Fatty acids, tall-oil, manganese salts

Endpoint summary

Description of key information

An acute oral toxicity study is available with Fatty acids, tall-oil, manganese salts, resulting in a LD50 of >2000 mg/kg bw.

Acute dermal and inhalation toxicity are addressed with existing data on the dissociation products manganese and tallate. Signs of acute dermal toxicity are not expected for fatty acids, tall-oil, manganese salts, since the two assessment entities manganese and tallate do not show signs of acute dermal toxicity in experimental testing (both LD50 > 2000mg/kg).

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Reference

Endpoint:

acute toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

03 December 2021 - 20 December 2021

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)

GLP compliance:

yes (incl. QA statement)

Test type:

acute toxic class method

Limit test:

yes

Species:

rat

Strain:

Wistar

Remarks:

Han:WIST rats

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Toxi-Coop Zrt., H-1122 Budapest, Magyar Jakobinusok tere 4B
- Hygienic level at supplier: SPF
- Hygienic level during the study: Standard housing conditions
- Number of animals: 6 animals, 3 animals/group
- Sex: Female, nulliparous and non-pregnant animals
- Age of animals at dosing: Young adult rats, approx. 9-10 weeks old
- Body weight range at dosing: 178-198 g. The maximum difference of individual animal weights from the mean of the treatment group did not exceed 20%.
- Acclimatisation period: At least 16 days
- Animal health: Only healthy animals were used for the test. The health status was certified by the Veterinarian.
- Housing: Group caging (3 animals/cage)
- Cage type: T3H polycarbonate
- Bedding and nesting: “SAFE 3/4-S-FASERN” certified wooden chips and “Sizzle pet” nest material were available to animals during the study.
- Enrichment: Animals were housed by group to allow social interaction and with deep wood sawdust bedding to allow digging and other normal rodent activities.
- Animals received standard laboratory rat diet, ad libitum, and tap water from the municipal supply, as for human consumption from drinking bottles designed for rodents, ad libitum.
- The night before treatment, the animals were fasted. Food, but not water, was withheld overnight. Animals were weighed before dosing. Food was replaced 3 hours after the treatment.

ENVIRONMENTAL CONDITIONS
- Lighting period: 12 hours daily, from 6.00 a.m. to 6.00 p.m.
- Temperature: 20 – 23 °C (target: 22 ± 3 °C)
- Relative humidity: 38 – 61 % (target: 30 – 70 %)
- Ventilation: 15-20 air exchanges/hour

IN-LIFE DATES: From 03 December 2021 to 20 December 2021

Route of administration:

oral: gavage

Vehicle:

corn oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 200 mg/mL
- Amount of vehicle (if gavage): 10 mL/kg bw
- Justification for choice of vehicle: The crushed test item did not dissolve in distilled water, in 1% methyl cellulose solution, in PEG 400 and in DMSO, partially dissolved in corn oil at room temperature and also dissolved partially in corn oil after 4 hours stirring with magnetic stirrer heated at 35 °C. Because the best results were achieved in corn oil, a harsher mechanical treatment was chosen: the sonication of the crushed test item with corn oil resulted in a gavage applicable suspension.
- Lot/batch no.: MKCM9808
- Manufacturer: Sigma-Aldrich
- Expiry date: 30 April 2026

DOSAGE PREPARATION: The test item was freshly formulated in the vehicle at the appropriate concentration (200 mg/mL), in the Pharmacy of NEXTREAT Laboratories on the day of administration. Appropriate amount (2g) of test item was weighed in, filled up to a volume of 10mL with the vehicle and was sonicated using the Bandelin Sonoplus MD 3100, equipped with a 2mm diameter MS-72 microtip, for 30 min, with 50% power, 30 sec pulse and 30 sec pause sequence. The sample tube was placed in a water bath keeping the sample below of a maximal temperature of 50 C. The formulation was stirred with a vortex before treatment.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: As starting dose level for acute toxicity study, a dose of 2000 mg/kg body weight (bw) has been selected based on the information published by ECHA on tall oil and Manganese.
- Initially three animals were treated at the starting dose of 2000 mg/kg bw (Group 1). As no mortality was observed in this group, a confirmatory group (Group 2) was treated at the same dose level. No mortality was observed in this confirmatory dose group, therefore no further testing was required according to the criteria for termination given in Annex 2d of OECD Guideline No. 423.

