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EC number: 265-745-8
CAS number: 65405-77-8
Although the low molecular weight of (Z)-3-hexenyl salicylate will
favour absorption from the gastrointestinal tract, the low water
solubility will limit how readily this compound dissolves in the
gastrointestinal fluid. (Z)-3-hexenyl salicylate is
highly lipophilic, however, and therefore micellular solubilisation will
No data is available on the hydrolysis of (Z)-3-hexenyl salicylate at
different pH values, however it is anticipated that the ester bond will
be vulnerable to hydrolysis in the gastrointestinal tract, to form
3-hexen-1-ol (hex-3-en-1-ol, leaf alcohol) and salicylic acid, which
will be readily absorbed from the gastrointestinal tract.
Acute oral and repeat dose toxicity studies have been conducted which
provide evidence of systemic toxicity, and therefore of oral absorption.
In an acute oral toxicity study (OECD 401) conducted with cyclohexyl
salicylate, there were signs of systemic toxicity (including death)
following administration (Potokar, 1984a).
Evidence of oral absorption was also seen in a repeat oral dose study
(OECD 422) conducted with (z)-3-hexenyl salicylate. Decreased
bilirubin levels, increased triglyceride levels and changes in
albumin/globulin ratios were observed in males and females. Effects
on liver and thymus weights were seen in males at the top dose level. Macroscopic
and histological findings were seen in the kidney, stomach, liver and
testes. Effects on reproduction and breeding were seen
which increased with dose level (Damme, 2013).
A repeat dose, reproductive toxicity study conducted with cyclohexyl
salicylate, rats showed signs of systemic toxicity, including reduced
weight gain, effects on liver weights and dystocia(Schmidt, 1995).
Other studies are available with (Z)-3-hexenyl salicylate (acute oral
toxicity study (Moreno, 1975)) and cyclohexyl salicylate
(28 day oral (Potokar, 1984b), 90 day oral(Pittermann,
1995), and developmental toxicity study (Pittermann, 1996)),
but in the absence of systemic signs of toxicity nothing can be inferred
about oral absorption from these studies.
For risk assessment purposes, because of the immiscibility of the
material in water (log Pow >4) absorption via the oral route is
unlikely, although in the absence of other information, for the purposes
of human DNEL setting, 50% bioavailability is assumed.
(Z)-3-hexenyl salicylate is a lipophilic, sparingly water soluble liquid. The
lipophilicity of the substance means that it will be taken up into the
stratum corneum, but the penetration into the epidermis will be limited
by the low water solubility and therefore the dermal absorption will be
low to moderate.
Some acute dermal toxicity studies report irritation to the skin (Kästner,
1984) (Moreno, 1975) from which some penetration might be
inferred, however in other studies available (Sanders, 1999)
(Middeke & Küster, 2001) (Kligman, 1975) (Ullmann, 1999) (Küster &
Goluchowski, 1999), no such reactions were seen or reported and
nothing can be concluded.
Estimation of mammalian dermal absorption is made in accordance with
principles adopted within the EFSA guidance on estimating dermal
absorption of pesticide active substances (EFSA, 2012)and
the PPR Panel opinion on the science behind the dermal absorption
guidance document(EFSA, 2011). On this
basis, a dermal absorption of 25% in humans is considered appropriate
for (Z)-3-hexenyl salicylate, and this default value will be used for
risk assessment purposes.
(Z)-3-Hexenyl salicylate has a low vapour pressure (0.15 Pa at 25°C) and
therefore inhalation of vapour is not anticipated. Use
of this substance will not result in aerosols, particles or droplets of
an inhalable size, therefore exposure via the inhalation route is
unlikely to occur.
In the absence of any experimental data on toxicity following inhalation
exposure, and considering that exposure via inhalation is unlikely, the
same extent of oral absorption (100%) will be used for inhalation for
risk assessment purposes.
Any (Z)-3-hexenyl salicylatethat is absorbed will be
distributed via the blood to the liver and other organs and tissues. Due
to its low water solubility and high log Pow, there is potential for
accumulation in fatty tissues. The changes in liver and thymus weights
and findings in the kidney, stomach, liver and testes in the OECD 422
study in rat, along with changes to clinical chemistry parameters,
provide evidence that the substance is widely distributed (Damme, 2013).
