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EC number: 204-677-5
CAS number: 124-07-2
Key studies on oral repeated dose toxicity
are available for the following category members:
Subchronic (84 days, rat): NOAEL oral
≥ 12500 mg/kg bw/day; CAS# 112-80-1, C18:1
Subacute (OECD 422, rat): NOAEL oral ≥ 1000 mg/kg bw/d; CAS# 112-85-6,
Subacute (OECD 407, rat): NOAEL oral ≥ 1000 mg/kg bw/day; CAS# 112-05-0,
Subacute (OECD 407, rat): NOAEL oral ≥ 1000 mg/kg bw/day; CAS#
70321-72-1, C8-18 and C18-unsatd, distn. residues
In conclusion, no human hazard for
systemic toxicity after repeated oral exposure was identified for the
members of the fatty acids category.
No data are available for repeated
dose toxicity after dermal exposure and inhalation, respectively.
Human health effects in regard to
repeated dose toxicity are predicted from adequate and reliable data for
source substances by read-across to the target substance within the
group applying the group concept in accordance with Annex XI, Item 1.5,
of Regulation (EC) No 1907/2006.
Fatty acids are found in all living
organism fulfilling three fundamental roles. Besides their function as
part of molecules like phospholipids and glycolipids important for the
cell-structure, they are often precursors of signalling molecules such
as prostanoids. The third and best understood role of fatty acid is
their role as nutritional energy source. Based on their physiological
function within the body no toxicity after repeated administration of
fatty acids is expected as demonstrated by animal studies with C6 fatty
acid (hexanoic acid), C9 fatty acids (nonanoic acid and azelaic acid),
C12 fatty acid (lauric acid), C22 fatty acid (docosanoic acid), C18:1
fatty acid (oleic acid), C18:2 conj. fatty acids (conjugated linoleic
acid), C18:3 fatty acid (linolenic acid), fatty acids, C8-18 and
C18-unsatd, distn. residues and fatty acids, tall oil.
A subchronic oral toxicity study was
performed with oleic acid (CAS# 112-80-1) in rats (1969). The animals
(10/sex/dose) were fed a diet containing 5, 10 and 25% oleic acid
equivalent to dose levels of 2500, 5000 and 12500 mg/kg bw/day for 84
days. A control group was administered the plain diet. Two control
animals and one female animal from the 10% dosage group died from blood
collection trauma. There were no other mortalities or clinical signs of
toxicity and no abnormal behavioural reactions were noted. The test
animals had slightly higher final body weights than controls, but the
differences were not statistically significant. Food consumption among
test animals was slightly lower than among the control animals. There
were no outstanding differences in haematologic, clinical chemistry or
urinalysis parameters among test and control animals. No abnormalities
were noted at gross examination. There were no significant differences
in organ/body weight ratios except for kidneys, adrenal glands and
brain. For these three organs, female test animals showed a higher
organ/body weight ratio than control animals. All of these differences
could be attributed to the slightly higher body weights observed in
every test group rather than a deleterious effect of the test material.
The absence of any abnormalities of these organs upon histopathologic
examination would support this conclusion. Some minor histopathologic
changes were noted among both the test and control animals, specifically
involving lesions in the trachea and lungs. These changes were judged to
be due to spontaneous disease (potential pneumonia), and not related to
the test material. Based on these results, a NOAEL of ≥25% oleic acid in
diet was derived, corresponding to a dose level of 12500 mg/kg bw/day.
Nonanoic acid (CAS# 112-05-0) was
tested in a subacute 28-day study according to OECD guideline 407 and in
compliance with GLP (2002). Wistar rats (5 rats/sex/dose) were
administered by gavage dose levels of 50, 150, 1000 mg/kg bw/day at a
frequency of 7 doses per week. No substance-related mortality occurred.
