Fatty acids, tall-oil, manganese salts

Endpoint summary

Description of key information

No repeated dose toxicity study with fatty acids, tall-oil, manganese salts is available, thus the repeated dose toxicity will be addressed with existing data on the individual moieties manganese and tallate.

Since naturally occurring fatty acids are void of any human health hazard potential, the hazard assessment will be derived based on the toxicological information for manganese.

Thus, due to adverse effects observed in long-term inhalation studies with manganese salts and considering the read-across principles for fatty acids, tall-oil, manganese salts based on the toxicological assessment of the individual moieties, it is therefore proposed to also read-across the classification of Specific target organ toxicity-repeated exposure, category 2 based on neurological effects (H373- brain, inhalation) of manganese sulphate to fatty acids, tall-oil, manganese salts.

Additional information

Read-across approach

Selected endpoints for the human health hazard assessment are addressed by read-across, using a combination of data on the metal cation and the organic acid anion. This way forward is acceptable, since metal carboxylates are shown to dissociate to the organic anion and the metal cation upon dissolution in aqueous media. No indications of complexation or masking of the metal ion through the organic acid were apparent during the water solubility and dissociation tests (please refer to the water solubility and dissociation in sections 4.8 and 4.21 of IUCLID). Once the individual transformation products of the metal carboxylate become bioavailable (i.e. in the acidic environment in the gastric passage or after phagocytosis by pulmonary macrophages), the “overall” toxicity of the dissociated metal carboxylate can be described by a combination of the toxicity of these transformation products, i.e. the metal cation and carboxylate anion according to an additivity approach.

Fatty acids, tall-oil, manganese salts is the manganese metal salt of fatty acids, tall-oil, which readily dissociates to the corresponding divalent manganese cation and tallate anions. The manganese cation and the tallate anions are considered to represent the overall toxicity of Fatty acids, tall-oil, manganese salts in a manner proportionate to the free acid and the metal (represented by one of its readily soluble salts). 

A detailed justification for the read-across approach is added as a separate document in section 13 of IUCLID.

 

Repeated dose toxicity

No repeated dose toxicity study with Fatty acids, tall-oil, manganese salts is available, thus the repeated dose toxicity will be addressed with existing data on the dissociation products manganese and fatty acids, tall-oil as detailed in the table below.

 

Table: Summary of repeated dose toxicity data of Fatty acids, tall-oil, manganese salts and the individual constituents.

	Manganese sulfate (CAS# 7785-87-7)	Fatty acids, tall-oil	Fatty acids, tall-oil, manganese salts (CAS# 8030-70-4)
Repeated dose oral toxicity	NOAEL(chronic, rat)=200 mg MnSO4/kg bw/day   NOAEL(chronic, rat)= 72.8 mg Mn/kg bw/day*	NOAEL >10,000 mg/kg bw/day	No data
Repeated dose inhalation toxicity	respirable IOELV= 0.05 mg/m³   inhalable IOELV=0.2 mg/m³   STOT RE 2 (H373), neurological effects	No data	No data   Self-classified STOT RE 2 (H373), neurological effects

* The registration dossier for manganese sulfate, the DNEL(dermal,systemic) was derived by route to route extrapolation form inhalation to dermal. This extrapolation is not justified, since (i) according to ECHA guidance R.8 preference should be given to experimental data in animals, instead of using occupational exposure limits as DNEL replacement, since this approach does not cover the extended exposure of the general population (ii) a relevant and reliable chronic repeated dose toxicity/carcinogenicity study in rats and mice is available for manganese sulfate (iii) the most sensitive endpoint for the inhalation route is neurotoxicity, which does not occur after oral or dermal exposure, hence the extrapolation from inhalation to the dermal route would be a serious overestimate of the underlying hazard. For the derivation of the DNEL(dermal, systemic), the NOAEL of 72.8 mg Mn/kg bw/day was used as point of departure.

 

Manganese

Oral data (information taken from IEH, 2004)

The effects of 13 weeks of dietary administration of manganese sulphate to F344/N rats (at 1600, 3130, 6250, 12500 or 25 000 ppm) and B6C3F1 mice (3130, 6250, 12 500, 25 000 or 50 000 ppm) have been reported by NTP (1993). In rats, inclusion levels equated to overall doses of 110 to 1700 mg/kg bw/day in males and 115 to 2000 mg/kg/day in females. Treatment was generally well tolerated in the rats although some reduction in weight gain (up to 11%) occurred in females at 6250 ppm or above. No clearly treatment-related changes in haematology or histopathology were noted. However, liver weight (absolute and relative to body weight) was reduced in males and females given 25 000 ppm, as was lung weight in treated female groups. In mice, achieved doses ranged from 330 to 7400 mg/kg bw/day in males and 390 to 6900 mg/kg/day in females. Although food intake was essentially unaffected, growth performance was impaired in all treated male groups, particularly at 50 000 ppm (65% reduction). Female mice at the highest level showed a 36% reduction in weight gain. Other effects in mice were limited to the 50 000 ppm group, where reduced liver weight was noted in males and changes suggestive of microcytic anaemia (i.e., reduced haematocrit, haemoglobin and mean erythrocytic volume) were noted for both sexes. At this level 3/10 males also showed epithelial hyperplasia and hyperkeratosis of the forestomach.