In the in vitro chromosome aberration test in Chinese hamster V79
cells (Baduhn, 1995) and the mammalian cell gene mutation assay in
Chinese hamster V79 cells(Poth, 1994),cyclohexyl salicylate was
shown not to be mutagenic, either in the presence or absence of
metabolic activation with S9-mix. On the basis of
these studies, no conclusions can be drawn about the metabolism of
cyclohexyl salicylate, or by analogy of (Z)-3-hexenyl salicylate.
The metabolism of (Z)-3-hexenyl salicylate is expected to proceed via
hydrolysis of the ester bond in the gastrointestinal tract, blood and
liver to form (Z)-3-hexen-1-ol (hex-3-en-1-ol, leaf alcohol) and
The metabolism of linear short chain aliphatic alcohols such as
3-hexen-1-ol is well documented (JECFA, 1999). (Z)-3-hexen-1-ol
will be oxidised to the aldehyde and then to the carboxylic acid, which
will be completely metabolised to CO2and H2O in
the fatty acid and tricarboxylic acid pathways. (Z)-3-hexen-1-ol
will also be conjugated with glucuronic acid.
Salicylic acid is a metabolite of aspirin (acetyl salicylic acid)
and therefore the metabolism of this moiety is also well documented (La
Du, Mandel & Way, 1979). Metabolism proceeds via glycine conjugation to
salicylurate (major metabolite in urine in man) and glucuronidation to
salicyl acyl glucuronide and salicyl phenolic glucuronide. Hydroxylation
is a minor route of metabolism, resulting in 2,5-dihydroxybenzoic acid
(gentisic acid), 2,3-dihydroxybenzoic acid and 2,3,5-trihydroxy benzoic
A postulated metabolic pathway for(Z)-3-hexenyl salicylate
is shown in background material.
Although (Z)-3-hexenyl salicylate is of low molecular weight, the low
water solubility will not favour direct urinary excretion, instead
biotransformation to more polar metabolites will be required to promote
Metabolites of(Z)-3-hexenyl salicylate are of low molecular
weight and are polar in nature, and therefore will be eliminated
primarily via the urine. Salicylic acid and its
metabolites are known to be eliminated in urine (La Du, Mandel &
Way, 1979). The carboxylic acid metabolite and
glucuronide conjugate of (Z)-3-hexen-1-ol are also expected to be
rapidly eliminated in urine.
A toxicokinetic profile for (Z)-3-hexenyl salicylate has been determined
on the basis of the physical-chemical properties of (Z)-3-hexenyl
salicylate, and on in vitro studies and acute and repeat dose
toxicity studies with(Z)-3-hexenyl salicylate and the
structurally similar analogue cyclohexyl salicylate.
Based on these data, (Z)-3-hexenyl salicylate is considered to be
partially absorbed (50%) following oral administration. A
dermal absorption value of 25% and an inhalation exposure value of 50%
will be used for risk assessment purposes.
Based on the physical-chemical properties of (Z)-3-hexenyl salicylate,
some absorption is expected by the oral and dermal routes. Acute
oral and repeat dose toxicity studies have been conducted with
(Z)-3-hexenyl salicylate and the structurally similar analogue
cyclohexyl salicylate which provide evidence of systemic toxicity, and
therefore of oral absorption. The effects on organs in the repeat dose
study with (Z)-3-hexenyl salicylate showed that the absorbed material is
widely distributed. For risk assessment purposes, (Z)-3-hexenyl
salicylate is considered to be partly absorbed (50%) following oral
Although no clear evidence of dermal absorption was seen in the acute
dermal toxicity, skin irritation or skin sensitisation studies, based on
estimation of mammalian dermal absorption in accordance with principles
adopted within the EFSA guidance on estimating dermal absorption of
pesticide active substances (EFSA, 2012), a dermal absorption value of
25% will be used for risk assessment purposes.
Exposure to (Z)-3-hexenyl salicylate via the inhalation route is not
expected, however in the absence of any experimental data on toxicity
following inhalation exposure, the same extent of oral absorption (50%)
will be used for risk assessment purposes.
(Z)-3-hexenyl salicylate is expected to undergo ester hydrolysis to form
(Z)-3-hexen-1-ol and salicylic acid. The metabolism of
these metabolites is well documented, and results in small, polar
metabolites which are readily excreted via the urine.
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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