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Description of key information

Studies on oral repeated dose toxicity were available for the following Category members (CAS No.): 
73398-61-5, 8001-79-4, 91845 -19-1 and for medium- and long-chain triglyceride mixtures.
All available studies resulted in oral NOAELs of 1000 mg/kg bw/d or greater than 1000 mg/kg bw/d.
Studies on dermal repeated dose toxicity were available for the following Category member (CAS No.): 73398-61-5.
A subacute (28 days) dermal NOAEL of 2000 mg/kg bw/d for rabbits was reported.

Key value for chemical safety assessment

Additional information

The available studies on oral and dermal repeated dose toxicity support the view that Fatty Acid Glycerides are inherently harmless, non-toxic substances:

 

Subchronic repeated dose toxicity oral:

 

A 90 day oral feeding study with Castor oil (CAS No. 8001 -79 -4) was performed equivalent to OECD Guideline 408 in F344/N rats and B6C3F1 mice (Irwin, NTP report 1992). The test substance was mixed at concentrations of 0, 0.62, 1.25, 2.50, 5.00, 10.0 % (w/w) to the diet and the animals were fed ad libitum for 13 weeks. 10 animals per sex and per dose were used. The highest dose was equivalent to approx. 5.7 g/kg/day for rats and approx. 15 g/kg/day for mice. Exposure to castor oil at dietary concentrations as high as 10% in 13-week studies did not affect survival or body weight gains of rats or mice. There were no biologically significant effects noted in hematologic analyses in rats. Mild increases in total bile acids and in serum alkaline phosphatase were noted at various times during the studies in rats receiving the higher dietary concentrations of castor oil. Liver weights were increased in male rats receiving the 10% dietary concentration and in male and female mice receiving diets containing 5% or 10% castor oil. However, there were no histopathologic lesions associated with these liver changes, nor were there any compound-related morphologic changes in any organ in rats or mice. No significant changes were noted in a screening for male reproductive endpoints, including sperm count and motility, and no changes were observed in the length of oestrous cycles of rats or mice given diets containing castor oil. Thus, no significant adverse effects of castor oil administration were noted in these studies. A NOAEL of 5000 mg/kg bw/day for rats and a NOAEL of 15000 mg/kg bw/day for mice could be identified.

 

A 90 day oral feeding study with medium chain triglycerides was performed similar to OECD Guideline 409 in adult beagle dogs (Matulka, 2009). The medium chain triglycerides (MCTs) were comprised of a glycerol backbone esterified to medium chain length (8–12 carbon) fatty acids (FA) and, were all saturated FA. All dogs received on 91 consecutive days approximately 200 g of conventional feed with 0%, 5%, 10%, or 15% MCT for a three hour feeding regimen (4 animals per dose). Based on examination of clinical signs, body weight measurements, food consumption level, physical examinations, haematology and serum chemistry, ophthalmic examinations, and urinalysis the NOAEL for medium chain triglycerides was found to be greater than 15 % , which was calculated to be approximately 3750 mg/kg/day.

   

A 90d oral feeding study (Klimmer, 1971) was performed in young Wistar rats with mixed decanoyl and octanoyl glycerides (CAS No. 73398 -61 -5). The test substance was mixed to the diet at concentrations of 10,000 and 50,000 ppm. 20 animals per dose were fed ad libitum. No treatment-related abnormalities were observed concerning clinical signs, body weight increase, food consumption, haematology, clinical chemistry, urine analysis and gross pathology. Thus, the NOAEL was found to be 5000 mg/kg bw/day assuming 1 ppm in food being equivalent to 0.1 mg/kg bw/ day for young rats.

 

A 56 day oral feeding study with medium- and long-chain triglycerides was performed in Wistar rats (Matsuo, 2004). The effects of structured medium- and long-chain triacylglycerols (MLCT) in diets containing 50, 100, 150 or 200 g test substance/kg bw on body fat accumulation were compared with those of long-chain triacylglycerols (LCT). The diets were fed to groups of 6 young adult male Wistar rats for 56 days. Based on clinical observations, body weight, food efficiency, liver weights and clinical serum chemistry the NOAEL for rats was found to be 20 g/kg bw.

