requires a substance to be soluble, both in lipid and in water, and is also dependent on its molecular weight (substances with molecular weights below 500 are favourable for absorption). Generally, the absorption of chemicals which are surfactants or irritants may be enhanced, because of damage to cell membranes.

1,1'-dithiobis[hexahydro-2H-azepin-2-one]is favourable for absorption, when taking its molecular weight (288.4294 g/mol) into account.The substance has in addition high water solubility (up to 1.4 g/L), so it is apparent, that its absorption is also favoured. This is also seen in the value of the LogPow (2.25) that shows the substance to be better soluble in n-octanol than in water (positive LogPow for lipophilic substances, negative LogPow for hydrophilic substances). Considering its high water solubility and the value for LogPow below 4, the absorption into the body will be favoured (LogPow between 0 and 4 are favourable for absorption). 1,1'-dithiobis[hexahydro-2H-azepin-2-one] is only irritating to eyes, but not to skin. Therefore, the above mentioned enhancement of absorption for irritants, applies only to a limited extent.

Absorption from the gastrointestinal tract:

Regarding oral absorption, in the stomach, a substance will most likely be hydrolysed, because this is a favoured reaction in the acidic environment of the stomach.

However, for 1,1'-dithiobis[hexahydro-2H-azepin-2-one] the class of AMIDES was detected as hydrolysable substance class. With the exception of a few halogenated acetamides, most amides hydrolyse to acids extremely slow with half-lives in centuries. Electronegative groups on carbon or nitrogen greatly accelerate base catalysed hydrolysis, but alkyl groups on nitrogen retard both acid and base catalysed processes. No neutral hydrolysis rate is evident for 1,1'-dithiobis[hexahydro-2H-azepin-2-one].

In accordance with the above mentioned principles and the results of the determination of hydrolysis, 1,1'-dithiobis[hexahydro-2H-azepin-2-one] is not hydrolysed in the stomach.

In the small intestine absorption occurs mainly via passive diffusion or lipophilic compounds may form micelles and be taken into the lymphatic system. Additionally, metabolism can occur by gut microflora or by enzymes in the gastrointestinal mucosa. However, the absorption of highly lipophilic substances (LogPow of 4 or above) may be limited by the inability of such substances to dissolve into gastrointestinal fluids and hence make contact with the mucosal surface. The absorption of such substances will be enhanced if they undergo micellular solubilisation by bile salts. Substances absorbed as micelles enter the circulation via the lymphatic system, bypassing the liver.

The available data suggest that orally administered 1,1'-dithiobis[hexahydro-2H-azepin-2-one] is well absorbed.

Absorption from the respiratory tract:

Concerning absorption in the respiratory tract, any gas or vapour has to be sufficiently lipophilic to cross the alveolar and capillary membranes (moderate LogPow values between 0-4 favourable for absorption). The rate of systemic uptake of very hydrophilic gases or vapours may be limited by the rate at which they partition out of the aqueous fluids (mucus) lining the respiratory tract and into the blood. Such substances may be transported out of the lungs with the mucus and swallowed or pass across the respiratory epithelium via aqueous membrane pores. Lipophilic substances (LogPow >0) have the potential to be absorbed directly across the respiratory tract epithelium. Very hydrophilic substances can be absorbed through aqueous pores (for substances with molecular weights below and around 200) or be retained in the mucus.

1,1'-dithiobis[hexahydro-2H-azepin-2-one] has a really low calculated vapour pressure and a high boiling point (calculated 248.6°C), which indicates a low availability for inhalation. However, the little amount of substance, which might be available for inhalation, is expected to be absorbed directly across the respiratory tract epithelium, due to its lipophilicity.

Based on this data, it can be speculated that 1,1'-dithiobis[hexahydro-2H-azepin-2-one] is not likely to be available in the air for inhalation, due to its really low vapour pressure.