Doses:

2000 mg/kg bw

No. of animals per sex per dose:

6 (3 animals per group)

Control animals:

no

Details on study design:

- Duration of observation period following administration: 14 days
- Clinical observations: Following the end of the dosage, the animals were observed individually once during the first 30 minutes, at 1, 2, 3, 4 and 6 hours after the treatment and once daily for 14 consecutive days thereafter. Individual observations were performed on the skin and fur, eyes and mucous membranes and also respiratory, circulatory, autonomic and central nervous system, somatomotor activity and behaviour pattern. Particular attention was directed to observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma. The time of death was recorded as precisely as possible.
- Body weight: The body weight of the animals was recorded on Days 0 (prior to dosing), 7 and 14 (prior to necropsy), with a precision of 1 g.
- Necropsy: Animals were subjected to a necropsy and a macroscopic examination. After examination of the external appearance, the cranial, thoracic and abdominal cavities were opened and the appearance of the tissues and organs were observed. All gross macroscopic changes were recorded for each animal.

Statistics:

The method used was not intended to allow the calculation of a precise LD50 value.

Key result

Sex:

female

Dose descriptor:

LD50

Effect level:

>= 2 000 mg/kg bw

Based on:

test mat.

Remarks on result:

not determinable due to absence of adverse toxic effects

Mortality:

Fatty acids, tall-oil, manganese salts did not cause mortality at 2000 mg/kg bw.

Clinical signs:

other:

Body weight:

lower than 10% body weight loss

Remarks:

There were no effects on body weight or body weight gain that could be attributed to treatment with the test item.

Gross pathology:

There were no macroscopic changes seen at necropsy.

Interpretation of results:

GHS criteria not met

Remarks:

The test substance is not classified according to Regulation (EC) No 1272/2008 (CLP)

Conclusions:

Under the conditions of this study, the acute oral LD50 value of the test item Fatty acids, tall-oil, manganese salts was found to be above 2000 mg/kg bw in female Han:WIST rats.
The study result triggers the following classification/labelling:
- Regulation (EC) No 1272/2008 (CLP): Unclassified
- GHS (rev. 7) 2017: Unclassified

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

LD50

Value:

> 2 000 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Acute toxicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

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.

 

Acute toxicity

An acute oral toxicity study is available with Fatty acids, tall-oil, manganese salts. Acute dermal and inhalation toxicity will be addressed with existing data on the dissociation products as detailed in the table below. Further details on the acute toxicity of the individual constituents within the framework of regulation (EC) 1907/2006 are given below.

 

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

	Manganese ion	Fatty acids, tall-oil	Fatty acids, tall-oil, manganese salts (CAS# 8030-70-4)
Acute oral toxicity	LD50(rat)= 642 mg/kg bw	LD50 >2000 mg/kg bw	LD50 > 2000 mg/kg bw (measured) LD50 1650 mg/kg bw (predicted)
Acute inhalation toxicity	LC50(rat)> 1.62 mg/L		waived, since the substance is used and placed on the market in a non-inhalable form
Acute dermal toxicity	waived	LD50 >2000 mg/kg bw	LD50 >2000 mg/kg bw (calculated)

 

Under the assumption that the constituents of Fatty acids, tall-oil, manganese salts show their toxicological profile individually upon dissolution and dissociation, the acute oral toxicity of Fatty acids, tall-oil, manganese salts can be calculated using the equation given in regulation (EC) 1272/2008, Annex I, Section 3.1.3.6.1. The calculated oral LD50 for Fatty acids, tall-oil, manganese salts is 1650 mg/kg. In an experimental acute oral toxicity study with Fatty acids, tall-oil, manganese salts according to the OECD 423 guideline, no mortalities were however observed at a dose of 2000 mg/kg bw, hence the substance is not to be classified according to regulation (EC) 1272/2008 for acute oral toxicity as well as for specific target organ toxicity, single exposure (STOT SE). Because the predicted LD50 based on data for the two transformation products is well below the measured acute oral LD50 for Fatty acids, tall-oil, manganese salts, it can be concluded that read-across for the two transformation products together with the additivity approach to predict the (eco)toxicological effects of the target substance is conservative and no synergistic effects are expected between the transformation products.