 

Subacute repeated dose toxicity oral:

 

A 28 day oral gavage study was performed according to 79/831/EWG, Annex V, Part B in male and female Sprague-Dawley rats (10 animals per dose) with C16 -18 and C18 mono- and dihydroxy fatty acid glycerides (CAS No. 91845 -19-1) at concentrations of 0, 100, 500 and 1000 mg/kg bw (Potokar, 1985). The test substance was administered once a day on 5 days per week using peanut oil as a vehicle. A post-exposure recovery satellite group of 5 male and 5 female animals was observed for an additional period of 33 days. Histopathologic evaluation revealed dilatation of lymphatic vessels in the small intestine stroma and the occurrence of foreign body giant cells and vacuolization in Peyer Plaques without signs of inflammation. These findings were observed at 500 and 1000 mg/kg/d and were considered to be adaptive responses, not adverse effects. No other treatment-related abnormalities were observed. The NOAEL was found to be 1000 mg/kg bw/day in male and female rats.

 

A 28-day oral gavage screening study (van Otterdijk, 2010) was performed with Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates (CAS 91052-13-0) according to OECD guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction /Developmental Toxicity Screening Test) in Crl:WI(Han) (outbred, SPF-Quality) Wistar Han rats. Doses of 0, 100, 300 and 1000 mg/kg bw/d were given to groups of four Main groups of 10 male and 5 female rats. Additionally, 5 Recovery group males and females in the control and high dose group were allowed 14 days of recovery. Additionally, 10 females were added to each group for the assessment of reproduction and developmental toxicity. Recovery animals were exposed for at least 28 days from start of treatment up to termination or start of recovery. Females used for the assessment of reproduction/developmental toxicity were exposed for 41-49 days, i.e. during 2 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation.

No treatment related abnormalities were found based on clinical signs, functional observations, body weights, food consumption, clinical pathology, macroscopy, organ weights, and histopathology examinations. Thus a 28 -day oral repeated dose NOAEL of 1000 mg/kg bw/d (highest dose tested) was found in Wistar rats.

 

Structural analogue read-across from Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates (CAS No. 91052-13-0) for systemic mammalian toxicity endpoints was judged to be justified for the following reasons: This read across substance is also a glyceride, containing mainly C12-14 fatty acid and actetate moiety as well as glycerol. It’s an organic liquid with a pour point of -8 °C and a melting point of 357.85 °C and a vapour pressure < 0.01 Pa at room temperature. In contrast to the glycerides of the fatty acid glyceride category, it has a higher water solubility of 8.75 mg/L, which might influence its environmental distribution, but not the mammalian metabolism upon systemic uptake. Therefore it is expected to feed into the same mammalian physiological pathways as the members of the fatty acid glyceride category, like citric acid cycle, sugar synthesis and lipid synthesis. These processes are described in detail within the category justification.

 

A 30 day oral gavage study was performed with Glycerides, mixed decanoyl and octanoyl (CAS No. 73398 -61 -5) in male Wistar rats (Klimmer, 1971). Groups of 10 animals received daily doses of up to approx. 10 g/kg bw/d. No treatment related abnormalities were observed based on clinical signs, body weight increase, food consumption, urine analysis and gross pathology at any dose level. No other parameters were analyzed. Based on the study results, a subacute NOAEL of 10000 mg/kg bw/d was found for male Wistar rats.

 

A 28 day safety evaluation of a medium- and long-chain triacylglycerol (MLCT) oil - placebo-controlled, double blind - human clinical trial study was performed utilizing 10 test subjects per group (Matulka, 2006). The test subjects were healthy men and women at the age range o 21–39 years. The study food (bread) containing either LCT (i.e., mixed rapeseed and soybean oils (7:3) as a control) or MLCT was consumed during the morning, afternoon, and evening meals. The amount of oil consumed via the bread source was calculated at 42 g per day. Food consumption was targeted at an average daily intake of 2100–2600 kcal and 70–80 g of fat. Monitoring of body weight, blood analysis and urinalysis revealed no significant differences between or within LCT and MLCT groups. No adverse effects of MLCTs were observed in humans when ingested at a dose of 42 g/day for 4 weeks.

 

Repeated dose toxicity dermal:

A subchronic dermal repeated dose toxicity study was performed with glycerides, mixed decanoyl and octanoyl (CAS No. 73398 -61 -5) in female rats (reviewed by Elder, 1980). A perfumed skin softener formulation containing 4% Caprylic/Capric Triglyceride was applied to the shaved skin of 15 female rats at a dose of 2 mL/kg five days per week for 13 weeks, equivalent to 75 mg/kg bw/d. This treatment had no effects on the body weight, clinical appearance or behaviour. All blood-cell and serum chemistry parameters measured one week before termination of the study were within normal limits and comparable to those seen in an equal group at controls. At necropsy, organ weights and gross finding revealed no effects of the test substance, and no histopathological changes were observed. There were no localized effects on the skin. Based on this study results the subchronic dermal NOAEL for female rats was found to be 75 mg/kg bw/d (highest dose tested).

