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Administrative data

Description of key information

Subacute (OECD 407, rat): NOAEL oral ≥ 1000 mg/kg bw/day; CAS 871-70-5, C18-di 

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
1 000 mg/kg bw/day
Study duration:

Additional information

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 acid (nonanoic acid and azelaic acid), C12 fatty acid (lauric acid) and C18-di (1,18 octadecanedioic acid).

These considerations are also supported by the repeated dose 28 day test (OECD 407 Albrecht, 2002) of C18 -di with NOAEL 1000 mg/kg bw.

These observations fit to available studies for the substance category with similar structural and toxicological properties. Read-across is performed based on a category approach.  

Nonanoic acid (CAS# 112-05-0) was examined in a subacute 28-day study according to OECD Guideline 407 and under GLP conditions in Wistar rats (5 rats/sex/dose) (van Otterdijk, 2002). The animals were administered by gavage doses 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 neurobehavioral 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 (Nagao et al., 2002). Groups of 13 male and 13 female Sprague-Dawley rats received daily doses of 100, 300 and 1000 mg/kg bw/d 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 histhopathological 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.

 There are several publications available, which also point out, that fatty acids have no toxicity after repeated administration. In general, the repeated dose studies reported in these publications were not performed according/similar to current guidelines and examine partially only less parameter. 

Repeated dose toxicity of lauric acid was analyzed 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 was noted. The performed gross organ pathology and did not reveal any significant differences of individual organ weights between the controls and test animals. Thus, the given dosage of 10% in diet is regarded as the NOAEL, which corresponds to ca. 5000 mg/kg bw/day, based on the average daily food consumption of 5 g/100 g bw.

 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.

 Investigations on the repeated dose toxicity of azelaic acid (CAS# 123-99-9) were carried out in Wistar rats andrabbits, fed azelaic acid incorporated into pellets (Mingrone et al., 1983). Rats (10/sex/dose) were given azelaic acid in concentrations 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 in 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.

Since the members of the category share structural and functional properties, these study results can be applied to all members of the category. The 28-day NOEL for 1,18 octadecanedioc acid in rats is 1000 mg/kg bw. 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 (reliable without restriction). 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.

On the basis of the results for C18 -di and the other category members

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.

Justification for classification or non-classification

Based on available data on repeated dose toxicity, fatty acids do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC.