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EC number: 500-204-4
CAS number: 68334-05-4
Justification for grouping of substances and read-across
There are no data available the toxicity to reproduction of Fatty
acids, C18-unsatd., dimers, 2-ethylhexyl esters (CAS 68334-05-4). In
order to fulfil the standard information requirements set out in Annex
X, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No
1907/2006, read-across from structurally related substances was
In accordance with Article 13 (1) of Regulation (EC) No 1907/2006,
"information on intrinsic properties of substances may be generated by
means other than tests, provided that the conditions set out in Annex XI
are met.” In particular for human toxicity, information shall be
generated whenever possible by means other than vertebrate animal tests,
which includes the use of information from structurally related
substances and/or common chemical precursors or similar
hydrolysis/breakdown products (grouping or read-across).
Having regard to the general rules for grouping of substances and
read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC)
No 1907/2006 whereby substances may be predicted as similar provided
that their physicochemical, toxicological and ecotoxicological
properties are likely to be similar or follow a regular pattern as a
result of structural similarity and/or common chemical precursors or
similar hydrolysis/breakdown products.
The read-across is either based structural similarity or on the
metabolism of Fatty acids, C18-unsatd., dimers, 2-ethylhexyl esters (CAS
68334-05-4), in particular on the fact that the substance undergoes
enzymatic ester hydrolysis resulting in the formation of Fatty acids,
C18-unsatd., dimers and 2-ethylhexanol. A detailed analogue approach
justification is provided in the technical dossier (see IUCLID Section
Overview of reproductive toxicity
Toxicity to reproduction – Fertility
Toxicity to reproduction – Developmental Toxicity
Fatty acids, C18-unsatd., dimers, 2-ethylhexyl esters
RA: CAS 104-76-7: equimolar NAEL = 987 mg/kg bw/day
Experimental result:NOAEL = 191 mg/kg bw/day
(a) The substance subject to registration is indicated in bold
(b) Reference (read-across) substances are indicated in normal
font. Lack of data for a given endpoint is indicated by “--“.
The above mentioned substances are considered to be similar on the
basis of common chemical precursors and common hydrolysis/breakdown
products. The available endpoint information is used to predict the same
endpoints for Fatty acids, C18-unsatd., dimers, 2-ethylhexyl esters (CAS
68334-05-4). A detailed analogue approach justification is provided in
the technical dossier (see IUCLID Section 13).
Toxicity to reproduction – fertility
No studies on toxicity to reproduction (fertility) were available
with fatty acids, C18 unsatd. Dimers, 2 -ethylhexyl esters. However,
data on the oral repeated dose toxicity of the hydrolysis product
2-Ethylhexanol (CAS 104-76-7) and Fatty acids, C18-unsatd., dimers
(61788-89-4) demonstrate no adverse effects on reproduction organs and
tissues after subchronic exposure up to and including the highest dose
tested. Therefore, based on the weight of evidence, a reproduction
toxicity study by any route of exposure is considered scientifically
unjustified and not necessary in terms of animal welfare.
In summary, the available data provide sufficient evidence to
conclude that the substance of Fatty acids, C18 unsatd. dimers, 2
-ethylhexyl esters is not toxic to reproduction.
for the requirement to perform an extended one-generation reproduction
toxicity study (standard configuration or with additional modules) was
included, as the study is not scientifically necessary and, considering
concerns regarding the use of vertebrate animals for experimental
A developmental and maternal NOAEL for 2-ethylhexanol (CAS No. 104-76-7) of 191 mg/kg bw/d was found in mice (Tyl, 1991, NTP).This corresponds to an equimolar developmental NAEL for fatty acids, C18 unsatd. dimers, 2 ethylhexyl esters of 987.35 mg/kg bw/d.