 

In addition to assessing the carcinogenicity of manganese sulphate, a 2-year study by the NTP provided detailed information on a range of non-neurological endpoints following long-term dietary exposure (NTP, 1993). In the study, F344/N rats and B6C3F1 mice were fed diets containing manganese sulphate at 1500, 5000 or 15 000 ppm for 2 years. Achieved dosages were, for rats, 60, 200 or 615 mg/kg bw/day in males and 70, 230 or 715 mg/kg/day in females and, for mice, 160, 540 or 1800 mg/kg/day in males and 200, 700 or 2250 mg/kg/day in females. Endpoints considered included survival, general signs of toxicity, growth performance, clinical pathology, metal content of some tissues, and pathology. In rats, reduced survival, associated with increased severity of nephropathy and renal failure, was noted in males given 15 000 ppm from week 93. Males of this group also showed a slightly (5%) lower body weight until week 80, after which the difference between treated and control animals increased to approximately 10%. Other treated rats were not thus affected, and the food intakes of all groups were similar. Hepatic iron levels were reduced at 9 and 15 months for rats given 5000 ppm or above, while renal copper levels were increased in males at 9 months and females at 9- and 15-months. Secondary to the increased nephropathy in high dose males, increased incidences of mineralisation of blood vessels and glandular stomach, parathyroid hyperplasia, and fibrous osteodystrophy were noted. A somewhat different picture was seen in the mice. Overall, despite similar food intakes, body weights were reduced by 6, 9 and 13% in female mice given 1500, 5000 or 15 000 ppm, respectively; males were not thus affected. Haematology and clinical chemistry were unaffected, although hepatic iron levels were lower at 9 and 15 months in females and at 15 months in males given 5000 or 15 000 ppm. Non-neoplastic effects of treatment were restricted to increased incidences of thyroid follicular dilatation and hyperplasia, in mice given 15 000 ppm, and of focal epithelial hyperplasia, in males given 15 000 ppm and all groups of treated females. The NOAEL for repeated dose toxicity was determined to be 5000 ppm MnSO4, corresponding to 200 mg/kg bw/day MnSO4 and 72.8 mg/kg bw/day Mn.

 

Inhalation data (information taken from SCOEL, 2011)

Because of the heterogeneity of the data (different types of industry, different manganese compounds and particle sizes, different study designs and different neurofunctional measurements), and the inherent limitations of every individual study, it is not possible to identify one single critical study that would be the best basis for setting the IOELVs. Some studies identified a LOAEL, other a NOAEL. Some studies relied on the respirable fraction; other on the inhalable or “total” (thoracic) fraction. A global approach using the most methodologically-sound studies, as used in the IEH Criteria document (2004) and a number of additional good quality studies published since this review was therefore considered to be the most robust and reliable approach. The studies by Roelset al. (1992), Gibbset al.(1999) Myerset al.2003b, Younget al. 2005, Bast-Pettersenet al.(2004) and Ellingsenet al.(2008) as well as Lucchiniet al.1999 in HC (2008) which showed adverse neurological effects and identified a point-of-departure (POD) in the dose-effect/response relationship may offer a basis for recommending an IOELV.

Thus, a reasonable respirable IOELV of 0.05 mg/m³ can be recommended, and a reasonable inhalable IOELV of 0.2 mg/m³ is also recommended. While recommending these values, SCOEL recognises that the overall systemic absorption of coarser particles (> respirable) is probably substantially lower than for the respirable fraction. Thus, SCOEL recommends both a respirable and an inhalable IOELV which would need to be observed conjointly.

 

Tallate

Oral route

According to Regulation (EC) No 1907/2006 Annex V substances obtained from natural sources and not modified such as vegetable fats and oils as well as fatty acids from C6 to C24 and their potassium, sodium, calcium and magnesium salts are excluded from the obligation to register.

The substance subjected to registration is a mixture of different saturated and unsaturated C16 -C18 fatty acids. Based on this, the following endpoint is covered by publicly available data on fatty acids with the same or similar structure.

