Registration Dossier

Administrative data

Description of key information

Based on a weight of evidence approach, all available acute oral toxicity studies within this category resulted in acute oral LD50 in rats greater than 2000 mg/kg bw.
The LC50 for 111-82-0 was found to be > 5 mg/L air.
No acute dermal toxicity studies were available.

Key value for chemical safety assessment

Acute toxicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

The short chain fatty acid methyl esters category (SCAE Me) covers fatty acid esters of methanol. The category contains both mono-constituent substances, with fatty acid C-chain lengths ranging from C6 to C18 and UVCB substances, composed of single methyl esters in variable proportions. Fatty acid esters are generally produced by chemical reaction of an alcohol (methanol) with an organic acid (e.g. octanoic acid) in the presence of an acid catalyst (Radzi et al., 2005). The esterification reaction is started by a transfer of a proton from the acid catalyst to the alcohol to form an alkyloxonium ion. Acid is protonated on its carbonyl oxygen followed by a nucleophilic addition of a molecule of the alcohol to a carbonyl carbon of acid. An intermediate product is formed. This intermediate product loses a water molecule and proton to give an ester (Liu et al, 2006; Lilja et al., 2005; Gubicza et al., 2000; Zhao, 2000). Monoesters are the final products of esterification.

SCAE Me esters category members include:

Mono-constituent substances:

* Hexanoic acid, methyl ester (CAS No.): 106-70-7 - (MW 130.19)

* Octanoic acid, methyl ester (CAS No.): 111-11-5 - (MW 158.24)

* Decanoic acid, methyl ester (CAS No.): 110-42-9 - (MW 186.29)

* Dodecanoic acid, methyl ester (CAS No.): 111-82-0 - (MW 214.35)

* Tetradecanoic acid, methyl ester (CAS No.): 124-10-7 - (MW 242.40)

* Hexadecanoic acid, methyl ester (CAS No.): 112-39-0 - (MW 270.46)

* Octadecanoic acid, methyl ester (CAS No.): 112-61-8 - (MW 298.51)

* 9-Octadecenoic acid (Z)-, methyl ester (CAS No.): 112-62-9 - (MW 294.48)

* 9, 12-Octadecadienoic acid (Z, Z)-, methyl ester (CAS No.): 112-63-0 - (MW 294.48)

* Hexadecanoic acid (CAS No.): 57-10-3 - (MW 256.43).

UVCB´s:

* Fatty acids, C6-10, methyl esters (CAS No.): 68937-83-7 - (MW 130.19-186.29)

* Fatty acids, C8-10, methyl esters (CAS No.): 85566-26-3 - (MW 158.24-186.29)

* Fatty acids, C10-16, methyl esters (CAS No.): 67762-40-7 - (MW 186.29-270.46)

* Fatty acids, C12-14 (even numbered), methyl esters (CAS No.): 308065-15-8 - (MW 214.35-242.40)

* Fatty acids, C8-18 and C18-unsatd., methyl ester (CAS No.): 67762-37-2 - (MW 158.24-298.51)

* Fatty acids, C12-18, methyl esters (CAS No.): 68937-84-8 - (MW 214.35-298.51)

* Fatty acids, 12-16 and C18-unsatd., methyl esters (CAS No.): 1234694-02-0 - (MW 214.35-298.51)

* Fatty acids, C16-18, methyl esters (CAS No.): 85586-21-6 - (MW 270.46-298.51)

* Fatty acids, palm-oil, methyl esters (CAS No.): 91051-34-2 - (MW 242.40-298.51)

* Fatty acids, C16-18 and C18-unsatd, methyl esters (CAS No.): 67762-38-3 - (MW -270.46-298.51)

* Fatty acids, C14-18 and C16-18-unsatd., methyl esters (CAS No.): 67762-26-9 - (MW 130.19–290.51)

* Fatty acids, coco, Me esters (CAS No.): 61788-59-8 - (MW 214.35-270.46)

* Fatty acids, tallow, Me esters (CAS No.): 61788-61-2 - (MW 242.40-298.51).

In accordance with Article 13 (1) of Regulation (EC) No. 1907/2006, “information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met. In particular, for environmental fate and ecotoxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structural related substances (grouping or read-across)”.