 

An additional study with a tanning butter formulation containing 22% Caprylic/Capric Triglyceride (CAS No. 73398 -61 -5) was applied to the clipped backs of three male and three female New Zealand stain albino rabbits at a dose of 2000 mg/kg five times per week for 28 days (reviewed by Elder, 1980). Throughout the test, no effects attributable to the treatment were noted on body weight, physical appearance and behaviour. Blood samples taken 23 days after initiation of the test showed no effects on haematocrit, haemoglobin concentration, cell counts, urea nitrogen, alkaline phosphatase or glutamic pyruvic transaminase activites, or glucose concentration. At the end of the test, no systemic, gross or histopathologic changes referable to the test material were observed. On the treated area of the skin there was slight to moderate erythema and slight peeling and cracking regardless of whether the skin was abraded or left intact. Based on the study results a sub-acute (28-day) dermal NOAEL of 2000 mg/kg bw/d was found for male and female rabbits.

 

Repeated dose toxicity inhalation:

Repeated dose toxicity inhalation studies were not available.

For the following reasons the inhalation route was judged to be of minor relevance:

- For liquid fatty acid glycerides with a vapour pressure at room temperature < 0.01 Pa exposure to vapour can be excluded.

- For waxy solid fatty acid glycerides inhalation exposure seems very unlikely.

- Fatty acid glycerides with melting temperatures below 55ºC are commonly presented in pellet, flake, block or paste form.

- Fatty acid glycerides with melting temperatures above 55ºC may be turned into powder using conventional spray-cooling technology

- The particle size of powdered fatty acid glycerides is not a function of chemical composition, but is determined by the spray-cooling conditions.

- For the majority of industrial applications powders with mean particle size (D(0.5)) above 150µm are preferred.

- Powders with mean particle size (D(0.5)) down to 40µm can be produced for special applications (mainly for use as food additives).

- For standard and coarse powders with mean particle size above 150µm the proportion of respirable dust (powder with particle size below 10µm is negligible.

- For fine powders the proportion of respirable dust is below 5.5% and is not considered to be significant.

- Fatty acid glycerides are not corrosive and are readily hydrolysed in the body by ubiquitously expressed lipases. The likelihood of persistence in the lungs is considered to be negligible.

- The potential risk to human health due to respirable dust in fine powders produced for special applications is very low.

   

Additional toxicological information (see 7.12):

 

In 1975, the FDA - Select Committee on GRAS Substances (SCOGS) summarized their opinion on the GRAS status of Glycerin and Glycerides (FDA, 1975): There was no evidence in the available information on mono- and diglycerides of fat-formaing fatty acids that demonstrates or suggests reasonable grounds to suspect a hazard to the public when they are used at levels that are now current or that might reasonably be expected in the future. Further, there was no evidence in the available information on acetooleins and acetostearins that demonstrates or suggests reasonable grounds to suspect a hazard to the public when they are used at levels that are now current or that might reasonably be expected in the future.

 

According to Annex I of theEU Directive No 95/2/ECon food additives other than colours and sweeteners, Mono- and diglycerides of fatty acids (E471) is listed as "Food Additive generally permitted for use in foodstuffs not referred to in article 2 (3)". Substances on this list may be added to all foodstuffs with the exception of those referred to in Article 2 (3) following thequantum satisprinciple. According to Annex II of this directive the maximum level of E 471 in non-emulsified oils and fats of animal or vegetable origin (except virgin oils and olive oils) is 10 g/L.

According to Annex VI of this directive the maximum level for the use of E 471 as "Food additive permitted in infant formulae for infants in good health" is 4g/L.

 

Pursuant to 21 CFR § 170.3, medium- and long-chain triacylglycerol (MLCT)-Oil has been determined generally recognized as safe (GRAS) by scientific procedures for its intended conditions of use (FDA, 2006). The safety of MLCT-Oil is supported by preclinical and clinical studies, and the fact that medium-chain triacylglycerols have been administered to patients withmalabsorption syndromes, added to infant formulations, and consumed in the diet from natural sources, while long-chain triacylglycerols contained in vegetable oils have been commonly consumed in the human diet. MLCT-Oil (containing approximately 12% MCFA) manufactured via transesterification from LCT (from vegetable oils such as rapeseed oil) and MCT (from coconut and/or palm kernel oil) to produce a novel food product, was granted “Food for Specified Health Use” (FOSHU) status by the Ministry of Health, Labor, and Welfare inon December 6, 2002. FOSHU is defined as a food that has beneficial, effective ingredients added to help in the maintenance of a healthy body condition.

 

 

Justification for classification or non-classification

According to DSD (67/548/EEC) or CLP (1272/2008/EC) classification criteria for repeated dose toxicity, no classification is required.