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EC number: 500-148-0
CAS number: 61788-89-4
Oral: NOAEL (rat) = 741 (male) and 855 (female) mg/kg bw/day
Justification for grouping of substances and read-across
In accordance with the specifications listed in Regulation (EC)
No. 1907/2006 Annex XI, 1.5 Grouping of substances and read across, the
similarity of category members has been shown to be justified based on
the scope of variability and overlapping of composition, representative
molecular structure, physico-chemical properties, tox-, ecotoxicological
profiles and supporting Information by various validated QSAR methods.
This information is given in further detail within the category
justification for the grouping of chemicals and read-across (see IUCLID
Section 13) for the dimerised fatty acids and its derivatives, and once
more within the endpoint summary and discussion for Toxicokinetics.
For assessment of human health hazards of the category members,
trends and similarities in toxicokinetic behaviour are most relevant. In
particular, the molecular weight-dependent decrease in oral and dermal
absorption and common metabolic pathways, which are explained by trends
in molecular structure and common functional groups (monomers, dimers
and trimers of similar long-chain fatty acids). This justifies the
assumption that the toxicological profile of all category members is
similar and effects or the lack of effects observed in toxicological
studies of one ore more substances can also be expected and explained
for the other substances in the category.
Therefore, in accordance with Annex XI, Item 1.5, of Regulation
(EC) No 1907/2006, in order to avoid the need to test every substance
for every endpoint, the category concept is applied for the assessment
of human health hazards. Thus where applicable, human health effects are
predicted from adequate and reliable data for reference substance(s)
within the group by interpolation to other substances in the group
All the available information from the substances within the
category is taken into account for each endpoint to be assessed. Key
studies are selected for assessment of the test substance and for
read-across as to fulfil the requirements laid down in Annex XI, Item
1.5, of Regulation (EC) No 1907/2006, i.e. in all cases the results are
adequate for the purpose of classification and labelling and/or risk
assessment; have adequate and reliable coverage of the key parameters
addressed in the corresponding test method referred to in Article 13(3);
cover an exposure duration comparable to or longer than the
corresponding test method referred to in Article 13(3) if exposure
duration is a relevant parameter; and adequate and reliable
documentation of the applied method is provided.
The toxic potential of fatty acids,
C18-unsaturated, dimers was assessed in rats in a 90-day feeding study
carried out according to OECD Guideline 408 and compliant with GLP.
Three groups of 20 male and 20 female Sprague-Dawley rats (4-5 weeks old
at study initiation) were fed the test material at 0, 0.1, 1 and 5%
(w/w) in purified diet ad libitum for 90 days. Based on the reported
body weight and food intake data, the approximate doses were 0, 74.1,
740.9, 3591.2 mg/kg bw/day for males and ca. 0, 90.5, 854.9, 4085.5
mg/kg bw/day for females (average dose weeks 0-13).
The animals were observed up to two times per
day. Food and water consumption was determined twice weekly. Body
weights were determined weekly. Ophthalmoscopy was carried out before
the start of the study and during the last week of the feeding period.
Before necropsy, blood samples were taken for
clinical pathology determinations. At necropsy, a full range of tissues
were taken for histological examination. All tissues from the control
and 5% groups were examined. Liver, adrenals, eyes, mesenteric lymph
nodes, spleen and thyroids (females) from all groups were also examined.
There were no decedents and no
treatment-related clinical signs in rats fed the test substance for
thirteen weeks. The lower food intake during the first four weeks of the
study in rats fed the test material at 5% in diet may reflect an initial
reluctance of the rats to eat the diet.
Decreases in organ weight and/or relative
organ weight of spleen, kidney and liver were observed, mainly after
feeding the test material at 1.0% and 5.0%, but bore no relation to any
effect which might have been expected on the basis of the histopathology
Plasma alkaline phosphatase activity (ALP)
was increased in males and females fed the test material at 1.0% or
5.0%. An increase in plasma ALP activity may reflect induction
(increased synthesis) in liver cells rather than increased release from
damaged cells. Another plasma enzyme derived from the liver in the rat,
alanine aminotransferase (ALT) was also increased in male and female
rats fed at 5.0%.
