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In accordance with Annex XI of Regulation (EC) No 1907/2006 no study on the repeated dose toxicity with UVCB 400160 was conducted. This is justified for 400160 as several pivotal studies have been performed with relevant structural analogues, i.e. with medium- and long-chain fatty acids as well as with 2-ethylhexanol, the alcoholic moiety of the mono- and diesters included in UVCB 400160, and in view of the comprehensive knowledge of the overall toxicokinetic and toxicological properties of fatty acids. Accordingly, also for animal saving reasons studies on repeated dose toxicity of UVCB 400160 are prevailed.
#61788-89-4) was administered to CD Sprague-Dawley rats (n =
20/sex/group) in the diet at concentrations of 0, 0.1, 1, or 5% for 13
weeks. The approximate doses were 0, 100, 1,000, or 5,000 mg/kg/day,
based on standard conversion factors (WHO 1990). Parameters
evaluated included clinical signs, body weight, food and water
consumption, ophthalmoscopy, hematology, clinical chemistry, gross
pathology, organ weights, and microscopic pathology.
occurred and no treatment-related effects on clinical signs, body
weight, body weight gain, water intake, or ophthalmoscopy were noted.
NOEL was not identified in this study, 0.1% (approximately 100
mg/kg/day) can be considered as NOAEL based on increases in clinical
chemistry parameters and histopathological findings at the higher doses.
A 90-day subchronic inhalation toxicity
study was performed on Wistar rats in accordance to OECD testing
guidelines to evaluate the toxicological profile of 2-ethylhexanol,
potential target organs, and a no-observable-adverse-effect-level
(NOAEL). 10 males and 10 females per group were exposed to
2-ethylhexanol vapours at concentrations of 15, 40 and 120 ppm (the
latter corresponding to the vapour saturation at 20°C) 6 hours/day for
90 days. The respective controls inhaled clean air under the same
conditions. No substance-related adverse effects were observed for body
weight, body weight gain, mortality, organ weights, clinical
biochemistry and haematological parameters including clotting time.
There were no findings related to the treatment with 2 -ethylhexanol
either at necropsy or at histological examination. The highest
concentration tested under these conditions (120 ppm corresponding to
638.4 mg/m³) was found to be the NOAEL for male and female rats.
pivotal studies have been performed with structural analogues of UVCB
400160 (CAS No. 68334-05-4; typically consisting of 16% diesters, 43.3%
monoesters, and 40.7% C18–unsaturated fatty acid dimers), in particular
with medium- and long-chain fatty acids as well as with 2-ethylhexanol
(2-EH), the alcoholic moiety of the mono- and diesters included in
studies on repeated-dose toxicity of medium- and long-chain fatty acids
as structural analogues of the fatty acid components of UVCB 400160 have
been performed. These studies lasting up to 47 weeks were conducted in
the rat (US EPA 2009; Bibra 1996) and the rabbit (Traul et al. 2000).
rats (20/sex/concentration) were administered fatty acids,
C18-unsaturated dimers (CAS 61788-89-4; corresponding to raw material of
400160) via the diet at 0, 0.1, 1 or 5% (corresponding to daily doses of
0, 100, 1000 or 5,000 mg/kg body weight (bw)) for 13 weeks (US EPA
2009). No deaths occurred and no treatment-related effects on clinical
signs, body weight, body weight gain or water intake were noted. A
transient, statistically significantly decrease in food consumption
occurred in both genders during the first four weeks of study at 5,000
mg/kg bw. Treatment-related clinical chemistry effects included
decreases in total cholesterol and triglycerides and beta globulin
fraction. Increases in alanine aminotransferase activity, total serum
protein, albumin levels, and alkaline phosphatase activity were
observed; prothrombin time was slightly increased. These effects on
clinical chemistry occurred in the two highest concentrations tested.
