Registration Dossier

Administrative data

Description of key information

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, C22
Subacute (OECD 407, rat): NOAEL oral ≥ 1000 mg/kg bw/day; CAS# 112-05-0, C9
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.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Referenceopen allclose all

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
17 Mar - 16 June 1969
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented study report which meets basic scientific principles.
Qualifier:
no guideline available
Principles of method if other than guideline:
Rats were fed a diet containing 5, 10 and 25% oleic acid over a time period of 84 days.
GLP compliance:
not specified
Species:
rat
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River
- Weight at study initiation: 115-116 g
- Housing: individually in wire bottomed steel cages, animals were also ear punched
- Diet (e.g. ad libitum): ad libitum
Route of administration:
oral: feed
Vehicle:
not specified
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): weekly
- Mixing appropriate amounts with (Type of food): standard rat ration


Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
84 days
Frequency of treatment:
no data
Dose / conc.:
5 other: %
Remarks:
equivalent to ca. 2500 mg/kg bw/day
(calculated based on the average daily food consumption of 5 g/100 g bw (WHO, 1987))
Dose / conc.:
10 other: %
Remarks:
equivalent to ca. 5000 mg/kg bw/day
(calculated based on the average daily food consumption of 5 g/100 g bw (WHO, 1987))
Dose / conc.:
25 other: %
Remarks:
equivalent to ca. 12500 mg/kg bw/day
(calculated based on the average daily food consumption of 5 g/100 g bw (WHO, 1987))
No. of animals per sex per dose:
10
Control animals:
yes
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations: abnormal reactions and mortality


BODY WEIGHT: Yes
- Time schedule for examinations: weekly for five rats of each sex of each group


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): Yes
- Food consumption for each animal determined: collected weekly for five rats of each sex in all groups

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at day 84 of feeding
- How many animals: five rats of each sex in the control and 25% dosage group and three rats of each sex in the 10% group
- Parameters checked: hematocrit, hemaglobin concentration, erythrocyte count, total and differential leukocyte count, reticulocyte count, prothrombin time and cell index (MCV, MCH, MCHC)


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at day 84 of feeding
- How many animals: five rats of each sex in the control and 25% dosage group and three rats of each sex in the 10% group
- Parameters checked: fasted serum glucose, total cholesterol, blood urea nitrogen, total protein, serum alkaline phosphatase (SAP), serum glutamic-pyruvic transaminase (SGPT), serum glutamic-oxalacetic tranaminase (SGOT), A/G ratio and Icterus index


URINALYSIS: Yes
- Time schedule for collection of urine: at day 84 of feeding
- Parameters checked: protein, glucose, pH, specific gravity and microscopic elements


NEUROBEHAVIOURAL EXAMINATION: Yes


Sacrifice and pathology:
GROSS PATHOLOGY: Yes, all animals that died during the study were examined grossly unless examination was precluded by post-mortem autolysis. At the end of the 90-day feeding period, all surviving rats were necropsied, and organ weights were recorded for liver, kidneys, spleen, gonads, adrenals, heart, thymus and brain.

HISTOPATHOLOGY: Yes, histopathological examinations were conducted on: brain, spinal cord, pituitary, thyroid, parathyroid, thymus, salivary glands, stomach, small and large intestines, liver, pancreas, kidneys, adrenals, spleen, heart, trachea, lungs, aorta, testes, seminal vesicle, ovary, uterus, prostate, urinary bladder, lymph nodes, peripheral nerve, bone marrow, skeletal muscle, bone (femur), eye and optic nerve.
Statistics:
Organ and body weights were analyzed using analysis of variance and a t-test.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
3 animals died due to blood collection trauma
Mortality:
mortality observed, treatment-related
Description (incidence):
3 animals died due to blood collection trauma
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
slightly higher final body weights in treatment groups, not statistically significant
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
slightly decreased in treatment groups, non-adverse
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
significant differences in organ/body weight ratios except for kidneys, adrenal glands and brain, non-adverse
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
Two control animals died on day 84. These deaths were related to blood collection. One female animal from the 10% dosage group also died from blood collection trauma. There were no other mortalities or clinical signs of toxicity.


BODY WEIGHT AND WEIGHT GAIN
The test animals had slightly higher final body weights than controls, but the differences were not statistically significant.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Food consumption among test animals was slightly lower than among the control animals.