Absorption following dermal exposure:

In order to cross the skin, a compound must first penetrate into the stratum corneum and may subsequently reach the epidermis, the dermis and the vascular network. The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the epidermis is most resistant to penetration by highly lipophilic compounds. Substances with a molecular weight below 100 are favourable for penetration through the skin and substances above 500 are normally not able to penetrate. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore if the water solubility is below 1 mg/l, dermal uptake is likely to be low. Additionally LogPow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal; TGD, Part I, Appendix VI). Above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow. Moreover vapours of substances with vapour pressures below 100 Pa are likely to be well absorbed and the amount absorbed dermally is most likely more than 10% and less than 100 % of the amount that would be absorbed by inhalation. If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration. During the whole absorption process into the skin, the compound can be subject to biotransformation.

In case of 1,1'-dithiobis[hexahydro-2H-azepin-2-one], the molecular weight is above 100 and below 500, which indicates a low potential to penetrate the skin. However, the low vapour pressure can be judged advantageous for dermal uptake. Based on this knowledge, 1,1'-dithiobis[hexahydro-2H-azepin-2-one] is expected to be absorbed following dermal exposure into the stratum corneum and into the epidermis, due to its molecular weight and its LogPow. However, the systemic toxicity of 1,1'-dithiobis[hexahydro-2H-azepin-2-one] via the skin is assumed to be low and this has been proven with the results of the acute dermal toxicity study, which showed no mortality after dermal application of 2000 mg/kg bw in rats.

Accumulation:

It is also important to consider the potential for a substance to accumulate or to be retained within the body. Lipophilic substances have the potential to accumulate within the body (mainly in the adipose tissue), if the dosing interval is shorter than 4 times the whole body half-life. Although there is no direct correlation between the lipophilicity of a substance and its biological half-life, substances with high LogPow values tend to have a longer half-life. On this basis, there is the potential for highly lipophilic substances (LogPow >4) to accumulate in biota which are frequently exposed. Highly lipophilic substances (LogPow between 4 and 6) that come into contact with the skin can readily penetrate the lipid rich stratum corneum but are not well absorbed systemically. Although they may persist in the stratum corneum, they will eventually be cleared as the stratum corneum is sloughed off. A turnover time of 12 days has been quoted for skin epithelial cells

Accordingly, the predicted LogPow and the experimentally determined water solubility of 1,1'-dithiobis[hexahydro-2H-azepin-2-one] indicate no potential for accumulation in the body.

Distribution:

In general, the following principle applies: the smaller the molecule, the wider the distribution. A lipophilic molecule (LogPow >0) is likely to distribute into cells and the intracellular concentration may be higher than extracellular concentration particularly in fatty tissues. It’s not possible to foresee protein binding, which can limit the amount of a substance available for distribution. Furthermore, if a substance undergoes extensive first-pass metabolism, predictions made on the basis of the physico-chemical characteristics of the parent substance may not be applicable.

In case of 1,1'-dithiobis[hexahydro-2H-azepin-2-one], no data is available for distribution patterns. The distribution of 1,1'-dithiobis[hexahydro-2H-azepin-2-one] is expected to be more extensive in fat tissues than in other tissues, due to its better solubility in octanol than in water (predicted LogPow of 2.25).

Metabolism:

Route specific toxicity results from several phenomena, such as hydrolysis within the gastrointestinal or respiratory tracts, also metabolism by gastrointestinal flora or within the gastrointestinal tract epithelia (mainly in the small intestine), respiratory tract epithelia (sites include the nasal cavity, tracheo-bronchial mucosa [Clara cells] and alveoli [type 2 cells]) and skin.

Hydrolysis does not to apply for 1,1'-dithiobis[hexahydro-2H-azepin-2-one], as determined experimentally. In addition, using Hydrowin the class of AMIDES was detected as hydrolysable substance class. With the exception of a few halogenated acetamides, most amides hydrolyse to acids extremely slow (half-life of centuries). Electronegative groups on carbon or nitrogen greatly accelerate base catalysed hydrolysis, but alkyl groups on nitrogen retard both acid and base catalysed processes. No neutral hydrolysis rate is evident. (Chemservice S.A., 2011). However, its metabolism is very likely to occur via the Cytochrome P450 group of metabolising enzymes, as it has been predicted with the TOXTREE modelling tool (Chemservice, 2011). There the chemical has been identified to bear primary and secondary sites and has more than 3 sites for metabolism by the Cytochrome P450 group of metabolising enzymes. The primary site of metabolism is the disulphide-bond, which is oxidised. The second sites of metabolism are the carbon-atoms of the heterocyclic cycles, which are predicted to be subject to aliphatic hydroxylations. No tertiary sites of metabolism were identified.