Slight increases in haemoglobin (at 5,000 mg/kg bw) were considered not
to be toxicologically significant. Necropsy and histopathological
examinations revealed slight to moderately enlarged mesenteric lymph
nodes (all concentrations), increased incidence of uterine fluid
distension (5,000 mg/kg bw; females), decreased absolute and relative
liver weight (100 mg/kg bw, females and 1,000 and 5,000 mg/kg bw, males
and/or females), decreased absolute and relative spleen weight (1,000
and 5,000 mg/kg bw males) and decreased absolute kidney weight (5,000
mg/kg bw, females). All effects other than enlarged lymph nodes and
fluid distention in the uterus were noted as being statistically
significant, although significance levels were not stated.
Histopathology revealed aggregation of macrophages in mesenteric lymph
nodes at all treatment levels, macrophages in brown pigment of the
spleen (all treatment groups of females and at 1,000 and 5,000 mg/kg bw
in males), cortical vacuolation in adrenals (1,000 and 5,000 mg/kg bw,
females), hepatic bile duct proliferation and sclerosis (5,000 mg/kg bw,
males), and thyroid follicular epithelial hypertrophy (5,000 mg/kg bw,
females). Although a NOEL was not identified in this study, a NOAEL of
100 mg/kg bw/day was derived based on clinical chemistry parameters and
histopathological findings. The LOAEL was
1,000 mg/kg bw/day (US EPA 2009).
18-week dietary study in rats, NOAEL was >5,000 mg/kg/d for lauric acid
and >7,500 mg/kg/day for oleic acid, respectively (DHI 2009). In a
90-day toxicity study in rabbits treated with medium-chain triglycerides
containing predominantly caprylic acid (C8) and decanoic acid (C10) with
less amounts of caproic acid (C6) and lauric acid (C12), no notable
toxicity was observed, irrespective of whether the product was
administered in the diet (up to 9,375 mg/kg bw/day) or by intramuscular
injection in rabbits (up to 0.5 mL/kg/day) (Traul et al. 2000).
exposure or carcinogenicity study was conducted in 15 male and 15 female
Wistar rats, fed with 40% medium-chain triglycerides (C8, C10) diet
daily for 47 weeks. Mortality, growth, organ weights and the cellular
structure of the liver and intestine were normal. Fat deposition was
lower than might be expected on normal fat diets (Bibra 1996). NOAELs of
decanoic acid and octanoic acid were equivalent to 2.5 g/kg/day and 7.4
g/kg/day, respectively (DHI 2009).
caprylic acid is listed by the FDA as a direct food substance affirmed
as generally recognized as safe (GRAS 1974), when used in foods at
concentrations ranging from 0.001 to 0.04% (depending upon the food)
according to good manufacturing practice (Code of Federal Regulations
FAO/WHO Expert Committee on Food Additives established for decanoic acid
no specific ADI (Acceptable Daily Intake), because it was expected that
the compound’s presence in food would not represent a human health
hazard (Bibra 1996). This view was based upon the occurrence of the acid
in edible fats and oils with long food-use history as well as data on
total daily intakes and the toxicology of the acid (JECFA 1986; Bibra
1996). Decanoic acid was also considered “safe in use” by the EU’s
Scientific Committee for food in their consideration of Chemically
Defined Flavouring Substances (Bibra 1996).
toxicity of 2-EH was investigated in repeated dose studies lasting up to
24 months in rats and mice (Astill et al. 1996; Klimisch et al. 1998;
al. (1996) investigated the subchronic toxicity of 2-EH at daily oral
doses up to 500 mg/kg bw in rats and mice over a period of 13 weeks.
Effects in rats were limited to dose levels of 250 and 500 mg/kg.
Principal effects were mild reductions in weight gain at 500 mg/kg,
moderate increases in relative stomach, liver, and kidney weights at 250
and 500 mg/kg, and inflammatory changes in the forestomach at 500 mg/kg.
Effects in the mouse were limited to increases in relative stomach
weight in males at 250 and 500 mg/kg and a low incidence of inflammatory
lesions in the forestomach at 500 mg/kg. No mortalities were observed in
this study (Astill et al. 1996).
subchronic inhalation toxicity study of 2-EH vapour in rats was
conducted by Klimisch et al. (1998). No substance-related adverse
effects were observed for body weight, body weight gain, mortality,
organ weights, clinical biochemistry and haematological parameters.