Slight to moderate breathing difficulties (rales and/or gasping) were
observed in several high dose animals on some days during week 3. These
signs subsided and were absent during week 4. Thus, these clinical signs
(generally minimal to mild) were regarded as being of no biological
relevance. No signs were noted in the low and intermediate dose groups.
Body weights and body weight gain were similar across controls and
treated groups. There was no effect on haematology and clinical
chemistry parameters. No changes were seen in hearing ability, pupillary
reflex, static righting reflex and grip strength, or in motor activity
in neurobehavioural functional tests.
At termination, absolute and relative
organ weights were similar between control and treated animals. An
irregular surface of the forestomach was noted in all high dose animals
at necropsy. A thickened glandular mucosa of the stomach was observed in
animals receiving the test substance. Since none of these cases could be
confirmed microscopically, they were considered to be of no
toxicological relevance. Histopathology revealed no other findings than
slight to marked hyperplasia of the squamous epithelium of the
forestomach in all high dose animals, and at a minimal degree in 3
animals of the 150 mg/kg bw/day dose group.
Based on these results, and taking
into account that there is no correlate for the rat’s forestomach in
humans the NOAEL for systemic toxicity is considered to be ≥1000 mg/kg
bw/day. The effects noted in the forestomach are considered to reflect
local irritation at the point of contact. Therefore, the NOAEL for local
toxicity is considered to be 150 mg/kg bw/day.
The repeated dose toxicity of
docosanoic acid (CAS# 112-85-6) was evaluated in a combined repeated
dose and reproductive/developmental toxicity screening test performed
under GLP according to OECD guideline 422 (2002). Groups of 13 male and
13 female Sprague-Dawley rats received daily doses of 100, 300 and 1000
mg/kg bw/day of docosanoic acid by gavage, respectively. While the males
were treated for 42 days, the females received the test substance from
14 days prior to mating until day 3 of lactation. As a result of this
treatment, neither mortality nor abnormalities in general condition were
observed. In addition, no changes in body weight, body weight gain and
food consumption were found. The observed minor changes in the
corpuscular haemoglobin concentration, glucose, chloride, calcium and
alkaline phosphate levels were regarded as incidental which also holds
true for the observed changes in liver weights in male and kidney
weights in females, respectively. All histopathological findings noted
in all dose groups were also detected in the control groups, so that all
findings could be regarded as not treatment-related. Overall, no
treatment-related adverse effect was apparent, so that the highest dose
of 1000 mg/kg bw/day is regarded as the NOAEL for docosanoic acid.
An oral 28-day repeated dose toxicity
study was performed equivalent to OECD guideline 407 with fatty acids,
C8-18 and C18-unsatd., distn. residues in male and female Wistar rats
(1983). Ten animals each per sex were treated by gavage with the test
substance at 50, 250 and 1000 mg/kg bw/day dissolved in olive oil.
Control animals received the vehicle only. The animals were treated 5
days/week resulting in a total of 21 applications within 28 days.
No mortalities or abnormal findings
occurred in any dose group. No treatment-related effects on body weight
gain, clinical chemistry, haematology and urinalysis were observed. No
abnormal findings were seen at gross pathology and organ weight
determinations. Histopathological examinations revealed inflamed edemas
and ulcerations of the forestomach in the low- and mid-dose group as
well as in the controls. In the highest dose group, the number of test
animals with inflamed edemas and ulcerations in the forestomach were
clearly reduced in comparison to the controls. In addition, the signs of
local irritation were completely reversed in the recovery animals.
Therefore, this effect was related to the vehicle. No treatment-related
effects were observed. Therefore, the NOAEL was determined to be ≥ 1000
There are several publications
available, which also point out, that fatty acids do not have toxic
properties after repeated administration. In general, the following
repeated dose studies reported in these publications were not performed
according/similar to current guidelines and examine partially only less
The effects of long-term feeding of
conjugated linoleic acid (41.9% c9,t11 and 43.5% t10,c12) in Fischer 344
rats were examined by Park et al. (2005). A limited number of weanling
male rats were fed either a control diet (n=10) or a diet containing 1%
(corresponding to 500 mg/kg bw/day) conjugated linoleic acid over a time
period of 18 months. After 12 weeks, 3 control and test animals were
randomly selected, sacrificed, and subjected to body fat analysis and
water content. At the end of the study period, all animals were
euthanized and examined for gross pathological changes and appropriate
tissues were examined histopathologically. Organ weights, clinical
chemistry, and haematological parameters were determined.
