1-(tert-dodecylthio)propan-2-ol

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: expert statement

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: The prediction of ADME was conducted according to the EU Technical Guidance Document on Risk Assessment (TGD, Part I, Appendix VI)

Data source

Reference

Reference Type:

other: expert statement

Title:

Unnamed

Year:

2012

Report date:

2011

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

other: acumulation

Test guideline

Qualifier:

no guideline required

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

1-(tert-dodecylthio)propan-2-ol

EC Number:

266-582-5

EC Name:

1-(tert-dodecylthio)propan-2-ol

Cas Number:

67124-09-8

IUPAC Name:

1-[(2,2-dimethyldecyl)sulfanyl]propan-2-ol

Radiolabelling:

other: not applicable

Results and discussion

Main ADME results

Main ADME results 1

Type:

absorption

Results:

GI-tract and skin absorption are possible; inhalation exposure is irrelevant and absorption is not applicable

Main ADME results 2

Type:

distribution

Results:

Via blood to target organs of toxicity

Main ADME results 3

Type:

metabolism

Results:

Metabolic changes assumed

Main ADME results 4

Type:

excretion

Results:

Elimination via urine or feces were supposed to be relevant

Main ADME results 5

Type:

other: accumulation

Results:

no accumulation is expected

Toxicokinetic / pharmacokinetic studies

Details on absorption:

The substance is expected to be absorbed after oral exposure, based on its low molecular weight, its slight water solubility and its LogPow of >4.72 - <6.51 (77% area = 5.7). Concerning the absorption after exposure via inhalation, as the chemical has low vapour pressure and a decomposition temperature of 164°C, it is clear, that the substance is poorly available for inhalation. Given its lipophilicity (LogPow > 4.72 - < 6.51, 77% area = 5.7) - if absorbed - it is expected to be absorbed directly across the respiratory tract epithelium. The chemical is expected to be also poorly absorbed following dermal exposure into the stratum corneum and to a certain extent into the epidermis, due to its molecular weight and its LogPow (5.7), low water solubility (4.84 mg/L) and low systemic toxicity after dermal exposure. , The substance does not indicate a potential for accumulation and is expected to be extensively metabolised mainly via the Cytochrome P450 group of metabolizing enzymes and subsequently eliminated via the urine and bile as glucuronic acid conjugates. Additionally it is possible to be metabolised to a sulfoxide or a sulfone, which would be excreted subsequently via the urine. The possibility of protein binding can not be ruled out without adequate experimental data, because it is theoretically possible for the sulphide to be metabolised to a thiol, which are able to react with amino acids.

Details on distribution in tissues:

The chemical is expected to be better distributed into the cells (in a lesser extent into the circulatory system), since it is a very lipophilic substance. The substance does not indicate a potential for accumulation.

Details on excretion:

The substance is expected to be extensively metabolised mainly via the Cytochrome P450 group of metabolizing enzymes and subsequently eliminated via the urine and bile as glucuronic acid conjugates. Additionally it is possible to be metabolised to a sulfoxide or a sulfone, which would be excreted subsequently via the urine. The possibility of protein binding can not be ruled out without adequate experimental data, because it is theoretically possible for the sulphide to be metabolised to a thiol, which are able to react with amino acids.

Metabolite characterisation studies

Metabolites identified:

no

Any other information on results incl. tables

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.

The reaction product of alkylthiol, C10-C12, branched, and propylene oxideis only slightly water soluble (4.84 mg/l), which possibly hinders absorption. In addition, the value of the LogPow (>4.72 and < 6.51, 77 % area = 5.7) demonstrates that the substance has likely a better solubility in octanol than in water (positive LogPow for lipophilic substances, negative LogPow for hydrophilic substances). Considering its LogPow above 4, the absorption into the body is assumed not be favoured (LogPow between 0 and 4 are favourable for absorption). However, it is favourable for absorption, when taking its molecular weight (233.4 - 261.5 g/mol) and its surface active properties into account. This thesis is supported by results of a mouse lymphoma assay (Brown, 2011), which showed a steep toxicity in the treated cells. Further enhancement is not expected, since the action product of alkylthiol, C10-C12, branched, and propylene oxide is not irritating to skin or eyes.