HAEMATOLOGY
There were no outstanding differences in hematologic parameters among test and control animals

CLINICAL CHEMISTRY
There were no outstanding differences in clinical chemistry parameters among test and control animals

URINALYSIS
There were no outstanding differences in urinalysis parameters among test and control animals

NEUROBEHAVIOUR
No abnormal behavioural reactions were noted in the study.

ORGAN WEIGHTS
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.

GROSS PATHOLOGY
No abnormalities were noted at gross examination.

HISTOPATHOLOGY: NON-NEOPLASTIC
Some minor histopathologic changes were noted among both the test and control animals, specifcially 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.

Dose descriptor:
NOAEL
Effect level:
>= 25 other: %
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: NOAEL corresponding to the highest dose tested
Dose descriptor:
NOAEL
Effect level:
>= 12 500 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: NOAEL corresponding to the highest dose tested
Critical effects observed:
no
Conclusions:
Oleic acid is practically nontoxic to rats in a repeated dose study when given doses of up to 25% in the diet. The NOAEL was ≥25% equivalent to ≥12500 mg/kg bw/day.
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
no
Qualifier:
according to
Guideline:
EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
Deviations:
no
GLP compliance:
yes (incl. certificate)
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: approx. 6 weeks
- Weight at study initiation: mean males: 217 g; females: 176
- Housing: in groups of 5. Singly during activity monitoring overnight.
- Diet: ad libitum starting at 4 hours after dosing
- Water: tap water ad libitum
- Acclimation period: at least 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21+/-3
- Humidity (%): 30-70
- Air changes/hour: 15
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
propylene glycol
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Formulations in vehicle were prepared daily within 4 hours prior to dosing.
Homogeneity and stability were checked.


VEHICLE
- Justification for use and choice of vehicle: based on results of a pre-test
- Concentration in vehicle: approx. 90-99.95%
- Amount of vehicle (if gavage): 5mL/kg bw/day
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
A GC/MS method was developed and evaluated
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily, 7 days per week
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
150 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on results of a pre-test using dose levels of 150 and 1000 mg/kg bw/day
Positive control:
no
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: once daily


BODY WEIGHT: Yes
- Time schedule for examinations: on days 1, 8, 15, 22, and 28


FOOD CONSUMPTION AND COMPOUND INTAKE (no feeding study): yes
- Time schedule: weekly


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to sacrifice
- Anaesthetic used for blood collection: Yes (iso-flurane)
- Animals fasted: Yes


CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: prior to sacrifice
- Animals fasted: Yes
- How many animals: all


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: Yes
- Time schedule for examinations: during week 4 of treatment
- Dose groups that were examined: all
- Battery of functions tested: sensory activity; grip strength; motor activity
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Statistics:
Dunnett-test and exact Fisher-test
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
breathing difficulties in 1000 mg/kg bw/d group (non-adverse)
Mortality:
mortality observed, treatment-related
Description (incidence):
breathing difficulties in 1000 mg/kg bw/d group (non-adverse)
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
hyperplasia of squamous epithelium of forestomach in 1000 mg/kg bw/d group (non-adverse)
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
No substance-related mortality occurred.
Slight to moderate breathing difficulties (rales and/or gasping) were seen in several high dose animals on some days during week 3. These signs subsided and were absent during week 4.
No signs were noted in the low and intermediate dose groups.


BODY WEIGHT AND WEIGHT GAIN
Body weight and body weight gain of treated animals remained in the same range as controls over the 4-week study period.


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
There was no effect on food consumption except from a slight transient reduction in high dose females during week 3.


HAEMATOLOGY
There was no effect on hematological parameters.


CLINICAL CHEMISTRY
There were no treatment-related differences between control and treated animals.


NEUROBEHAVIOUR
No changes were noted in hearing ability, pupillary reflex, static righting reflex and grip strength, or in motor activity.


ORGAN WEIGHTS
Absolute and relative organ weights were similar between control and treated animals.


GROSS PATHOLOGY
Finding No. 1: an irregular surface of the forestomach was noted in all high dose animals.
Finding No. 2: a thickened glandular mucosa of the stomach was observed among the treated animals. Since none of these cases could be confirmed microscopically, they were considered to be of no toxicological relevance.


HISTOPATHOLOGY: NON-NEOPLASTIC
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 intermediate dose group animals.