In addition to increases in plasma ALP level
derived from the liver, treatment-related effects were observed on
microscopic examination of that organ. Histological examination of liver
from animals in the 5.0% treatment group revealed an increase in biliary
hyperplasia. Interference in bile flow could be related to the observed
increase in ALP, which is a sensitive indicator of cholestasis. Changes
in ALP develop before there are any detectable increases in plasma
bilirubin levels. It should be noted that while a very small increase in
plasma bilirubin was observed in male rats fed the test material at 5.0%
or 1.0%, the levels measured were below the sensitivity of the method
and must be viewed with caution. Although the bile duct proliferation
and sclerosis recorded in the liver may correlate with the increase in
ALP, it should be noted only very minor biliary changes were seen in a
few female rats.
A small reduction in plasma calcium was
observed in male and female rats fed the test material at 5.0%. Small
reductions in both total serum protein and albumin were also observed in
male and female rats in the 5.0% groups. It is possible the calcium and
serum protein changes may be connected. However, reduction in plasma
calcium was not always accompanied by a parallel reduction in plasma
albumin. The changes in plasma calcium and serum proteins are small,
probably representing a physiological rather than a pathological
response to treatment with the test material.
The plasma lipids cholesterol and
triglyceride were reduced in male and female rats in the 5.0% and 1.0%
treatment groups. It is possible that the test material blocks the
absorption of lipid and other nutrients from the gut. Such activity
could also explain changes in plasma electrolytes and intermediate
metabolites. The reduction in periportal hepatocyte vacuolation seen on
histological examination of the liver could correlate with the reduced
plasma lipids, indicating some alteration in lipid metabolism, another
possible explanation for the plasma lipid, serum protein and calcium
The pigment present in the macrophages in the
mesenteric lymph nodes and spleen did not stain with Perls' stain for
haemosiderin or aldehyde fuchsin for lipofuscin, but did stain with
Schmorl's stain for lipofuscin. Lipofuscin is derived from oxidation of
unsaturated lipids or lipoproteins. The test material is composed of a
mixture of monomers, dimers and trimers of various fatty acids. It is
likely that the pigment represents either lipofuscin produced by
oxidation of some component of the test material, or that the test
material itself stains positively.
There was no evidence of any degenerative
effect associated with pigmented macrophages. It is probable that they
represent a physiological response to dietary administration of lipid
materials such as the test material. Accumulations of macrophages in the
mesenteric lymph nodes commonly occur as a result of ageing, or
following administration of pigmented or lipid substances in the diet.
Although the pigment appeared darker in the spleen than in the
mesenteric lymph node, this may reflect a difference in density. The
pigment was present alongside normal levels of haemosiderin which
appeared tinctorially distinct. The coloured nature of the compound is
also likely to have been responsible for the alteration in the colour of
the caecal contents that was observed at necropsy.
Increased cortical vacuolation in the
adrenals, coupled with decreased cytoplasmic rarefaction probably
indicates altered steroidogenesis. This was not accompanied by any
evidence of degenerative change. The significance of the reduced
extramedullar haemopoiesis in the adrenals is uncertain, but may
possibly correlate with the reduction in neutrophil count in females fed
the test material at 5.0% and 1.0%. All of the changes in the adrenal
are minor in nature and of limited importance.
The increase in thyroid follicular epithelial
hypertrophy in female rats alone is unusual. The hypertrophy comprised
of a slight increase in height of the follicular epithelium combined
with a reduction in the sise of the follicular lumen and in the amount
of colloid therein. Goitrogenic compounds that interfere with synthesis
of thyroid hormones or stimulate increased degradation of T4 in the
liver can cause changes of this nature.
A no-effect-level was not identified.
However, based on clinical chemistry parameters and histopathological
findings, 1% (w/w) test material in diet can be considered a
no-observed-adverse-effect-level (NOAEL), corresponding to a dose of 741
and 855 mg/kg bw/day for males and females, respectively (Spurgeon and
There are no studies available in which
potential toxic effects after long-term dermal exposure have been
studied. However, the whole body of evidence on the toxicokinetic
behaviour and toxicological activity of fatty acids, C18-unsaturated,
dimers and/or structurally related compounds indicate that both systemic
bioavailability and toxic effects are unlikely to occur upon dermal
There are no data available.
Due to their physicochemical properties (low
vapour pressure), exposure to fatty acids, C18-unsaturated, dimers via
inhaltion is unlikely.
Potential inhalation exposure to aerosols of
formulations intended for spray applications is expected to be low and
without concern of any health hazard under normal conditions of use (s.
CSR Chapter 9 and 10).
The available information on the repeated
dose toxicity of fatty acids, C18-unsaturated, dimers is conclusive but
not sufficient for classification.
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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