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EC number: 266-582-5
CAS number: 67124-09-8
Short description of key information on bioaccumulation potential result: 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. Concerning its distribution in the body, the chemical is expected to be better distributed into the cells, since it is a very lipophilic substance. 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.Short description of key information on absorption rate: Due to logPow of 5.7, low water solubility (4.84 mg/L) and absence of systemic toxicity by dermal route of exposure low dermal absorption is expected for the target chemical.
toxicokinetic profile of the test substance was not determined by actual
absorption, distribution, metabolism or excretion measurements. Rather,
the physical chemical properties of this substance were integrated with
data from acute and repeated-dose toxicity studies to create a
prediction of toxicokinetic behavior.
Discussion on bioaccumulation potential result:
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
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.
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.
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
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 that the
reaction product of alkylthiol, C10-C12, branched, and propylene oxide is
marginally available in the air for inhalation, due to its low vapour
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. 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.
ofthe reaction product of alkylthiol, C10-C12, branched, and propylene
oxide, no data is available for distribution patterns. According
to profiling using QSAR OECD Toolbox 2.3, no alerts for protein binding
were found for the target chemical.
distribution of the 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.
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 cells. Accordingly,
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.
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.
above, hydrolysis does not apply for the 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.
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
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.
possibility of protein binding, QSAR
OECD Toolbox 2.3 determined no alerts for protein binding regarding the
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.
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 either oxidised or unchanged via the urine or 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.
Discussion on absorption rate:
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.
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%) (Schuhmacher-Wolz 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.
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).
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.Reproduction or further distribution of this information may be subject to copyright protection. Use of the information without obtaining the permission from the owner(s) of the respective information might violate the rights of the owner.
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