In this particular case, the similarity of the SCAE Me category members is justified in accordance with the specifications listed in Regulation (EC) No 1907/2006, Annex XI, 1.5. The key points the members of the category members share are:

* Common origin:Fatty acid esters (C6-C18) of methanol

* Common precursors and the likelihood of common breakdown products:Fatty acid methyl esters are hydrolysed to the corresponding alcohol (methanol) and fatty acid by esterases (Fukami and Yokoi, 2012), even though it was shown in-vitro that the hydrolysis rate of methyl oleate was lower when compared with the hydrolysis rate of the triglyceride Glycerol trioleate (Mattson and Volpenhein, 1972). Depending on the route of exposure, esterase-catalysed hydrolysis takes place at different places in the organism: After oral ingestion, esters of methanol and fatty acids will undergo chemical changes already in the gastro-intestinal fluids as a result of enzymatic hydrolysis. In contrast, substances that are absorbed through the pulmonary alveolar membrane or through the skin enter the systemic circulation directly before entering the liver where hydrolysis will basically take place. The first cleavage product, the fatty acid, is stepwise degraded by beta-Oxidation based on enzymatic removal of C2 units in the matrix of the mitochondria in most vertebrate tissues. The C2 units are cleaved as acyl-CoA, the entry molecule for the citric acid cycle. For the complete catabolism of unsaturated fatty acids such as oleic acid, an additional isomerization reaction step is required (see figure below). The alpha- and omega-oxidation, alternative pathways for oxidation, can be found in the liver and the brain, respectively (CIR, 1987). For the second cleavage product methanol, the metabolism is predominating: Initially, methanol is slowly oxidized in the liver by the enzyme alcohol dehydrogenase (ADH) to formaldehyde, which itself is oxidized very rapidly by the enzyme aldehyde dehydrogenase (ALDH) to formic acid. Finally, formic acid is slowly metabolised to CO2and H2O (ICPS, 2002).

* Consistent trends in physico-chemical properties:Water solubility values of the category members tend to decrease at increasing fatty acid C-chain lengths, ranging from 1330 mg/L (C6) to 0.0003 mg/L for C18, whereas partition coefficient values, as expected, increase at increasing C-chain lengths (ranging from 2.3 for C6 to 8.3 for C18). Adsorption to soil and sediment particles is a relevant property for substances containing C8 fatty acids onwards (log Kow > 3). Only the substance with the shortest fatty acid chain length (C6) is considered to have low adsorption potential (log Kow = 2.3). Vapour pressure decreases at increasing chain lengths (ranging from 496 Pa (C6) to 0.00018 Pa (C18) at 25°C). In view of the values reported for C6, C8 (71.9 Pa) and C10 (4.9 Pa), at least partial volatilization of substances containing these fatty acids can be expected. Due to their structural similarities, all category members show consistent trends and therefore, a regular pattern in their physico-chemical properties. Therefore, in accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.5, these substances may be considered as a category.

* Consistent trends in environmental fate and ecotoxicological profile:The members of the SCAE Me category are readily biodegradable and show low bioaccumulation potential in biota (due to metabolism). The water solubility of the mono-constituent substances within the category decreases at increasing C-chain lengths with a turning point from water soluble to insoluble observed at C14 (water solubility 0.05 mg/L). For the substances containing C6, C8, C10 and C12 fatty acids, water solubilities of 1330 mg/L, 64.4 mg/L, 10.6 mg/L and 7.76 mg/L have been reported respectively. Substances containing C-chain lengths > C14 are insoluble in water, including all UVCB substances within the category (water solubilities < 1 mg/L). Nevertheless, regardless the main environmental compartment of concern (water, soil, sediment) the SCAE Me´s will not be persistent in the environment considering their readily biodegradable nature.Regarding the aquatic toxicity profile in the category, no acute toxicity to fish species is observed. On the other hand, the short-term tests conducted with aquatic invertebrates (Daphnia) and algae for the mono-constituent substances show a toxicity trend. The toxicity increases at increasing C-chain length (starting from C8) up to a toxicity peak at C12 (for which L(E)C50s and NOECs < 1 mg/L have been reported). With decreasing water solubility at longer C-chain lengths (C14), no toxicity up to the highest attainable concentration is observed in Daphnia and algae. For the UVCBs, in those cases where toxicity data are not available, structurally related read-across substances are used in accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.5: either mono-constituent substances (considering the predominant fatty acid chain lengths in the UVCB) or other analogue UVCBs.

Due to the structural similarities and consistent trend in physico-chemical properties and available data on acute toxicity, the members of the SCAE Me category can be considered as a category of substances, according to Regulation (EC) No. 1907/2006, Annex XI, 1.5. A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Section 13) as well as in the Chemical Safety Report (see Part B).

References:

* CIR (1987). Final report on the safety assessment of oleic acid, lauric acid, palmitic acid, myristic acid, stearic acid. J. of the Am. Coll. of Toxicol.6 (3): 321-401.