To identify other possible sites for phase-1 reactions, the molecular structure was investigated. The 2 carbonyl-groups are likely to be oxidised by cytochrome P450 enzymes, yielding hydroxyl-groups. In addition, it is possible that the disulphide-bond is cleaved by reduction, yielding 2 thiol groups. The cycle can be cleaved at the nitrogen-sulphur-bond, leading to the formation of an amino- and a thiol group. Additionally theoretically a cleavage of the cycle is possible. However, this is not likely to happen as the nitrogen-atom in the cycle is electrophilic and will be the preferred site of reaction and furthermore hydrolysis was found to be of minor importance.

The above mentioned functional groups will react in phase 2 of the biotransformation with different molecules, leading to the formation of conjugations. For the hydroxyl-groups of the ring it is most likely that they will be conjugated to glucuronic acid, activated sulphate or activated methionine. The thiol groups could be conjugated to activated sulphate or to glutathione, which is a universal detoxifying reaction and leads to subsequent elimination via bile, or after transformation to a cysteine-adduct and subsequent acetylation via the urine as mercapturic acid.

In conclusion, it is most likely that the substance of interest will be subject to metabolism by cytochrome P450 enzymes and subsequent glucuronidation. In addition, it is most likely that the existing disulphide-bond will be cleaved by glutathione, yielding to thiol-groups, subsequent subject to conjugation with activated sulphate of glutathione. However, it has to be kept in mind, that metabolites conjugated to glucuronic acid, can be subject to enterohepatic recycling, and therefore re-enter to system. Concerning the possibility of protein binding, this cannot be ruled out, without adequate 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 gastrointestinal mucosa). For non-polar volatile substances and metabolites exhaled air is an important route of excretion. Substances that are excreted favourable in the urine tend to be water-soluble and of low molecular weight (below 300 in the rat) and be ionized at the pH of urine. Most will have been filtered out of the blood by the kidneys though a small amount may enter the urine directly by passive diffusion and there is the potential for reabsorption into the systemic circulation across the tubular epithelium. Substances that are excreted in the bile tend to be amphipathic (containing both polar and nonpolar regions), hydrophobic/strongly polar and have higher molecular weights and pass through the intestines before they are excreted in the faeces and as a result may undergo enterohepatic recycling which will prolong their biological half-life. This is particularly a problem for conjugated molecules that are hydrolysed by gastrointestinal bacteria to form smaller more lipid soluble molecules that can then be reabsorbed from the GI tract. Those substances less likely to recirculate are substances having strong polarity and high molecular weight of their own accord. Other substances excreted in the faeces are those that have diffused out of the systemic circulation into the GIT directly, substances which have been removed from the gastrointestinal mucosa by efflux mechanisms and non-absorbed substances that have been ingested or inhaled and subsequently swallowed. Non-ionized and lipid soluble molecules may be excreted in the saliva (where they may be swallowed again) or in the sweat. Highly lipophilic substances that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with or without metabolism with skin cells.

For 1,1'-dithiobis[hexahydro-2H-azepin-2-one] no data is available concerning its elimination. Based on its chemical structure, its molecular weight and its high water solubility, it is assumed to be excreted either oxidised or unchanged via the urine or via the bile as conjugates with glucuronic acid.However, it has to be kept in mind, that metabolites conjugated to glucuronic acid, can be subject to enterohepatic recycling, and therefore re-enter to system.