 

The results of various in vivo studies clearly demonstrate that fatty acids are not toxic via the oral route. “Fitzhugh et al. (1960) fed lauric acid (C12) to five male rats at the 10% level of their diet for 18 weeks. A control group of 5 males was fed concurrently. There were no observable clinical effects, no adverse effects on weight gain, nor was there any mortality. Gross organ pathology and comparison of individual organ weights showed no significant differences between the controls and test animals. In a 24-week oral study, rats were fed doses of 15% oleic acid (C18) (approximately 7.5 g/kg body weight per day). Normal growth and general good health was reported in the rats and the NOAEL was reported to be >7,500 mg/kg body weight per day (IUCLID, 2000e). Caprenin, a randomised triglyceride primarily comprising caprylic (C8), capric (C10), and behenic (C22) acids, was administered in a semi-purified diet to weanling Sprague-Dawley rats (25/sex/group) at dose levels of 5.23, 10.23 or 15.00% (w/w) for 91 days. Corn oil was added at 8.96, 5.91 and 3.00%, respectively, to provide essential fatty acids and digestible fat calories. Survival, clinical signs, body weight, feed consumption, feed efficiency, organ weights, organ-to-body-weight ratios, organ-to-brain-weight ratios, haematological values and clinical chemistry parameters were evaluated in all groups. Histopathology of a full complement of tissues was evaluated in the control group as well as the high-dose caprenin group. No significant differences in body weight gain were measured with the balanced caloric diets, although feed conversion efficiency was reduced in the high-dose caprenin group. No adverse effects from the ingestion of caprenin were detected. The authors concluded that the results establish a no-observable-adverse-effect level (NOAEL) of more than 15% (w/w) caprenin in the diet (or more than 83% of total dietary fat), which is equal to a mean exposure level of more than 13.2 g/kg/day for male rats and more than 14.6 g/kg/day for female rats (Webb et al. 1993)” (HERA, 2002).

“Albino rats (10 animals of both sexes and mixed strain per group) were given a rice diet with 10% (equivalent to 9,000 mg/kg bw per day) capric-, lauric- or palmitic acid for a maximum of 150 days (Mori, 1953). Interim sacrifices were performed throughout the experiment and stomachs were examined for gross lesions. According to the author, no remarkable changes were detected in the forestomach or glandular stomach” (EFSA NDA Panel, 2017).

 

Dermal route

According to Regulation (EC) No 1907/2006 Annex V substances obtained from natural sources and not modified such as vegetable fats and oils as well as fatty acids from C6 to C24 and their potassium, sodium, calcium and magnesium salts are excluded from the obligation to register.

The substance subjected to registration is a mixture of different saturated and unsaturated C16 -C18 fatty acids. Based on this, the following endpoint is covered by publicly available data on fatty acids with the same or similar structure.

 

“In a subchronic study, no adverse effects were produced from topical application of myristic acid (C14) to rabbit skin. One-half ml of a 30% preparation of myristic acid in ether and propylene glycol (solvents at a 1:1 ratio in concentration) was massaged into the depilated skin of the flanks of 5 rabbits daily for 30 days. The opposite flank of the rabbits was depilated and treated with solvent only. No significant macroscopic changes were observed. Microscopic lesions included thinning of collagen fibres in the superficial layer of the dermis after 10 days and a loose dermal infiltrate of lymphomononuclear cells and histocytes after 20 and 30 days (CIR, 1987). A formulation “bath soap and detergent” containing 10-25% sodium stearate (C18) was used to conduct a dermal toxicity study in rabbits. Formulations at a dose of 2.0 g/kg were applied for 3 months to the skin by syringe daily, five days a week. No “untoward reactions” were observed (CIR, 1982)” (HERA, 2002).

The available data demonstrate the low toxicity of fatty acids and their salts, which is consistent with their long history of safe use in foods and the fact that many of the fatty acids are listed as GRAS.

 

Fatty acids, tall-oil, manganese salts

Since no repeated dose toxicity study is available specifically for Fatty acids, tall-oil, manganese salts, information on the individual moieties manganese and tallate will be used for the hazard assessment and when applicable for the risk characterisation of Fatty acids, tall-oil, manganese salts. For the purpose of hazard assessment of Fatty acids, tall-oil, manganese salts, the point of departure for the most sensitive endpoint of each moiety will be used for the DNEL derivation. Since naturally occurring fatty acids are void of any human health hazard potential, the hazard assessment will be derived based on the toxicological information for manganese. In case of manganese in fatty acids, tall-oil, manganese salts, the NOAEL of 72.8 mg Mn/kg bw/day obtained in a repeated dose toxicity study will be used.

Justification for classification or non-classification

Since naturally occurring fatty acids are void of any human health hazard potential, the hazard assessment will be derived based on the toxicological information for manganese. Thus, due to adverse effects observed in long-term inhalation studies and considering the read-across principles for fatty acids, tall-oil, manganese salts based on the toxicological assessment of the individual moieties, it is therefore proposed to also read-across the classification of Specific target organ toxicity-repeated exposure, category 2 based on neurological effects (H373- brain, inhalation) of manganese sulphate to Fatty acids, tall-oil, manganese salts.