* Fukami, T. and Yokoi, T. (2012). The Emerging Role of Human Esterases. Drug Metabolism and Pharmacokinetics, Advance publication July 17th, 2012.

* Gubicza, L. et al. (2000). Large-scale enzymatic production of natural flavour esters in organic solvent with continuous water removal. Journal of Biotechnology 84(2): 193-196

* International Programme on Chemical Safety, ICPS (2002). Poisons Information Monograph 335, Methanol. http://www.inchem.org/documents/pims/chemical/pim335.htm

* Lilja, J. et al. (2005). Esterification of propanoic acid with ethanol, 1-propanol and butanol over a heterogeneous fiber catalyst. Chemical Engineering Journal, 115(1-2): 1-12

* Liu, Y. et al. (2006). A comparison of the esterification of acetic acid with methanol using heterogeneous versus homogeneous acid catalysis. Journal of Catalysis 242: 278-286

* Mattson, F.H. and Volpenhein, R.A. (1972). Hydrolysis of fully esterified alcohols containing from one to eight hydroxyl groups by the lipolytic enzymes of the rat pancreatic juice. Journal of lipid research 13: 325-328

* Radzi, S.M. et al. (2005). High performance enzymatic synthesis of oleyl oleate using immobilised lipase from Candida antartica. Electronic Journal of Biotechnology 8: 292-298

* Zhao, Z. (2000). Synthesis of butyl propionate using novel aluminophosphate molecular sieve as catalyst. Journal of Molecular Catalysis 154(1-2): 131-135.

Acute toxicity

 

CAS #,

Carbon range

Acute Oral

Acute Inhalation

Acute Dermal

106-70-7

(C6)

Experimental result: LD50 rat > 2 g/kg

RA from 111-82-0: LC50 > 5mg/L

Not required (waiving)

111-11-5

(C8)

Experimental result: LD50 rat > 2 g/kg

RA from 111-82-0: LC50 > 5mg/L

Not required (waiving)

110-42-9

(C10)

RA from 111-11-5: LD 50 rat > 2 g/kg

RA from 111-82-0: LC50 > 5mg/L

Not required (waiving)

111-82-0

(C12)

Experimental result: LD50 rat > 2 g/kg

Experimental result: 4 h LC50 rat > 5 mg/L (aerosol)

Not required (waiving)

124-10-7

(C14)

RA from 111-82-0: LD50 rat > 2 g/kg

RA from 111-82-0: LC50 > 5mg/L

Not required (waiving)

112-39-0

(C16)

Experimental result: LD50 rat > 2 g/kg

RA from 111-82-0: LC50 > 5mg/L

Not required (waiving)

112-61-8

(C18)

Experimental result: LD50 rat > 2 g/kg

RA from 111-82-0: LC50 > 5mg/L

Not required (waiving)

112-63-0

(C18’’)

Experimental result: LD50 rat > 2 g/kg

Not to be registered

Not to be registered

112-62-9

(C18’)

RA from 91051-34-2: LD50 rat > 5 g/kg

RA from 111-82-0: LC50 > 5mg/L

Not required (waiving)

85566-26-3

(C8-C10)

RA from 111-11-5: LD50 rat > 2g/kg

RA from 111-82-0: LC50 > 5mg/L

Not required (waiving)

67762-40-7

(C10-C16)

RA from 111-82-0:

LD50 rat > 2g/kg

RA from 111-82-0: LC50 > 5mg/L

Not required (waiving)

308065-15-8

(C12-C14)

RA from 111-82-0 and 112-39-0:

LD50 rat > 2g/kg

RA from 111-82-0: LC50 > 5mg/L

Not required (waiving)

68937-83-7

(C6-C10)

Not to be registered

Not to be registered

Not to be registered

67762-37-2

(C8-C18, C18uns)

Not to be registered

Not to be registered

Not to be registered

68937-84-8

(C12-C18)

RA from 112-61-8:

LD50 rat > 2 g/kg

RA from 111-82-0: LC50 > 5mg/L

Not required (waiving)

1234694-02-0

(C12-C16, C18uns)

RA from 112-61-8, 111-82-0 and 112-63-0:

LD50 rat > 2 g/kg

RA from 111-82-0: LC50 > 5mg/L

Not required (waiving)

85586-21-6(C16-C18)

RA from 112-61-8 and 112-39-0: LD50 rat > 2 g/kg

RA from 111-82-0: LC50 > 5mg/L

Not required (waiving)

91051-34-2

(C14-C18, C18uns) 