 

Conduct of an acute dermal toxicity study is unjustified as the physicochemical properties of the manganese cation do not suggest a significant rate of absorption through the skin. Further the LD50 for the fatty acids is above 2000 mg/kg bw, hence does not require a classification for acute dermal toxicity. Based on the above given information Fatty acids, tall-oil, manganese salts is not expected to show any acute toxic effects via dermal route (cf. Annex VIII section 8.5 Column 2 of regulation (EC) 1907/2006).

 

For further information on the toxicity of the individual constituents, please refer to the relevant sections in the IUCLID and CSR.

 

Manganese

Acute toxicity: oral

Acute toxicity was determined in male and female Wistar rats. The lowest LD50 -value was 642 mg Mn/kg.

 

Acute toxicity: dermal

Classification for the acute dermal toxicity is not considered necessary as the substance is not classified for acute oral toxicity and absorption through the skin is likely to be less than oral.

 

 

Tallate

Acute oral:

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.

 

According to the HERA document on fatty acid salts “the available data for fatty acids provide a clear picture of low acute toxicity for this class of chemicals. All oral LD50values were greater than 2,000 mg/kg, with little mortality being observed even at the highest doses tested in the studies (IUCLID, 2000c, 2000e, 2000f, 2000g; Clayton & Clayton, 1982; CIR, 1987). The available data for the fatty acid salts also indicate that these are of low acute toxicity. For example, an acute oral LD50value of >5,000 mg/kg (highest dose tested) has been reported for sodium soap. This test was done according to GLP and OECD Guideline 401 (IUCLID, 2000f), while in another study also done to GLP and according to Directive 84/449/EEC, B.1, an LD50value of >2,000 mg/kg (highest dose tested) was reported for fatty acids, C16-18 and C18-unstad., sodium salts (IUCLID, 2000f)” (HERA, 2002).

“In an OECD TG 401 study, a group of five rats/sex was administered octadecanoic acid (as a 50% suspension in DMSO) at a dose of 5000 mg/kg bw. There was one death. Animals exhibited transient piloerection, excessive salivation, and diminished activity. At necropsy, the male animal that died exhibited a stomach full of test substance; surviving animals showed remnants of test substance in the stomach with swelling of the mucous membrane. The LD50 was > 5000 mg/kg bw” (OECD SIDS, 2014).

“International-BioResearch (1974, as referred to by CIR, 1987) determined the acute oral toxicity in groups of five male albino rats. Animals were administered by gavage lauric-, myristic-, palmitic- or stearic acid with increasing doses of up to 10,000 mg/kg bw and oleic acid up to 20,000 mg/kg bw. It was observed that for all these fatty acids the LD50value was above the maximum level tested. No mortality was observed in five albino rats gavaged with 5 g/kg bw oleic acid (commercially supplied); clinical signs were not reported during the 7-day post-exposure period (CTFA, 1978, as referred to in CIR, 1987)” (EFSA NDA Panel, 2017).

“Any toxic effects, such as excessive salivation, diarrhoea, central nervous system depression, loss of reflex actions or coma, shown at higher doses, decrease in severity with an increase in the chain length of the fatty acid (Pi-Sunyer et al., 1969). These reported effects are a result of the high doses administered and the fact that unlike humans rats don’t have a vomiting reflex. Therefore, these high dose effects are not considered relevant for human exposure” (HERA, 2002).