Conclusion:

In order to assess the toxicological behaviour of 1,1'-dithiobis[hexahydro-2H-azepin-2-one], the available and predicted physico-chemical data have been evaluated. The substance is expected to be well absorbed after oral exposure, based on its low molecular weight, its high water solubility and its LogPow of 2.25. Concerning the absorption after exposure via inhalation, as the chemical has really low calculated vapour pressure and a high boiling point (248.6°C), it is clear, that the substance has a low availability for inhalation. Given its lipophilicity (LogPow of 2.25), if any of the substance is available for inhalation, it is expected to be absorbed directly across the respiratory tract epithelium. 1,1'-dithiobis[hexahydro-2H-azepin-2-one] is expected to be absorbed following dermal exposure into the stratum corneum to a certain extent and into the epidermis, due to its molecular weight and its LogPow. However, the systemic toxicity via the skin is assumed to be low and this has been proven with the results of the acute dermal toxicity study, which showed no mortality after dermal application of 2000 mg/kg bw in rats. The substance is not expected to bear accumulative potential. 1,1'-dithiobis[hexahydro-2H-azepin-2-one] is expected to be metabolised via the Cytochrome P450 group of metabolizing enzymes and subsequently eliminated via the bile as glucuronic acid conjugates or, due to its high water-solubility and its low molecular weight oxidised or unchanged via the urine.

Discussion on absorption rate:

Assessment of toxicological behaviour

Absorption following dermal exposure

In order to cross the skin, a compound must first penetrate into the stratum corneum and may subsequently reach the epidermis, the dermis and the vascular network. The stratum corneum provides its greatest barrier function against hydrophilic compounds, whereas the epidermis is most resistant to penetration by highly lipophilic compounds. Substances with a molecular weight below 100 are favourable for penetration through the skin and substances above 500 are normally not able to penetrate. The substance must be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore if the water solubility is below 1 mg/l, dermal uptake is likely to be low. Additionally LogPow values between 1 and 4 favour dermal absorption (values between 2 and 3 are optimal; TGD, Part I, Appendix VI). Above 4, the rate of penetration may be limited by the rate of transfer between the stratum corneum and the epidermis, but uptake into the stratum corneum will be high. Above 6, the rate of transfer between the stratum corneum and the epidermis will be slow and will limit absorption across the skin. Uptake into the stratum corneum itself may be slow. Moreover vapours of substances with vapour pressures below 100 Pa are likely to be well absorbed and the amount absorbed dermally is most likely more than 10% and less than 100 % of the amount that would be absorbed by inhalation. If the substance is a skin irritant or corrosive, damage to the skin surface may enhance penetration. During the whole absorption process into the skin, the compound can be subject to biotransformation.

In case of 1,1'-dithiobis[hexahydro-2H-azepin-2-one], the molecular weight is above 100 and below 500, which indicates a low potential to penetrate the skin. However, the low vapour pressure can be judged advantageous for dermal uptake. Based on this knowledge, 1,1'-dithiobis[hexahydro-2H-azepin-2-one] is expected to be absorbed following dermal exposure into the stratum corneum and into the epidermis, due to its molecular weight and its LogPow. However, the systemic toxicity of 1,1'-dithiobis[hexahydro-2H-azepin-2-one] via the skin is assumed to be low and this has been proven with the results of the acute dermal toxicity study, which showed no mortality after dermal application of 2000 mg/kg bw in rats.

Conclusion

In order to assess the toxicological behaviour of 1,1'-dithiobis[hexahydro-2H-azepin-2-one], the available and predicted physico-chemical data have been evaluated. The substance is expected to be well absorbed after oral exposure, based on its low molecular weight, its high water solubility and it's LogPow of 2.25. Concerning the absorption after exposure via inhalation, as the chemical has really low calculated vapour pressure and a high boiling point (248.6°C), it is clear, that the substance has a low availability for inhalation. Given its lipophilicity (LogPow of 2.25), if any of the substance is available for inhalation, it is expected to be absorbed directly across the respiratory tract epithelium. 1,1'-dithiobis[hexahydro-2H-azepin-2-one] is expected to be absorbed following dermal exposure into the stratum corneum to a certain extent and into the epidermis, due to its molecular weight and its LogPow. However, the systemic toxicity via the skin is assumed to be low and this has been proven with the results of the acute dermal toxicity study, which showed no mortality after dermal application of 2000 mg/kg bw in rats. The substance is not expected to bear accumulative potential. 1,1'-dithiobis[hexahydro-2H-azepin-2-one] is expected to be metabolised via the Cytochrome P450 group of metabolizing enzymes and subsequently eliminated via the bile as glucuronic acid conjugates or, due to its high water-solubility and its low molecular weight oxidised or unchanged via the urine.