Survival rate, weight gain and water
consumption did not differ between treatment and control groups. Food
consumption was significantly lower in the group fed conjugated linoleic
acid compared to controls, however since body weight of test animals did
not differ to that of control animals, this effect is not considered
adverse. Body fat analysis and water content at 12 weeks revealed no
significant difference between groups in percentage body fat, empty
carcass weights, or percentage body water. Blood glucose levels were
significantly lower and mean corpuscular volume was significantly higher
in animals fed conjugated linoleic acid compared to controls. As there
were no difference in haematocrit, the observed differences do not
indicate health concern. Blood urea nitrogen and cholesterol levels were
elevated beyond the normal range in both groups, but were not
significantly different between groups. Protein was detected in the
urine of animals from both groups; however, the protein levels in the
rats fed conjugated linoleic acid were significantly lower than that of
the control group. All animals from both groups had chronic renal
diseases (chronic interstitial nephritis, nephrosis, and/or
glomerulosclerosis). The chronic renal failure was thought by the
authors to be due to the high protein content of the diets and was not
considered to be compound-related. There were no significant differences
between groups in organ weights. The incidences of pituitary or
testicular tumors, prostatitis, or lymphoma were not significantly
different between groups. Based on the results of this study, the NOAEL
was considered to be ≥ 500 mg conjugated linoleic acid/kg bw/day in the
In another chronic study with
conjugated linoleic acid, weanling male rats received a diet containing
1.5% of a synthetic conjugated linoleic acid preparation (42.5% c9,tll
and/or t9,cl1 isomers, 43% t10,c12, 4.3% other conjugated linoleic acid
isomers, 7.1% linoleic acid, and 3.1% other constituents (not further
specified)) for 9 months (Scimeca, 1998).
Body weights and food consumption were
recorded and physical examinations were performed weekly throughout the
study. At the end of the study period, all surviving animals were
necropsied and examined histologically and organ weights were
determined. Haematological and clinical chemistry parameters were
measured. According to the authors rats ingested an average daily
conjugated linoleic acid dose in a range from 1970 ± 11 to 467 ± 52
mg/kg bw/day from week 1 to study week 36. However, since this is a
broad range, an average conjugated linoleic acid intake of 750 mg/kg
bw/day was calculated based on an average food consumption of 5g/100g
bw/day (WHO, 1987).
Animals fed conjugated linoleic acid
did not show any clinical signs of toxicity, nor were there any
differences in body weight gain or food consumption relative to the
Likewise, there were no significant
compound-related histopathological or microscopic changes in the organs,
or changes in haematological or clinical chemistry parameters. Based on
the results of this study, the NOAEL for conjugated linoleic was
determined to be 750 mg/kg bw/day.
Repeated dose toxicity of lauric acid
was tested in a study, where 5 male Osborne-Mendel rats were fed a diet
containing 10% lauric acid for 18 weeks (Fitzhugh et al., 1960). As
results, no clinical effects, no adverse effects on weight gain nor any
mortality were noted. The performed gross organ pathology did not reveal
any significant differences of individual organ weights between the
controls and test animals. Thus, the test concentration of 10% in diet
is regarded as the NOAEL, which corresponds to ca. 5000 mg/kg bw/day,
based on an average daily food consumption of 5 g/100 g bw/day.
Investigations on the repeated dose
toxicity of azelaic acid (CAS# 123-99-9) were carried out in Wistar rats
and New Zealand rabbits, fed azelaic acid incorporated into pellets
(Mingrone et al., 1983). Rats (10/sex/dose) were given azelaic acid at
dose levels of 140 and 280 mg/kg bw/day and rabbits (10/sex/dose) were
administered azelaic acid at doses of 200 and 400 mg/kg bw/day for 180
days, respectively. Both species showed normal growth compared to the
control animals. No effects on biological parameters of haematology and
clinical chemistry were observed and there were no findings at
histological examinations (liver, kidneys, suprarenal glands, intestine,
testicles, ovaries, uterus, lung, heart and brain). Thus, the NOAELs for
the subchronic toxicity study were regarded to be ≥ 280 mg/kg bw/day for
rats and ≥ 400 mg/kg bw/day for rabbits, respectively.
The repeated dose toxicity of fatty
acids, tall oil (CAS# 61790-12-3) which consists predominantly of C18
unsaturated and saturated fatty acids was examined in a 90-day
subchronic toxicity study in Charles River rats (Pine Chemical
Association, 2004). The test substance was administered to the animals
(10 rats/sex/dose) in the diet at concentrations of 0, 5, 10 and 25%
(corresponding to 2500, 5000 and 12500 mg/kg bw/day). No deaths occurred
in the test animals; however two control animals died during blood
sampling. No clinical signs and no changes in body weight and body
weight gain were noted. The food consumption was slightly decreased in
the mid- and high-dose group. No changes in haematology, clinical
chemistry or urinalysis parameters were determined. At gross pathology,
no treatment-related effects were observed in any of the groups. No
consistent organ weight changes and no histopathological effects were
reported at any dose. Based on this data, the NOAEL for fatty acids,
tall oil was considered to be ≥ 12500 mg/kg bw/day.
Moody and Reddy (1977) exposed rats to
2, 4 and 8% hexanoic acid (corresponding to 1000, 2000, 4000 mg/kg
bw/day; CAS# 142-62-1) in diet for 3 weeks before alterations in body
weight gain, liver size, hepatic enzyme activity and hepatic peroxisome
proliferation were examined. Since no effects were induced by hexanoic
acid, the NOAEL was considered to be ≥ 4000 mg/kg bw/day.
Rodrigues et al. (2010) analysed
effects of oleic acid (CAS# 112-80-1) and linoleic acid (CAS# 60-33-3)
after repeated dose exposures in male Wistar rats with special focus on
neutrophils. In detail, 10 rats per dose group were exposed once daily
to 110, 220 and 440 mg/kg bw oleic acid or linoleic acid via gavage over
10 days. Control animals received 220 mg water/kg bw /day. In addition
to specific alterations in neutrophils, effects on water, food and
calory intake as well as alterations in biochemical parameters including
enzyme activities of alanine transaminase (ALT), aspartate transaminase
(AST) and lactate dehydrogenase (LDH) were determined Moreover
histological examinations on the small intestine including villus:crypt
ratio, epithelium, reactivity of the crypt, claciform cells number,
payer plates reactivity, muscle layer and nerve plexus were performed.
In regard to signs of general toxicity, no mortality or clinical signs
such as diarrhoea or hair loss were reported. Food, calorie and water
intake were not modified by administration of oleic acid and linoleic
acid in all dose groups. Moreover, no alterations in the activity of
AST, ALT or LDH were observed in the high-dose group and no changes in
the histopathological examinations were determined. Oleic acid and
linoleic acid modified several neutrophil functions, indicating that
these fatty acids may affect the course of inflammation. As the effects
on neutrophils represent cell-specific alterations relevant for the
immune system which itself represents an adaptive system to many kinds
of stressors and exogenous stimuli, they do not clearly indicate adverse
effects on the test animals. In contrast, endpoints covering clinical
signs, mortality, food and water consumption, haematological parameter
and histopathological findings clearly stand for no significant adverse
effects of oleic and linoleic acid. Thus, the highest dose of 440 mg/kg
bw is regarded as NOAEL in the conducted study for both test substances.
