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EC number: 203-347-8
CAS number: 105-95-3
Ethylene Brassylate is bioavailable via oral route. Limited systemic absorption via inhalation and dermal route is anticipated. The substance will cross cellular barriers or will be distributed into fatty tissues. Ethylene Brassylate is expected to undergo hydrolysis and to be mainly excreted in urine.
There is no specific requirement to generate
toxicokinetic information in REACH. Therefore, the toxicokinetic profile
of Ethylene Brassylate (i.e. absorption, distribution, metabolism and
elimination) was derived from the relevant available information. The
physical chemical characteristics of the substance, the results obtained
from acute and repeated-dose toxicity studies, as well as information
gained from genotoxicity assays were used to predict the toxicokinetic
behaviour of Ethylene Brassylate.
Physico chemical characteristics:
Ethylene Brassylate is a liquid substance
having a relatively low molecular weight of 270.37 g/mol. The substance
is slightly water soluble (14.8 mg/L), highly lipophilic based on the
octanol/water partition coefficient (log Kow = 4.3) and not volatile
according to its vapour pressure (0.017 Pa at 20°C).
The physical chemical characteristics
described above suggest that Ethylene Brassylate is of adequate
molecular size to participate in endogenous absorption mechanisms within
the mammalian gastrointestinal tract. Being lipophilic, Ethylene
Brassylate may be expected to cross gastrointestinal epithelial barriers
even if the absorption may be limited by the inability of the substance
to dissolve into gastro-intestinal fluids and hence make contact with
the mucosal surface. Moreover, the absorption will be enhanced if
Ethylene Brassylate undergoes micellular solubilisation by bile salts.
Substances absorbed as micelles will enter the circulation via the
lymphatic system, bypassing the liver. In an acute oral gavage study,
one death and clinical signs of toxicity such as lethargy were observed
at 5000 mg/kg bw. However, no significantly adverse effects were
observed at the highest practicable & biologically-relevant
concentration (i.e. 1000 mg/kg bw/day) in a 90-day a 28-day repeated
dose and the prenatal developmental toxicity studies performed on
read-across substances using the oral route (gavage). In the 90-day
study, effects observed in the kidney of high-dose male rats were
consistent with well-documented sex and species-specific responses to
the administration of hydrocarbons. The lack of significant adverse
findings following repeated oral dosing may be due to limited
gastrointestinal absorption of the test material and/or its metabolites,
or due to a very low inherent toxicity of Ethylene Brassylate. However,
the observation of systemic effects, even if of very low toxicological
concern, indicates the oral bioavailability of Ethylene Brassylate
and/or its metabolites.
Regarding the dermal absorption, Ethylene
Brassylate being lipophilic (log Kow = 4.3), the rate of uptake into the
stratum corneum is expected to be high while the rate of penetration is
likely to be limited by the rate of transfer between the stratum corneum
and the epidermis. Moreover, it is assumed that the dermal uptake is
also limited by the slight water solubility of Ethylene Brassylate.
These assumptions are supported by the absence of systemic effects
following single-dose dermal application of Ethylene Brassylate up to
5000 mg/kg bw which would suggest a limited systemic absorption through
cutaneous barriers. Moreover, enhanced skin penetration is not expected
since Ethylene Brassylate is not a skin irritant or corrosive.
The potential for inhalation toxicity was
not evaluated in vivo. However, the vapour pressure of Ethylene
Brassylate (0.017 Pa at 20°C) indicated an absence of volatility and
therefore no exposure by inhalation is anticipated. Thus, at ambient
temperature, no respiratory absorption is expected under normal use and
handling of the substance
Systemic distribution of Ethylene Brassylate
can be predicted from its physical chemical characteristics. Considering
that the substance is highly lipophilic (log Pow >4) and slightly water
soluble, it is suggested that, upon systemic absorption, Ethylene
Brassylate may be transported through the circulatory system in
association with a carrier molecule such as a lipoprotein or other
macromolecule. Afterwards, based on its lipophilic character, the
substance will readily cross cellular barriers or will be distributed
into fatty tissues with a low potential to accumulate.
The WHO International Programme on Chemical
Safety has made a safety evaluation of certain food additives and
contaminants. This report describes the likely metabolic route for
various aliphatic primary alcohols, aldehydes, carboxylic acids,
acetals, and esters containing additional oxygenated functional groups,
including Ethylene Brassylate. Esters or diesters are expected to
undergo hydrolysis to their corresponding alcohol, which would be
further metabolized. Hydrolysis of Ethylene Brassylate is expected to
occur in most tissues but predominantly in the intestinal tract, blood
and liver and is catalysed by carboxylesterases or esterases. The
presence of a second oxygenated functional group has little if any
effect on hydrolysis of these esters. This report indicates that
hydrolysis of the cyclic diester Ethylene Brassylate would be expected
to occur on the basis of the hydrolysis of structurally related lactones
like omega-6-hexadecenlactone. In simulated intestinal fluid,
omega-6-hexadecenlactone underwent nearly complete hydrolysis (92%) to
its open-chain form within 15 minutes.
Ethylene Brassylate having a molecular
weight lower than 300, it is expected to be mainly excreted in urine and
no more than 5-10% may be excreted in bile. Any substance that is not
absorbed from the gastro-intestinal tract, following oral ingestion,
will be excreted in the faeces. Following dermal exposure, highly
lipophilic substances, such as Ethylene Brassylate, that have penetrated
the stratum corneum but not penetrated the viable epidermis may be
sloughed off with skin cells.