Dose descriptor:
NOAEL
Remarks:
systemic
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Absence of adverse effects. Rales and hunched posture in some rats at 1000 mg/kg bw/day were generally minimal to mild and only seen on some days during week 3 and subsided thereafter, and were, therefore, regarded as being of no biological relevance.
Dose descriptor:
NOAEL
Remarks:
local
Effect level:
150 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
histopathology: non-neoplastic
Critical effects observed:
no
Conclusions:
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.
Endpoint:
short-term repeated dose toxicity: oral
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan, Hino, Tokyo
- Age at study initiation: 8 weeks
- Weight at study initiation: male: 312.1 - 363.7 g; female: 205.3 - 230.8 g
- Housing: metal wire floor cages
- Diet: ad libitum CE-2, CLEA Japan
- Water: ad libitum tap water
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 1
- Humidity (%): 50 - 65
- Air changes (per hr): 15
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
prepared more frequently than once a week; aliquots were kept by each concentration refrigerated in airtight conditions

VEHICLE
- Justification for use and choice of vehicle (if other than water): due to insolubility in water
- Amount of vehicle (if gavage): 5 mL/kg bw
- Lot/batch no. (if required): V6H2050
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
- males: 42 days
- females: from 14 days prior to mating to day 3 of lactation
Frequency of treatment:
once daily
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
13
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: based on preliminary result in a 14 day-repeated dose toxicity study, where no signs of toxicity were found
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once a day

DETAILED CLINICAL OBSERVATIONS: No

BODY WEIGHT: Yes
- Time schedule for examinations: males: days 1, 8, 15, 22, 29, 36, 42; pregnancy females: premating days 1, 8, 15; pregnancy days: 0, 7, 14, 20; lactation days: 0, 4; non pregnancy females: day 1, 8, 15, 22, 25

FOOD CONSUMPTION:
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes (males only)
- Time schedule for collection of blood: prior to autopsy
- Anaesthetic used for blood collection: Yes (identity): pentobarbital sodium
- Animals fasted: 18 - 24 hours before sacrifice
- How many animals: all surviving animals
- Parameters checked: red blood cell count (RBC), white blood cell count (WBC), haemoglobin content (Hb), mean corpuscular volume (MCV), haematocrit (Ht), mean corpuscular haemoglobin content (MCH), mean corpuscular haemoglobin concentration (MCHC)

CLINICAL CHEMISTRY: Yes (males only)
- Animals fasted: 18 - 24 hours before sacrifice
- How many animals: all surviving animals
- Parameters checked: total protein, albumin, total cholesterol concentration, glucose, urea nitrogen, creatinine, alkaline phosphatase activity, GOT, GPT, γ-GTP, triglyceride concentration, inorganic phosphorus, total bilirubin, calcium, sodium, potassium, chlorine, A/G ratio

URINALYSIS: No

Sacrifice and pathology:
Organ weights:
male: heart, liver, kidneys, thymus, testes, epididymides
female: heart, liver, kidneys, thymus

Pathological findings and histopathology (control and 1000 mg/kg bw/day group):
male: heart, liver, spleen, kidney, adrenal, testis, epididymis, brain, thymus, bladder
female: brain, liver, spleen, thymus, kidney, adrenal, bladder, heart, ovary
Statistics:
Yates test, Mann-Whitney U test, Fisher exact test, Bartlett test, Dunnett test, Scheffe test, Kruskal-Wallis test
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
significant increase was observed in 100 mg/kg bw/day group, not considered to be related to treatment
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
significant decrease was observed in 100 mg/kg bw/day group during lactation, not considered to be related to treatment
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
significant decrease of mean corpuscular haemoglobin concentration in the 300 and 1000 mg/kg bw/day groups; fndings are not dose-dependent
Clinical biochemistry findings:
effects observed, non-treatment-related
Description (incidence and severity):
significant decreased ALP level in all dose groups; significant decreased glucose level in the 1000 mg/kg bw/day group; signifant increase in chloride, decrease in calcium content and in total protein in the 300 mg/kg bw/day group; fndings are not dose-dependent and considered incidental
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, non-treatment-related
Description (incidence and severity):
kidney weight significantly reduced (p<0.05) in the 300 mg/kg bw group in females; significant increased actual weight ratio of liver weight (p <0.05) in the 100 mg/kg bw/day group; considered as incidental
Gross pathological findings:
effects observed, non-treatment-related
Description (incidence and severity):
observations were considered incidential
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
observations were considered incidential
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
- Males: No deaths or abnormalities in general condition were observed in any of the treated groups
- Females: No deaths were observed in any treated group

BODY WEIGHT AND WEIGHT GAIN
- Males: significant increase (p<0.01) compared to control was observed in 100 mg/kg bw/day group between 8 - 15 days and between 15 - 29 days. However, since no change was observed in other groups, it was considered not related to the dosing of compound.
- Females: no significant changes in body weight were noted

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
- Males: no changes in food consumption related to the dosing of compound
- Females: significant decrease (p<0.01) compared to control was observed during lactation in 100 mg/kg bw/day group. However, since no other changes in food consumption were noted in 300 mg/kg bw/day and 1000 mg/kg bw/day, it was not related to the dosing with the compound.

