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Administrative data

Description of key information

Based on read-across from a supporting substance (structural analogue) following a category approach:
Oral: NOAEL (rat) = 741 (male) and 855 (female) mg/kg bw/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
741 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

Justification for grouping of substances and read-across

In accordance with the specifications listed in Regulation (EC) No. 1907/2006 Annex XI, 1.5 Grouping of substances and read across, the similarity of category members has been shown to be justified based on the scope of variability and overlapping of composition, representative molecular structure, physico-chemical properties, tox-, ecotoxicological profiles and supporting Information by various validated QSAR methods. This information is given in further detail within the category justification for the grouping of chemicals and read-across (see IUCLID Section 13) for the dimerised fatty acids and its derivatives, and once more within the endpoint summary and discussion for Toxicokinetics.

For assessment of human health hazards of the category members, trends and similarities in toxicokinetic behaviour are most relevant. In particular, the molecular weight-dependent decrease in oral and dermal absorption and common metabolic pathways, which are explained by trends in molecular structure and common functional groups (monomers, dimers and trimers of similar long-chain fatty acids). This justifies the assumption that the toxicological profile of all category members is similar and effects or the lack of effects observed in toxicological studies of one ore more substances can also be expected and explained for the other substances in the category.

Therefore, in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, in order to avoid the need to test every substance for every endpoint, the category concept is applied for the assessment of human health hazards. Thus where applicable, human health effects are predicted from adequate and reliable data for reference substance(s) within the group by interpolation to other substances in the group (read-across approach).

All the available information from the substances within the category is taken into account for each endpoint to be assessed. Key studies are selected for assessment of the test substance and for read-across as to fulfil the requirements laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, i.e. in all cases the results are adequate for the purpose of classification and labelling and/or risk assessment; have adequate and reliable coverage of the key parameters addressed in the corresponding test method referred to in Article 13(3); cover an exposure duration comparable to or longer than the corresponding test method referred to in Article 13(3) if exposure duration is a relevant parameter; and adequate and reliable documentation of the applied method is provided.

 

Discussion

There are no data available on the repeated dose toxicity of fatty acids, C16-C18 and C18 unsaturated, branched and linear. However, there are reliable data on toxic effects after subchronic oral exposure to a structurally related member of the chemical category. Furthermore, available information on another related substance, tall oil fatty acids, was taken into account. Thus, read-across based both on a category approach and on data from a structural analogue was conducted.

Oral

The toxic potential of fatty acids, C18-unsaturated, dimers (CAS No. 61788-89-4) was assessed in rats in a 90-day feeding study carried out according to OECD Guideline 408 and compliant with GLP. Three groups of 20 male and 20 female Sprague-Dawley rats (4-5 weeks old at study initiation) were fed the test material at 0, 0.1, 1 and 5% (w/w) in purified diet ad libitum for 90 days. Based on the reported body weight and food intake data, the approximate doses were 0, 74.1, 740.9, 3591.2 mg/kg bw/day for males and ca. 0, 90.5, 854.9, 4085.5 mg/kg bw/day for females (average dose weeks 0-13).

The animals were observed up to two times per day. Food and water consumption was determined twice weekly. Body weights were determined weekly. Ophthalmoscopy was carried out before the start of the study and during the last week of the feeding period.

Before necropsy, blood samples were taken for clinical pathology determinations. At necropsy, a full range of tissues were taken for histological examination. All tissues from the control and 5% groups were examined. Liver, adrenals, eyes, mesenteric lymph nodes, spleen and thyroids (females) from all groups were also examined.

There were no decedents and no treatment-related clinical signs in rats fed the test substance for thirteen weeks. The lower food intake during the first four weeks of the study in rats fed the test material at 5% in diet may reflect an initial reluctance of the rats to eat the diet.

Decreases in organ weight and/or relative organ weight of spleen, kidney and liver were observed, mainly after feeding the test material at 1.0% and 5.0%, but bore no relation to any effect which might have been expected on the basis of the histopathology findings.

Plasma alkaline phosphatase activity (ALP) was increased in males and females fed the test material at 1.0% or 5.0%. An increase in plasma ALP activity may reflect induction (increased synthesis) in liver cells rather than increased release from damaged cells. Another plasma enzyme derived from the liver in the rat, alanine aminotransferase (ALT) was also increased in male and female rats fed at 5.0%.

In addition to increases in plasma ALP level derived from the liver, treatment-related effects were observed on microscopic examination of that organ. Histological examination of liver from animals in the 5.0% treatment group revealed an increase in biliary hyperplasia. Interference in bile flow could be related to the observed increase in ALP, which is a sensitive indicator of cholestasis. Changes in ALP develop before there are any detectable increases in plasma bilirubin levels. It should be noted that while a very small increase in plasma bilirubin was observed in male rats fed the test material at 5.0% or 1.0%, the levels measured were below the sensitivity of the method and must be viewed with caution. Although the bile duct proliferation and sclerosis recorded in the liver may correlate with the increase in ALP, it should be noted only very minor biliary changes were seen in a few female rats.

A small reduction in plasma calcium was observed in male and female rats fed the test material at 5.0%. Small reductions in both total serum protein and albumin were also observed in male and female rats in the 5.0% groups. It is possible the calcium and serum protein changes may be connected. However, reduction in plasma calcium was not always accompanied by a parallel reduction in plasma albumin. The changes in plasma calcium and serum proteins are small, probably representing a physiological rather than a pathological response to treatment with the test material.