- JECFA (2000) ALIPHATIC PRIMARY ALCOHOLS,
ALDEHYDES, CARBOXYLIC ACIDS, ACETALS, AND ESTERS CONTAINING ADDITIONAL
OXYGENATED FUNCTIONAL GROUPS. WHO food additives series 44.
Justification for Read-Across of Toxicity
data from Globalide/Habanolide (reaction mass of:
(E)-oxacyclohexadec-12-en-2-one (E)-oxacyclohexadec-13-en-2-one a)
(Z)-oxacyclohexadec-(12)-en-2-one and b)
(Z)-oxacyclohexadec-(13)-en-2-one; EC 422-320-3; CAS 111879 -80 -2) and
1,4-dioxacyclohexadecane-5,16-dione (EC 259-423-6; CAS 54982 -83 -1) to
Hypothesis for the analogue approach:
This report addresses the use of a
read-across by analogue approach on:
- Globalide/Habanolide, to fill the
sub-chronic repeated dose toxicity data gap of Ethylene brassylate
- 1,4-dioxacyclohexadecane-5,16-dione, to
fill the sub-acute repeated dose toxicity data gap of Ethylene brassylate
- Globalide/Habanolide, to fill the
pre-natal developmental toxicity data gap of Ethylene brassylate.
This read across is based on the hypothesis
that source and target substances have similar toxicological properties
because they have structural similarity and are anticipated to follow
the same metabolism pathway. This prediction is supported by common
physico-chemical and toxicological data on the three substances.
Target substance and source substance:
Ethylene Brassylate (EINECS 203-347-8) is
considered the target substance and Globalide/Habanolide &
1,4-dioxacyclohexadecane-5,16-dione are the source substances. All three
compounds are cyclic esters (macrocyclic musks) containing long chains
in the ring, Ethylene brassylate and 1,4-dioxacyclohexadecane-5,16-dione
contains two ester groups whereas Globalide/Habanolide contains one
Therefore, the source and the target
substances share structural similarities with common functional groups,
esters, and chains in the ring having the same length.
Source substance 1
Source substance 2
Reaction mass of: (E)-oxacyclohexadec-12-en-2-one (E)-oxacyclohexadec-13-en-2-one a) (Z)-oxacyclohexadec-(12)-en-2-one and b) (Z)-oxacyclohexadec-(13)-en-2-one
Purity / Impurities:
Macrocyclic musks are typically very pure (>
95%) and it is not expected that any of the impurities will affect the
physico-chemical parameters, environmental fate, ecotoxicological and
toxicological properties. Therefore, it is concluded that the impurities
will not affect the read-across.
Analogue approach justification:
Empirical structure similarity between
Ethylene brassylate and Globalide/Habanolide /
Globalide/Habanolide is a cyclic aliphatic
ester, Ethylene brassylate and 1,4-dioxacyclohexadecane-5,16-dione are
cyclic aliphatic di-esters. All three compounds have a similar molecular
weight (see Table 2) and have a structural similarity (see Attachment).
75 mg/L (20°C)
0.017 Pa (20°C)
0.039 Pa (20°C)
0.028 Pa (25°C)
The physico-chemical properties relating to
toxicokinetics of Ethylene Brassylate, Globalide/Habanolide and
1,4-dioxacyclohexadecane-5,16-dione are relatively similar. All three
substances are highly lipophilic, only slightly water soluble and are
not volatile. Due to these similar physico-chemical properties it is
anticipated that the toxicokinetic behaviour of Ethylene brassylate,
Globalide/Habanolide and 1,4-dioxacyclohexadecane-5,16-dione is alike.
In addition to the structural similarity,
the metabolism of the three substances is also anticipated to be
similar, with hydrolysis to their corresponding alcohols and acids. The
WHO report indicates that studies on the absorption, metabolism, and
elimination of esters and diesters show that they are readily hydrolysed
and absorbed and are completely metabolized. Many of these substances or
their metabolites are endogenous in humans. Furthermore, the presence of
a second oxygenated functional group has little if any effect on the
hydrolysis of these esters.
Toxicity profile similarity:
The toxicity profiles for Ethylene
Brassylate, Globalide/Habanolide and 1,4-dioxacyclohexadecane-5,16-dione
are compared below for those endpoints for which data of the source and
target chemical are available.
Globalide / Habanolide
Acute oral toxicity
LD 50 ≥ 5000 mg/kg bw
LD 50 ≥ 2000 mg/kg bw
LD50 = 4500 mg/kg bw
Acute dermal toxicity
28-day repeated dose toxicity
NOAEL = 1000 mg/kg bw/day
90-day repeated dose toxicity
Prenatal developmental toxicity study
The results of the available toxicological
data for Ethylene brassylate, Globalide/Habanolide and
1,4-dioxacyclohexadecane-5,16-dione are identical for acute toxicity,
irritation, sensitisation and mutagenicity end-points. Furthermore, the
similarity of the structural and physico-chemical properties is
pronounced. On this basis it is considered appropriate and
scientifically justified to read-across the data of the:
- Repeated dose (28-day) toxicity study on
1,4-dioxacyclohexadecane-5,16-dione to Ethylene brassylate. In this case
the NOAEL for repeated dose toxicity is 1000 mg/kg bw/day in an OECD
407, 28-day oral toxicity study in the rat.
- Repeated dose (90-day) toxicity study on
Globalide/Habanolide to Ethylene brassylate. In this case the NOAEL for
repeated dose toxicity is 1000 mg/kg bw/day in an OECD 408, 90-day oral
toxicity study in the rat.
- Reproductive and pre-natal developmental
toxicity study on Globalide/Habanolide to Ethylene brassylate. In this
case the NOAEL for developmental toxicity is 1000 mg/kg bw/day in an
OECD 414 pre-natal developmental study.
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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