The above mentioned properties determine the absorption of thereaction product of alkylthiol, C10-C12, branched, and propylene oxideas intermediate, based on the absorption-hindering properties (slight water solubility and high LogPow) and the absorption-enhancing properties (low molecular weight, surface activity) and the observed effects in toxicological experiments. Oral route 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. For the reaction product of alkylthiol, C10-C12, branched, and propylene oxide no studies were undertaken to determine the potential for hydrolysis. However, the substance lacks hydrolysable groups and has a low water solubility. Therefore it is not likely that hydrolysis applies. In accordance with the above mentioned principles, it is very unlikely forthe reaction product of alkylthiol, C10-C12, branched, and propylene oxide to be 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 reaction product of alkylthiol, C10-C12, branched, and propylene oxidewill be absorbed, possibly via micelles. However, the extent of absorption is reduced by the lipophilicity of the substance, which limits its uptake via the gastrointestinal fluids.

Inhalation route

The reaction product of alkylthiol, C10-C12, branched, and propylene oxidehas a low vapour pressure, which indicates only marginal availability for inhalation. However, due to its high LogPow, the amount available is assumed to be absorbed directly across the respiratory tract epithelium. Based on this data, it can be expected thatthe reaction product of alkylthiol, C10-C12, branched, and propylene oxideis marginally available in the air for inhalation, due to its low vapour pressure.

Dermal route

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 of 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 ofthe reaction product of alkylthiol, C10-C12, branched, and propylene oxide, the molecular weight is above 100 and below 500, which indicates a low potential to penetrate the skin. The small amount ofthe reaction product of alkylthiol, C10-C12, branched, and propylene oxide,which is absorbed following dermal exposure into the stratum corneum is however unlikely to be transferred into the epidermis, due to its molecular weight and its LogPow. The systemic toxicity ofthe reaction product of alkylthiol, C10-C12, branched, and propylene oxidevia 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.

It is stated by Schuhmacher-Wolz et al., that a high lipophilicity (LogPow above 5) generates a diminished skin penetration (< 10%) (Schumacher et al., 2003). As 77 % of the constituents of the reaction mass in question have a LogPow of 5.7, this applies for the substance of interest.

In conclusion, the evaluation of all the available indicators and the results of toxicity studies allow the allocation of the chemical in question into the group of chemicals with a low dermal absorption. In detail the molecular weight, the physical state, the low water solubility, the high LogPow and the negative results for acute toxicity and irritation justify the use of a factor of 50 % for the estimation of dermal uptake for thereaction product of alkylthiol, C10-C12, branched, and propylene oxide (Schuhmacher –Wolz et al., 2003).

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 ofthe reaction product of alkylthiol, C10-C12, branched, and propylene oxide, no data is available for distribution patterns. The distribution ofthe reaction product of alkylthiol, C10-C12, branched, and propylene oxideis expected to be more extensive in fat tissues than in other tissues, due to its better solubility in octanol than in water (LogPow of > 4.72 and < 6.51, 77 % area = 5.7). The physico-chemical data indicate a general possibility forthe reaction product of alkylthiol, C10-C12, branched, and propylene oxide to cross to a certain extent the blood-brain barrier (due to high lipophilicity) and could induce central nervous system responses. However, no clear central nervous system responses were observed in the repeated dose study or in the one-generation study. The one generation study in rats showed increased salivation as a clinical symptom, this, however, may be due to local effects. Therefore the transfer of the substance over the blood-brain-barrier is not expected to play a significant role.

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 longer half-lives. 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 cellsAccordingly, the experimentally determined LogPow, water solubility and predicted behaviour concerning absorption and metabolism ofthe reaction product of alkylthiol, C10-C12, branched, and propylene oxidedoes not indicate a potential for accumulation in the body.

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.

As specified above,hydrolysis does not apply forthe reaction product of alkylthiol, C10-C12, branched, and propylene oxide. 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 S.A., 2011). There, the chemical has been identified to bear primary, secondary and tertiary sites and more than 4 sites for metabolism by the Cytochrome P450 group of metabolising enzymes. The primary site of metabolism is the sulphur, which is predicted to be subject to S-oxidation. The secondary site of metabolism is the carbon-atom next to the sulphur in direction of the short chain, which is predicted to be subject to aliphatic hydroxylation. The tertiary site of metabolism is predicted to be the hydroxyl group which will be subject to alcohol oxidation. Moreover further aliphatic hydroxylation was predicted to occur at the terminal carbon-atom of the long carbon chain.