There were no findings related to the treatment with 2-EH either at
necropsy or at histological examination. The highest concentration
tested under these conditions (120 ppm corresponding to 638.4 mg/m3)
was found to be the NOAEL for male and female rats.
(0, 50, 200, or 750 mg/kg bw/day) was administered by gavage to groups
of 50 male and 50 female mice for 18 months, no 2-EH-related changes
were observed in mice administered 50 or 200 mg/kg bw. At 750 mg/kg bw,
in both genders the following effects were observed: Decreased body
weight gain associated with substantial reduction in feed
consumption; an increased mortality, treatment-related haematological
changes, including slightly increased polymorphonuclear neutrophils and
slightly decreased lymphocytes, treatment-related, but not statistically
significant, increased focal hyperplasia of the epithelium of the
forestomach. Also, a slight increase in the incidence of hepatocellular
carcinomas in high-dose females was statistically significant when
compared to the incidence in vehicle control females but not when
compared to the incidence in water-gavage control females. No
statistically significant increase in tumour incidence occurred in male
mice. Therefore, 2-EH was not oncogenic in the mouse under the
conditions of this study (WHO 1993).
study in rats lasting 24 months, 2-EH (0, 50, 100, 150 or 500 mg/kg
bw/day) was administered by gavage to groups of 50 male and 50 female
Fischer 344 rats five days/week. No compound-related changes were
associated with administration of 50 mg/kg bw/day for 24 months;
however, body weights and bodyweight gains of rats receiving 50, 150, or
500 mg 2-EH/kg bw/day were decreased in a statistically significant
dose-dependent manner compared to vehicle control rats. Feed consumption
of male and female rats receiving 500 mg/kg bw/day showed occasional
statistically significant decreases compared to both control groups of
rats, but no dose-response relationship was observed. A 2-EH-associated
increase in mortality was observed for female mice of the high-dose
group only (WHO 1993).
to molecular weight and physicochemical properties the various compounds
of UVCB 400160 are able to penetrate mucosa or human skin subsequent to
oral or dermal exposure. After absorption, the esters are being
partially or completely hydrolysed to the corresponding dicarboxylate
acids and 2-EH. Fatty acids are being further metabolized via
β-oxidation leading to C2-moieties that finally enter the citric acid
cycle for endoxidation.
accordance with the long history of safe use in foods for fatty acids
and glycerides the data summarized above demonstrate low toxicity of
fatty acids and their salts after subchronic and chronic administration
(HERA 2002). The low toxicity of fatty acids concerning repeated dose
administration becomes also evident by considering their safety
evaluation with respect to exemption of fatty acids from the obligations
to register in accordance with article 2(7)(a) of Annex IV of REACH
Regulation (EC) No 1907/2006. Data available on repeated-dose toxicity
were considered sufficient to fulfil the Annex IV inclusion criteria.
Therefore no concerns were stated with respect to the endpoint
repeated-dose toxicity (DHI 2009). The reasons why fatty acids were
finally not included in Annex IV were a skin and eye-irritating
potential as well as ecotoxicological concerns (Commission of the
European Communities 2009; DHI 2009).
subjected to extensive oxidative metabolism and glucuronidation followed
by rapid excretion, primarily in the urine. Long-term studies in various
species did not reveal any significant systemic toxicity even at high
conclusion, in accordance with Annex XI of Regulation (EC) No 1907/2006
waiving of the endpoint repeated dose toxicity is justified for UVCB
400160 as several pivotal studies have been performed with relevant
structural analogues, i.e. with medium- and long-chain fatty acids as
well as with 2-EH, the alcoholic moiety of the mono- and diesters
included in UVCB 400160, and in view of the comprehensive knowledge of
the overall toxicokinetic and toxicological properties of fatty acids.
Accordingly, also for animal saving reasons studies on repeated dose
toxicity of UVCB 400160 are prevailed.
According to Regulation (EC) No 1272/2008 no
classification of 400160 is required. The LOAEL observed for
2-ethylhexanol in rats and mice were 250 mg/kg bw/day which is above the
guidance value for category 2 classification. The NOAEL for fatty acid
dimers in rats was 100 mg/kg bw/day. No significant toxic effects were
observed at this concentration, therefore no classification is required.
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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