The plasma lipids cholesterol and triglyceride were reduced in male and female rats in the 5.0% and 1.0% treatment groups. It is possible that the test material blocks the absorption of lipid and other nutrients from the gut. Such activity could also explain changes in plasma electrolytes and intermediate metabolites. The reduction in periportal hepatocyte vacuolation seen on histological examination of the liver could correlate with the reduced plasma lipids, indicating some alteration in lipid metabolism, another possible explanation for the plasma lipid, serum protein and calcium changes.

The pigment present in the macrophages in the mesenteric lymph nodes and spleen did not stain with Perls' stain for haemosiderin or aldehyde fuchsin for lipofuscin, but did stain with Schmorl's stain for lipofuscin. Lipofuscin is derived from oxidation of unsaturated lipids or lipoproteins. The test material is composed of a mixture of monomers, dimers and trimers of various fatty acids. It is likely that the pigment represents either lipofuscin produced by oxidation of some component of the test material, or that the test material itself stains positively.

There was no evidence of any degenerative effect associated with pigmented macrophages. It is probable that they represent a physiological response to dietary administration of lipid materials such as the test material. Accumulations of macrophages in the mesenteric lymph nodes commonly occur as a result of ageing, or following administration of pigmented or lipid substances in the diet. Although the pigment appeared darker in the spleen than in the mesenteric lymph node, this may reflect a difference in density. The pigment was present alongside normal levels of haemosiderin which appeared tinctorially distinct. The coloured nature of the compound is also likely to have been responsible for the alteration in the colour of the caecal contents that was observed at necropsy.

Increased cortical vacuolation in the adrenals, coupled with decreased cytoplasmic rarefaction probably indicates altered steroidogenesis. This was not accompanied by any evidence of degenerative change. The significance of the reduced extramedullar haemopoiesis in the adrenals is uncertain, but may possibly correlate with the reduction in neutrophil count in females fed the test material at 5.0% and 1.0%. All of the changes in the adrenal are minor in nature and of limited importance.

The increase in thyroid follicular epithelial hypertrophy in female rats alone is unusual. The hypertrophy comprised of a slight increase in height of the follicular epithelium combined with a reduction in the sise of the follicular lumen and in the amount of colloid therein. Goitrogenic compounds that interfere with synthesis of thyroid hormones or stimulate increased degradation of T4 in the liver can cause changes of this nature.

A no-effect-level was not identified. However, based on clinical chemistry parameters and histopathological findings, 1% (w/w) test material in diet can be considered a no-observed-adverse-effect-level (NOAEL), corresponding to a dose of 741 and 855 mg/kg bw/day for males and females, respectively (Spurgeon and Hepburn, 1993).

Fatty acids, C16-C18 and C18 unsaturated, branched and linear are derived from and closely related to tall oil fatty acids (61790-12-3) as to composition and structure. Therefore, available information on the toxicity of tall oil fatty acids after repeated oral exposure was also taken into account.

Summarised data published on the website of the US Environmental Protection Agency reports the results of a 90-day feeding study with tall oil fatty acids (TOFA) (http: //www. epa. gov/chemrtk/pubs/summaries/tofars/c13055tc. htm). According to the data reported, Charles River rats (10/sex/dose) were administered TOFA at 0, 5, 10 and 25% (approximately corresponding to 0, 2500, 5000 and 12500 mg/kg -bw/day) in the diet for 90 days. No adverse effects on body weight, clinical laboratory parameters, organ weights or gross or microscopic findings were observed. There was a slight decrease in food consumption in the 10 and 25% (approximately 5000 and 12,500 mg/kg-bw/day) groups. Based on the results the NOEL was 2500 mg/kg-bw/day.

When fed to male weanling Sprague-Dawley rats for 4 weeks as 15% of total caloric intake, tall oil fatty acids were non-toxic. At 30 and 60% of total caloric intake, a growth-retarding or toxic effect was reported. Similarly, growth was reduced in rats fed tall oil fatty acids for approximately 40 days at 6% of their diet by mass, which equals to 15% of the total calories (CIR, 1989).

Taking into account the results of the Two-Generation Reproduction Toxicity study also perfomed with tall oil fatty acids (s. Toxicity for reproduction), in which no adverse effects were observed in animals orally exposed to doses up to ca. 4000-5000 mg/kg bw/day, the available information indicates a very low level of toxicity for fatty acids, C16-C18 and C18 unsaturated, branched and linear after repeated oral exposure.

Therefore, based on the weight of evidence, the oral NOAEL in rats was considered to be in the range of 4000-5000 mg/kg bw/day.

 

Dermal

There are no studies available in which potential toxic effects after long-term dermal exposure have been studied. However, the whole body of evidence on the toxicokinetic behaviour and toxicological activity of fatty acids, C16-C18 and C18 unsaturated, branched and linear and/or structurally related compounds indicate that both systemic bioavailability and toxic effects are unlikely to occur upon dermal exposure.

 

Inhalation

There are no data available.

Due to their physicochemical properties (low vapour pressure), exposure to fatty acids, C16-C18 and C18 unsaturated, branched and linear via inhaltion is unlikely.

Potential inhalation exposure to aerosols of formulations intended for spray applications is expected to be low and without concern of any health hazard under normal conditions of use (s. CSR Chapter 9 and 10).

Justification for classification or non-classification

Based on read-across from a supporting substance (structural analogue) within a category approach, the available information on the repeated dose toxicity of fatty acids, C16-18 and C18-unsaturated, branched and linear is conclusive but not sufficient for classification.