HAEMATOLOGY
- Males: a significant decrease (p<0.01) of mean corpuscular haemoglobin concentration (MCHC) compared to control was found in the 300 and 1000 mg/kg bw/day dose group, respectively (control: 34.7 ± 0.5%; 100 mg/kg bw/day: 34.4 ± 0.2%; 300 mg/kg bw/day: 33.9 ± 0.4%**; 1000 mg/kg bw/day: 33.9 ± 0.3%**; **p<0.01). No other differences were noted.

CLINICAL CHEMISTRY
- Males: a significant decreased ALP level (p<0.05) compared to control was found in all dosing groups (control: 237 ± 45 U/L; 100 mg/kg bw/day: 200 ± 35 U/L*; 300 mg/kg bw/day: 195 ± 35 U/L*; 1000 mg/kg bw/day: 197 ± 41 U/L*; *p<0.05). A significant decreased glucose level (p<0.05) compared to control was found in the high dose group (control: 152 ± 16 mg/dL; 1000 mg/kg bw/day: 135 ± 14 mg/dL*; *p<0.05). While a significant increase in chloride (p<0.05) was found in the 300 mg/kg bw/day group, a significant decrease in calcium content (p<0.01) and in total protein (p<0.05) was noted in this group. However, all the findings lack a dose-dependency and were regarded as incidental.

ORGAN WEIGHTS
- Males: in 100 mg/kg bw/day males, the actual weight ratio of liver weight compared to control values were increased (p <0.05) . No other significant differences were found in all groups. Thus, this finding lacks a dose-dependency and was regarded as incidental.
- Females: actual kidney weight was significantly reduced (p<0.05) in the 100 mg/kg bw/day group. No other weight changes were noted. Thus, this finding lacks a dose-dependency and was regarded as incidental.

GROSS PATHOLOGY
Males:
- Heart: myocardial degeneration was noted in one animal of the control group and the 1000 mg/kg bw/day group, respectively
- Liver: periportal fatty change of the liver was found in all animals of the control and the high dose group. Focal necrosis was noted in one animal of the high-dose group.
- Spleen: all animals of the control and the high-dose group showed brown pigment deposits of the spleen as well as extramedullary hematopeiosis
- Kidney: while fibrosis was only found in 1/13 animals of the control group, eosinophilic bodies and basophilic tubules in the cortex were noted in animals of both control and 1000 mg/kg bw/day groups
- Adrenal gland: one animal of the high-dose group showed fibrosis
- Testis: atrophy of the seminiferous tubules was observed in two animals of the 1000 mg/kg bw/day dose group, with one animal affected on both sides and one side affected in the other animal. No other abnormalities were noted.
- Epididymis: abnormal sperm granuloma was found in one animal of the control group
- Brain: no abnormal findings noted
- Thymus: no abnormal findings noted
- Bladder: no abnormal findings noted

Females:
- Brain: one animal of the high-dose group showed abnormal mineral deposition in the thalamus
- Liver: focal necrosis and fibrosis was found in one animal of the control group, while one animal of the high-dose group showed only focal necrosis
- Spleen: brown pigmentation and extramedullary hematopeiosis was found in animals of the control and the high-dose group, but no varying degrees of frequency was observed
- Thymus: atrophy and bleeding was observed in animals of both groups, control and high-dose group, respectively
- Kidney: basophilic tubules of the cortex and a dilatation of the renal pelvis was seen in the control and high-dose group
- Adrenal gland: cortical necrosis was observed in one animal of the control group
- Heart: no abnormal findings noted
- Bladder: no abnormal findings noted

Key result
Dose descriptor:
NOAEL
Remarks:
repeated dose toxicity
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no adverse substance-related systemic effects were noted
Critical effects observed:
no
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
22 Jul 1981 - 28 Aug 1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
(no data on test substance purity, 6 months post-treatment period; cage side observations were limited to mortality and clinical signs; no data on food consumption)
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
other: Wistar (MuRa Han 67)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Mus Rattus, Brunnthal, Germany
- Age at study initiation: about 5 weeks
- Weight at study initiation: 124 g (mean males), 112 g (mean females)
- Housing: males in groups of 2-3 animals, females in groups of 5 animals in macrolon cages with soft wood bedding
- Diet: Altromin 1324 DK, pelleted, ad libitum
- Water: municipal tap water, ad libitum
- Acclimation period: eight days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21
- Humidity (%): 60 - 80
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 22 Jul 1981 To: 28 Aug 1981
Route of administration:
oral: gavage
Vehicle:
olive oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
- daily prior to application

VEHICLE
- Justification for use and choice of vehicle (if other than water): olive oil
- Amount of vehicle (if gavage): 5 mL/kg bw
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
21 applications within 28 days
Frequency of treatment:
daily, 5 days/week (21 applications in total)
Dose / conc.:
50 mg/kg bw/day (actual dose received)
Dose / conc.:
250 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10 (main test)
5 (recovery groups)
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: LD50 > 5000 mg/kg bw
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations checked: mortality, clinical signs

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination of the experiment, 24 h prior to sacrifice via cardiocentesis
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes (24 h)
- How many animals: all
- Parameters checked: erythrocytes, haemoglobin, haematocrit, leucocytes, mean corpuscular volume, complete blood count

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination of the experiment, 24 h prior to sacrifice via cardiocentesis
- Animals fasted: Yes (24 h)
- How many animals: all
- Parameters checked: urea, creatinine, sodium, potassium, glucose, calcium, phosphorus, chloride, total protein, glutamate oxaloacetate transaminase (GOT), γ-glutamyl transferase (GGT), glutamate pyruvate transaminase (GPT)

URINALYSIS: Yes
- Time schedule for collection of urine: no data
- Metabolism cages used for collection of urine: no data
- Animals fasted: no data
- Parameters checked: volume, pH, protein, glucose, blood, ketones, urobilinogen, sediment, ingredients (bacteria, cells, crystals)

OTHER:
- amount of faeces within 24 h, appearance, colour
Sacrifice and pathology:
GROSS PATHOLOGY: Yes; absolute and relative weights of the following organs of all animals were determined: adrenal glands, brain, gonades, heart, kidneys, liver, spleen, thyroids
HISTOPATHOLOGY: Yes: the following organs of 5 male and female animals each of each dose group were fixed in 10 % formalin and tissue sections were stained in haemytoxylin/eosin: adrenals, aorta thoracica, bladder, cerebellum, cerebrum, colon, epididymis, eyes (cornea, iris, retina), gastroesophageal vestibule, heart, kidney, liver, lung, lymph nodes, nerve peripher, oesophagus, ovaries, pancreas, parathyroids, prostate, salivary glands, seminal vesicles, skeletal muscles, skin, small intestine, spleen, stomach, thymus, testes, trachea, thyroids, tongue, uterus
Statistics:
T-test was used in general, U-test was used for organ weights.
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
No effects observed.

BODY WEIGHT AND WEIGHT GAIN
No effects observed.

HAEMATOLOGY
Some significant increases and decreases in different parameters (erythrocytes, haematocrit, mean corpuscular volume, haemoglobin, GPT, protein, calcium, chloride) were observed in both sexes of all treatment groups. Taken the individual values of these animals into consideration, the effects are considered to be by chance findings. In addition, no dose-related trend was observed and the values were in the biological range for animals of this strain and age.

CLINICAL CHEMISTRY
No effects observed.

URINALYSIS
No effects observed.

ORGAN WEIGHTS
No effects observed. In particular, no effects on gonades in both sexes were observed.

GROSS PATHOLOGY
No effects observed. In particular, no effects on gonades in both sexes were observed.

HISTOPATHOLOGY: NON-NEOPLASTIC
Inflamed oedemas and ulcerations of the forestomach were observed in the low- and mid-dose group as well as in the controls. In the highest dosage group, the number of test animals with inflamed oedemas 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.
In particular, no effects on testes, prostate, semicle vesicles, epididymis, uteri and ovaries were observed.
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: NOAEL corresponding to the highest dose tested.
Critical effects observed:
no
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises adequate, reliable studies (Klimisch score 1 and 2) and consistent studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on a common functional group, common precursors/breakdown products and similarities in repeated dose toxicity properties (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.6, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

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.

 

Subchronic

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.

 

Subacute

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 mg/kg bw/day.

 

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 parameters.

 

Chronic

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 diet.

 

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 control group.

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.

 

Subchronic

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.

 

Subacute

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 weight.

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.

 

References

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.

Justification for classification or non-classification

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.