 

Acute dermal:

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 HERA document on fatty acids salts concluded that “the available acute dermal toxicity data for the fatty acids (and their salts) provide a clear picture of low acute toxicity for this group of chemicals. All dermal LD50values were greater than >2,000 mg/kg (BIBRA, 1996; IUCLID, 2000e; Clayton & Clayton, 1982; CIR, 1982, 1987). In a dermal study in which concentrations of sodium stearate (C18) ranged between 10-25% in a 20% bath soap detergent form, the LD50was >3000 mg/kg (highest dose tested) (CIR, 1982). In a dermal study in guinea pigs, application of commercial grade oleic acid (3,000 mg/kg) produced no deaths and no signs of toxicity. The number of applications was not stated (CIR, 1987)” (HERA, 2002).

Acute toxicity of an abundantly available essential nutrient for animals and humans such as stearic acid would be grossly implausible and can therefore safely be excluded. Classification is not warranted.

 

Fatty acids, tall-oil, manganese salts

The measured oral LD50 for fatty acids, tall-oil, manganese salts is >2000 mg/kg bw.

 

Acute dermal toxicity is not expected to occur with fatty acids, tall-oil, manganese salts due to its poor percutaneous absorption and the lack of systemic acute toxicity as obtained in acute oral toxicity studies:

In the absence of measured data on dermal absorption, current guidance suggests the assignment of either 10 % or 100 % default dermal absorption rates. In contrast, the currently available scientific evidence on dermal absorption of metals yields substantially lower figures, which can be summarised briefly as follows:

Measured dermal absorption values for metals or metal compounds in studies corresponding to the most recent OECD test guidelines are typically 1 % or even less. Therefore, the use of a 10 % default absorption factor is not scientifically supported for metals. This is corroborated by conclusions from previous EU risk assessments (Ni, Cd, Zn) and current metal risk assessments under REACH, which have derived dermal absorption rates of 2 % or far less (but with considerable methodical deviations from existing OECD methods) from liquid media.

However, considering that under industrial circumstances many applications involve handling of dry powders, substances and materials, and since dissolution is a key prerequisite for any percutaneous absorption, a factor 10 lower default absorption factor may be assigned to such “dry” scenarios where handling of the product does not entail use of aqueous or other liquid media. This approach was taken in the in the EU RA on zinc. A reasoning for this is described in detail elsewhere (Cherrie and Robertson, 1995), based on the argument that dermal uptake is dependent on the concentration of the material on the skin surface rather than it’s mass.

The following default dermal absorption factors for metal cations are therefore proposed (reflective of full-shift exposure, i.e. 8 hours):

From exposure to liquid/wet media: 1.0 %

From dry (dust) exposure: 0.1 %

This approach is consistent with the methodology proposed in HERAG guidance for metals (HERAG fact sheet - assessment of occupational dermal exposure and dermal absorption for metals and inorganic metal compounds; EBRC Consulting GmbH / Hannover /Germany; August 2007).

 

A study for acute toxicity via inhalation was not conducted with fatty acids, tall-oil, manganese salts, since it is produced and placed on the market in a form in which no inhalation hazard is anticipated, thus acute toxic effects are not likely to occur during manufacture and handling of that substance. For further information on the toxicity of the individual moieties, please refer to the relevant sections in the IUCLID and CSR.

 

The measured oral LD50 for fatty acids, tall-oil, manganese salts is >2000 mg/kg bw, hence the substance is not to be classified according to regulation (EC) 1272/2008 for acute oral and dermal toxicity as well as for specific target organ toxicity, single exposure (STOT SE).

 

Justification for classification or non-classification

The experimentally measured oral LD50 for Fatty acids, tall-oil, manganese salts is > 2000 mg/kg, hence the substance is not to be classified according to regulation (EC) 1272/2008 for acute oral toxicity as well as for specific target organ toxicity, single exposure (STOT SE).

Conduct of an acute dermal toxicity study is unjustified as the physicochemical properties of the manganese cation do not suggest a significant rate of absorption through the skin. Further the LD50 for the fatty acids is above 2000 mg/kg bw, hence does not require a classification for acute dermal toxicity. Based on the above given information Fatty acids, tall-oil, manganese salts is not expected to show any acute toxic effects via dermal route (cf. Annex VIII section 8.5 Column 2 of regulation (EC) 1907/2006).