In conclusion, 2-EH administered in the diet during gestation (gd 0-17)
in CD1 mice at concentrations comparable to or exceeding those employed
for DEHP and MEHP in the same study design, resulted in no maternal or
developmental toxicity. It is therefore clear that 2-EH plays
essentially no role in the expression of DEHP-induced maternal and
Overview of developmental toxicity
Toxicity to reproduction – (pre-natal) development
No studies on developmental toxicity and teratogenicity were
available with Fatty acids, C18 unsatd. dimers 2-ethxlhexyl esters.
Therefore, the metabolite 2-ethylhexanol was used for determination of
The information available on the developmental
toxicity/teratogenicity of Fatty acids, C18-unsaturated, dimers is
limited to summarised data from a Reproduction/Developmental Toxicity
Screening Test electronically published by the US Environmental
which a NOAEL for both systemic and reproductive/developmental toxicity
of 1858 mg/kg bw/day was reported.
There are no further data available on potential
developmental/teratogenic effects of Fatty acids, C18-unsaturated,
dimers or any other member of the chemical category they belong to. Skin
contact and, to a lesser extent, ingestion represent the likely routes
of human exposure. Taking into account the toxicokinetic behaviour of
fatty acids in general and the available toxicity studies on Fatty
acids, C18-unsaturated, dimers and/or structurally related substances,
the weight of evidence does not indicate any potential for the induction
of developmental/teratogenic effects by either route of exposure. For
dimerised fatty acids, a very low level of absorption by the
gastrointestinal tract is expected. Considering the low water solubility
and lipophilic nature, the dermal absorption is expected negligible.
A developmental toxicity study was performed with 2-ethylhexanol,
which was administered microencapsulated in the diet to pre-mated CD-1
mice (Tyl, 1991). Twenty-eight animals per group were treated
continuously from Day 0 to Day 17 of gestation with dietary
concentrations of 0.009, 0.03 or 0.09% in feed equivalent to 17, 59 and
191 mg/kg/day of the test substance. No females died, delivered early or
were removed from the study. Pregnancy rates were high and equivalent
across all groups (93-96%), maternal weight change for the gestational
(and treatment) period (GD 0-17) was unaffected, as was weight change
corrected for gravid uterine weight and maternal organ weights and food
consumption were also unaffected. There were no effects of exposure on
the number of ovarian corpora lutea, or of uterine implantation sites
(resorptions, dead foetuses or live foetuses) per litter. Live litter
size and foetal body weight per litter (all foetuses, males or females)
were equivalent across all groups. There were also no treatment-related
effects on the incidence of malformations (external, visceral, skeletal
or total) or variations, whether expressed as number or percentage of
foetuses per litter or of litters with one or more affected foetuses.
Examination of individual foetal findings also indicated no specific
malformations or variations with a dose-related incidence. In
conclusion, the administered in the diet during gestation (GD 0-17) in
CD1 mice at concentrations of 17, 59 and 191 mg/kg bw/day resulted in no
maternal or developmental toxicity.
Based on the results, the developmental NOAEL for 2-ethylhexanol
in mice was found to be 191 mg/kg bw/day.
Conclusions for toxicity to reproduction (development)
No studies on developmental toxicity and teratogenicity were
available with Fatty acids, C18 unsatd. dimers, 2 -ethxlhexyl esters.
Therefore, the hydrolysis product 2-ethylhexanol was used for
determination of possible hazards. The results of the toxicologically
most critical metabolite 2-ethylhexan-1-ol (NOAEL = 191 mg/kg bw/day)
was used for further assessment.
Effects on developmental
A waiver for the
requirement to perform a prenatal developmental toxicity study in a 2nd
species was included, as this requirement is considered not to add new
information for hazard assessment and therefore is scientifically and,
considering concerns regarding the use of vertebrate animals for
experimental purposes, unjustified.
Based on read-across from the structurally similar substances, the
available data on toxicity to reproduction do not meet the
classification criteria according to Regulation (EC) 1272/2008 or
Directive 67/548/EEC, and are therefore conclusive but not sufficient
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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