Experimental result: LD50 rat > 5 g/kg

RA from 111-82-0: LC50 > 5mg/L

Not required (waiving)

67762-38-3

(C16-C18, C18uns)

RA from 91051-34-2: LD50 rat > 5 g/kg

RA from 111-82-0: LC50 > 5mg/L

Not required (waiving)

67762-26-9

(C14-C18, C18uns)

Experimental result: LD50 rat > 2g/kg

Not to be registered

Not to be registered

61788-59-8

(C12-C16)

Experimental result: LD50 rat > 5 g/kg

Not to be registered

Not to be registered

 

 

Acute oral toxicity

Since no studies investigating the acute oral toxicity of fatty acids, C16-18, methyl esters (CAS 85586-21-6) are available, in accordance to Regulation (EC) No. 1907/2006 Annex XI, 1.5 a read-across to the structurally related category members methyl octanoate (CAS 111-11-5), decanoic acid, methyl ester (CAS 110-42-9), methyl laurate (CAS 111-82-0), methyl palmitate (CAS 112-39-0), methyl hexanoate (CAS 106-70-7), methyl stearate (CAS 112-61-8), fatty acids, coco, methyl esters, C8 -18 (CAS 61788-59-8), fatty acids, C14-18 and C16-18-unsatd., methyl esters (CAS 67762-26-9) and methyl linoleate (CAS 112-63-0) was conducted.

 

CAS 111-11-5

For methyl octanoate (CAS 111-11-5), an acute oral toxicity study according to EU Method B.1 (Potokar, 1988) is available. Groups of 5 male and 5 female Wistar rats received doses of 2000 mg methyl octanoate /kg bw in arachis oil by oral gavage. The animals were observed for 14 days. All animals survived. No signs of systemic toxicity were observed and no abnormalities during gross necropsy were seen. Thus, the acute oral LD 50 in rats was determined to be greater than 2000 mg/kg bw.

 

CAS 110-42-9

For decanoic acid, methyl ester (CAS 110-42-9), a study similar to OECD guideline 401 (Michael, 1965) is available. 10 rats were orally exposed to a single dose of 14,000 mg/kg bw by gavage. The animals were observed for 14 days. No mortality occurred during the study period. Slight gasping, salivation, abdominal griping, diarrhea and decrease in motor activity were reported during the first day following dosing. The oral LD 50 in rats was determined to be greater than 14,000 mg/kg bw.

 

CAS 111-82-0

Two reliable studies investigating the acute toxicity via the oral route ofmethyl laurateare available (CAS 111-82-0). An acute oral toxicity study was performed with methyl laurate (CAS 111-82-0) according to OECD Guideline 401 (Sterzel, 1990). Groups of 5 male and 5 female Wistar rats received doses of 2000 mg methyl laurate /kg bw in arachis oil by oral gavage. The animals were observed for 14 days. All animals survived. No signs of systemic toxicity occurred. With exception for one female animal with a strong hydrometra no abnormalities were observed during gross necropsy. Thus, the acute oral LD 50 in rats was determined to be greater than 2000 mg/kg bw.

In another study methyl laurate (CAS 111-82-0) was administered to groups of 5 male and 5 female Sprague-Dawley rats at a dose of 20,000 mg/kg bw by oral gavage (Bjorkquist, 1982). The animals were observed for 14 days. All animals survived. Diarrhoea occurred in 4m/4f (male/female) and 3m/3f animals at days 1 and 2 after dosing. No other clinical signs of systemic toxicity were observed. In this study the acute oral LD50 in rats was determined to be greater than 20 g/kg bw. 

 

CAS 112-39-0

An acute oral toxicity study is available for methyl palmitate (CAS 112-39-0) according to OECD Guideline 401 (Pittermann, 1992). Groups of 5 male and 5 female Wistar rats received doses of 2000 mg methyl palmitate /kg bw in arachis oil by oral gavage. The animals were observed for 14 days. All animals survived. No signs of systemic toxicity were observed and no abnormalities during gross necropsy were seen. Under the conditions used in this study, it was concluded that the test substance has no toxic effect when administered to the rat at a level of 2000 mg/kg bw. The acute oral LD50 for methyl palmitate in male and female rats was determined to be greater than 2000 mg/kg bw.

 

CAS 106-70-7

For methyl hexanoate (CAS No. 106-70-7), an acute oral toxicity study according to OECD Guideline 401 under GLP conditions is available (Pittermann, 1992). Groups of 5 male and 5 female Wistar rats received doses of 2000 mg methyl hexanoate/kg bw in water by oral gavage. The animals were observed for 14 days. All animals survived. During the observation period no signs of systemic toxicity occurred and no abnormalities during gross necropsy were seen. Thus, the acute oral LD 50 for methyl hexanoate in rats was determined to be greater than 2000 mg/kg bw.