The effect of linoleic acid on the
haemopoietic system was investigated in rats (Khan et al., 1994). Five
animals each were administered linoleic acid (CAS# 60-33-3) in mineral
oil at a dose level of 0.7 mmol/kg bw/day (equivalent to 200 mg/kg
bw/day) by gavage for 1, 7 or 28 days, respectively. No haematological
changes were noted in the examined parameters (blood erythrocyte count,
haemoglobin, packed cell volume, mean corpuscular volume, mean
corpuscular haemoglobin, haematocrit, platelets, white blood cell count,
leukocyte differential counts and methaemoglobin). Biochemical assays in
serum revealed, that LDH activity was not altered by linoleic acid
treatment. Serum AST was diminished to 72% and 74% of control values in
animals treated for 7 and 28 days, respectively. Serum ALT activity was
decreased in the linoleic acid exposed animals at Days 1 and 7 being 81
and 65% of controls, respectively. On day 28 the changes in serum ALT
activity were no longer of statistical significance. Since the changes
in these markers of cell or tissue injury were not accompanied by any
histopathological findings in the examined organs (heart, liver, lung,
brain, spleen, kidneys, thymus, testes and pancreas), the changes in the
aminotransferases were not considered as adverse. No organ weight
changes were noted and linoleic acid treatment had no effect on splenic
iron content at any of the three time points. Thus, based on the results
of this study, the NOAEL (subacute) was considered to be ≥ 200 mg
linoleic acid/kg bw/day.
Since the members of the fatty acids
category share structural and functional properties, these study results
can be applied to all members of the category. Thereby, a
substance-specific adjustment of the NOAEL is not performed. As overall
NOAEL for all fatty acids within the category 1000 mg/kg bw/day is
chosen as “worst case” among the available key studies, which were
judged with reliability 1 or 2 (reliable). In addition nonanoic acid and
docosanoic acid, which elicit a NOAEL ≥ 1000 mg/kg bw/day are
representing category members with a low and the highest molecular
Together, the study data do not
provide any evidence of systemic toxicity after repeated administration
of fatty acids which is supported by the physiological function of fatty
acids within the body.
Fitzhugh, O.G. et al. (1960) Oral
toxicities of lauric acid and lauric acid derivates. Toxicol Appl
Pharmacol. 2:59 - 67.
Khan, M. F. et al. (1994)
Hematopoietic Toxicity of Linoleic Acid Anilide: Importance of Aniline.
Fundam Appl Toxicol 25:224 - 232.
Mingrone, G. et al. (1983). TOXICITY
OF AZELAIC ACID. DRUGS EXPTL. CLIN. RES. 9(6):447 – 455
Moody, D. E. and Reddy, J.K. (1978).
Hepatic Peroxisome (Microbody) Proliferation in Rats Fed Plasticizers
and Related Compounds. Toxicol. Appl. Pharmacol. 45:497 – 504.
Park, Y. et al. (2005).Effects of
conjugated linoleic acid on long term feeding in Fischer 344 rats. Food
and Chemical Toxicology 43:1273 – 79.
Pine Chemical Association (2004).
Final Submission for Tall Oil Fatty Acids and Related Substances - VII.
Robust Summaries of Data for Tall Oil Fatty Acids and Related
Substances.Bibliographic source: no data
Scimeca, J.A. (1998) Toxicological
Evaluation of Dietary Conjugated Linoleic Acid in Male Fischer 344 Rats.
Food and Chemical Toxicology 36(5):391 - 395.
Rodrigues, H.G. et al. (2010). Dietary
Free Oleic and Linoleic Acid Enhances Neutrophil Function and Modulates
the Inflammatory Response in Rats. Lipids 45:809 – 819.
All available data on repeated dose toxicity
of the members of the fatty acids category do not meet the criteria for
classification according to Regulation (EC) No 1272/2008, and are
therefore 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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