To identify all possible sites for phase I and II reactions, the molecular structures of the main constituents in the reaction product of alkylthiol, C10-C12, branched, and propylene oxide were investigated in detail. In a first step, it is stated that the pre-existing hydroxyl group can be subject to immediate phase II metabolism, resulting in a conjugation to glucuronic acid or activated sulfate and subsequent excretion via the urine or faeces.This hydroxyl-group can however also be subject to phase I metabolism by Cytochrome P450s or by alcohol dehydrogenase to a ketone.

In addition, the methyl groups are possibly subject to oxidative desalkylation and as a consequence the molecular weight and the length of the molecule would decrease. As specified above, the carbon atoms in the chain are most likely subject to aliphatic hydroxylation, possibly yielding multiple hydroxyl groups, which is facilitating the elimination. The sulphur is likely to be subject to oxidation, yielding a sulfoxide (R-S(=O)-R), as indicated above. This sulfoxide is possibly converted to a sulfone (R-S(=O)2)-R), which is conjugated and excreted via urine or faeces.

The existing or newly introduced functional groups will react in phase II of the biotransformation with different molecules, leading to the formation of conjugations. For the hydroxyl-groups it is most likely that they will be conjugated to glucuronic acid, activated sulphate or activated methionine.

In conclusion, it is most likely that the substance of interest will be subject to extensive metabolism mainly by cytochrome P450 enzymes and subsequent glucuronidation. However, it has to be kept in mind, that metabolites conjugated to glucuronic acid, can be subject to entero-hepatic recycling, and therefore re-enter to system. In addition, it is possible that metabolism occurs also via alcohol oxidation.

Concerning the possibility of protein binding, this cannot be ruled out, without adequate experimental data. Theoretically it is possible for the sulphide to be metabolised to a thiol, which might react with amino acids.

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.

Forthe reaction product of alkylthiol, C10-C12, branched, and propylene oxideno data is available concerning its elimination. Concerning the above mentioned behaviour predicted for its metabolic fate, it is very likely that the parent substance will be excreted after extensive metabolism as metabolites and/or conjugates.

Based on its chemical structure and its molecular weight, it is assumed to be excreted eitheroxidised or unchanged via the urineor 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 entero-hepatic recycling, and re-enter the system.

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results
The chemical is expected to be absorbed after oral and dermal exposures but poorly available for absorption by inhalation. The substance is assumed to be ditributed into the cells, metabolised and excreted via urine. No accumulation is expected.

Executive summary:

In order to assess the toxicological behaviour ofthe reaction product of alkylthiol, C10-C12, branched, and propylene oxide, the available and predicted physico-chemical and toxicological data have been evaluated. The substance is expected to be absorbed after oral exposure, based on its low molecular weight, its slight water solubility and its LogPow of >4.72 - <6.51 (77% area = 5.7). Concerning the absorption after exposure via inhalation, as the chemical has low vapour pressure and a decomposition temperature of 164°C, it is clear, that the substance is poorly available for inhalation. Given its lipophilicity (LogPow > 4.72 - < 6.51, 77% area = 5.7) - if absorbed - it is expected to be absorbed directly across the respiratory tract epithelium.The reaction product of alkylthiol, C10-C12, branched, and propylene oxideis expected to be also poorly absorbed following dermal exposure into the stratum corneum and to a certain extent into the epidermis, due to its molecular weight and its LogPow. The systemic toxicity after dermal exposure 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. Dermal absorption is considered to be 50% due to logPow of 5.7 (major component), low water solubility (4.84 mg/L) and low systemic toxicity after dermal exposure. Concerning its distribution in the body,the reaction product of alkylthiol, C10-C12, branched, and propylene oxideis expected to be better distributed into the cells, since it is a very lipophilic substance. The substance does not indicate a potential for accumulation.The reaction product of alkylthiol, C10-C12, branched, and propylene oxideis expected to be extensively metabolised mainly via the Cytochrome P450 group of metabolizing enzymes and subsequently eliminated via the urine and bile as glucuronic acid conjugates. Additionally it is possible to be metabolised to a sulfoxide or a sulfone, which would be excreted subsequently via the urine. The possibility of protein binding can not be ruled out without adequate experimental data, because it is theoretically possible for the sulphide to be metabolised to a thiol, which are able to react with amino acids.