 

CAS 112-61-8

Another acute oral toxicity study is available for methyl stearate (CAS No. 112-61-8) according to OECD Guideline 401 (Pittermann, 1992). Groups of 5 male and 5 female Wistar rats received doses of 2000 mg methyl stearate /kg bw in arachis oil by oral gavage. The animals were observed for 14 days. All animals survived. No signs of systemic toxicity were observed and no abnormalities during gross necropsy were seen. The acute oral LD50 for methyl stearate in rats was determined to be greater than 2000 mg/kg bw.

 

CAS 61788-59-8

Fatty acids, coco, Methyl esters (C8 -18, CAS No. 61788 -59 -8) has been tested in an acute oral toxicity study according to EU Method B.1 (Kästner, 1981). Groups of 5 male and 5 female Wistar rats received doses of 5000 mg Fatty acids, coco, Me esters / kg bw in water by oral gavage. The animals were observed for 14 days. All animals survived. During the observation period no signs of systemic toxicity occurred and no abnormalities during gross necropsy except for a slightly reddened gastric mucosa of female animals were seen. Thus, the acute oral LD 50 in rats was determined to be greater than 5000 mg/kg bw.

 

CAS 67762-26-9

For fatty acids, C14-18 and C16-18-unsatd., Methyl esters (CAS No. 67762-26-9) an acute oral toxicity study is available according to EU Method B.1 (Potokar, 1988). Groups of 5 male and 5 female Wistar rats received doses of 2000 mg /kg bw in arachis oil by oral gavage. The animals were observed for 14 days. All animals survived. During the observation period no signs of systemic toxicity occurred and no abnormalities during gross necropsy were seen. Thus, the acute oral LD 50 for Fatty acids, C14-18 and C16-18-unsatd., Methyl esters in male and female Wistar rats was determined to be greater than 2000 mg/kg bw.

 

CAS 112-63-0

An acute oral toxicity study with methyl linoleate (CAS No. 112-63-0) according to OECD Guideline 401 is available (Pittermann, 1992). Groups of 5 male and 5 female Wistar rats received doses of 2000 mg methyl linoleate/kg bw in arachis oil by oral gavage. The animals were observed for 14 days. All animals survived. During the observation period no signs of systemic toxicity occurred and no abnormalities during gross necropsy were seen. Thus, the acute oral LD 50 for methyl linoleate in male and female rats was determined to be greater than 2000 mg/kg bw.

 

 

Acute inhalation toxicity

Since no studies investigating the acute inhalation toxicity of fatty acids, C16-18, methyl esters (CAS 85586-21-6) are available, in accordance to Regulation (EC) No. 1907/2006 Annex XI, 1.5 a read-across to the structurally related category member methyl laurate (CAS 111-82-0) was conducted.

 

CAS 111-82-0

An acute inhalation toxicity study was performed with methyl laurate (CAS No. 111 -82 -0) according to OECD guideline 436 (Huygevoort, 2010). Three Crl:WI (Han) rats per sex wereexposed(head/nose only) to an aerosol of the test material with an actual concentration of 5.6 ± 0.5 mg/L air (nominal concentration was 7.1 mg/L) for a exposure duration of four hours. No mortality occurred. Lethargy, hunched posture and/or laboured respiration were noted among all animals at 1 hour after exposure, with hunched posture persisting until Day 2 after exposure. No clinical signs were noted during exposure. Body weight gain in males and females were within the range expected for rats of this strain and age used in this type of study. No abnormalities were found at macroscopic post mortem examination of the animals. Thus, the LC 50 after acute inhalation of methyl laurate in male and female rats was found to be greater than 5.6 mg/l air.

 

 

Acute dermal toxicity

Reliable studies on the acute dermal toxicity are not available for the members of the SCAE methyl esters. Testing via dermal route is not necessary as dermal uptake of the category members is negligible due to Dermwin v2.0 QSAR predictions and appropriate data for oral and inhalation route is available.

 

 

Based on a weight of evidence approach, no classification for acute toxicity for all substances within the fatty acid methyl esters category is required.

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met.

Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint".

Since the group concept is applied to the members of the SCAE Me category, data will be generated from a representative category member to avoid unnecessary animal testing. Additionally, once the group concept is applied, substances will be classified and labelled on this basis.

The available data on acute toxicity of Fatty acids, C16-18, methyl esters is conclusive but not sufficient for classification.