2-ethyl-3-hydroxy-4-pyrone

Endpoint summary

Description of key information

A toxicokinetic assessment was conducted in accordance with REACH Annex VIII 8.8.1. The substance Ethyl Maltol is a solid. It is an organic mono-constituent, with a purity of 99.5% to 100%, and a typical concentration of 99.9%

 

A full ADME toxicokinetic study in the rat is not available. The Joint FAO/WHO Expert Committee on Food Additives (JECFA) has indicated a metabolic pathway for Ethyl Maltol [1]. The toxicokinetic analysis is based on the expert opinion, in vivo animal models and physicochemical data. In vivo studies covering the oral route are available (acute,sub-chronicin the rat and dog, combined chronic toxicity/carcinogenicity and one generation study in the rat and dog) are available. There are no studies covering the inhalational route available. Further details on endpoints are available in the IUCLID 6 registration dossier.

 

Based on the available in vivo toxicological data, Ethyl Maltol is readily absorbed via the oral route; absorption via the dermal and inhalational routes is expected to be low. Ethyl Maltol will be distributed throughout the body. The JECFA expert opinion indicates that Ethyl Maltol

is predominantly metabolized to sulfate and glucuronic acid conjugates, which are then eliminated in the urine.

 

The absorption rates of 50% (oral), 50% (dermal) and 100% (inhalation) are accepted for chemical risk assessment purposes.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

1.     Physicochemical properties

 

In accordance with the ECHA Guidance on Information Requirements and Chemical Safety

Assessment, Chapter R.7C Section R.7.12 (Endpoint Specific Guidance), the physicochemical

properties can provide an insight into the potential behaviour of Ethyl Maltol in the body.

 

Absorption - oral

The molecular weight of Ethyl Maltol is 140.137 g/mol which is favourable for oral absorption (<500 g/mol). The log Kow (2.9 at 25°C) indicates it is lipophilic and the water solubility (9345.4 mg/L at 24℃) indicates it is soluble in water. These characteristics will facilitate transport of Ethyl Maltol via passive diffusion and oral absorption is expected to occur.

 

Absorption – dermal

The log Kow and water solubility of Ethyl Maltol are in the optimal range for dermal absorption though the molecular weight is above the favourable range (<100 g/mol). Some dermal absorption can be expected to occur.

 

Absorption – inhalation

The particle size distribution report for Ethyl Maltol indicated that 0.73% of particles are in the <100µm range, therefore it is considered to have no or low dustiness. As very few particles are available in the inhalable fractions of air (<100 μm), exposure via inhalation is expected to be negligible.

 

Distribution/Metabolism/Excretion

Based on the molecular weight, water solubility, log Kow and structure, Ethyl Maltol is likely to be widely distributed, and is expected to be metabolised and excreted in the urine.

 

2.     Other data in the literature

 

The JECFA [1] indicate that Ethyl Maltol is classified as a γ-pyrone. lt is a hydroxyl-substituted 4Hpyran-4-one and is expected be metabolized similarly to phenol, primarily undergoing phase II conjugation of the free hydroxy substituent.

 

3.     Information from other studies in the dossier

 

Absorption – oral

In an acute oral study (equivalent or similar to OECD 401), the rat LD50 was 1220 mg/kg bw.

 

In a combined chronic toxicity/carcinogenicity and one generation key study (Equivalent or similar to OECD 415, Ethyl Maltol was administered to 4 groups of Charles River male and female rats (25/sex/group) in the diet at dose levels of 0, 50, 100 and 200 mg/kg bw/day daily for 2 years. Between 15 and 21 and 30 and 36 weeks, 10 males and 10 females per level were mated to produce two separate litters. The offspring were killed at weaning. In the parental group, five of each sex were killed after 1 year and the remaining five of each sex at the end of the study. All dose levels of ethyl maltol were well tolerated throughout the 2-year feeding period. The test and control animals grew and maintained the body weight in a comparable manner. Pathologic changes consistent with aged rats were observed primarily in the pulmonary, endocrine, urinary, and cardiovascular systems. Neoplasia occurred in a random manner with no apparent relationship between number, location, or type of tumors and treatment. A fall in fertility was noted in test and control groups at the second mating but controls were affected also (60% conception at 200 mg/kg bw/day, 50% conception for controls). This was due presumably to the advanced age of the animals. Ethyl maltol had no effect on gestation, parturition or lactation. Ethyl maltol had no effect on fetal development and no gross internal abnormalities were noted. In the 1st F1 litter, at 0 mg/kg bw/day, the 21 day survival rate was 93%; at 200 mg/kg bw/day it was 92%. In the 2nd F1 litter, at 0 mg/kg bw/day, the 21 day survival rate was 49%; at 200 mg/kg bw/day it was 66%. There was no difference in the average weight of pups at 21 days lactation between controls and treated groups. The NOAEL (parental/offspring) was ≥200 mg/kg bw/day.

 

In a combined chronic toxicity/carcinogenicity and one generation study (Equivalent or similar to OECD 415, Ethyl Maltol was administered to 4 group Beagle male and female dogs (8/group) by capsule at dose levels of 0, 50, 100, 200 mg/kg bw/day 5 day/week for 2 years. Whenever females displayed signs of estrus, they were mated with a male from the same drug level group. Dosing was continuous and covered gestation, parturition, and lactation. The offspring were examined closely for signs abnormal development. Two dogs per dose were killed after 1 year on test, and the remaining animals after a total of 2 years; both groups were autopsied. No effects observed on parental clinical signs, mortality, body weight, food consumption, haematological, urinalysis, organ weight, gross pathological, histopathological (non-neoplastic) and histopathological (neoplastic). Single, slightly elevated SGPT values occurred in 4 dogs receiving 200 mg/kg/day. While breeding efforts were not remarkably successful, a total number of 15 normal pups were delivered by two bitches which had received ethyl maltol at the high and intermediate dose levels from 6 to 20 months before parturition. No adverse toxic, reproductive or embryogenic effects at doses up to and including 200 mg/kg bw/day were observed. The NOAEL (parental/offspring) was ≥200 mg/kg bw/day.  

 

In a subchronic repeated dose toxicity supporting study (Equivalent or similar to OECD 408), Ethyl Maltol was administered to 4 groups of Charles River male and female rats (10/sex/group) in the diet at dose levels of 0, 250, 500, 1000 mg/kg bw/day daily for 90 days. Body weight gains for female rats fed 500-1000 mg/kg bw/day, were slightly, but not significantly, less than those of comparable controls or the female group receiving 250 mg/kg bw/day. The same dose levels had no effect on male rat development. There were no effects observed on clinical chemistry and urinalysis parameters. At autopsy, all organ weights of treated rats compared favorably with those of controls and no gross pathologic changes were observed. Microscopically, kidney lesions were noted in the rats receiving 1000 mg/kg bw/day. The basic change was distinguished by an extremely dilated, acellular glomerular tuft with protein loss into Bowman’s space and cast formation within the lumina of dilated corticomedullary tubules. The NOAEL (male/female) was 500 mg/kg bw/day.  

 

In a subchronic repeated dose toxicity supporting study (Equivalent or similar to OECD 409), Ethyl Maltol was adminitered to 4 groups of male and female Beagle dogs (4/group, not distributed according to sex) by capsule at dose levels of 0, 125, 250, 500 mg/kg daily for 90 days.  No effects were observed on clinical signs, mortality, body weight, food consumption, ophthalmological, haematological, urinalysis and organ weight. No abnormalities observed in behaviour. At clinical biochemistry, all dogs receiving the highest dose of ethyl maltol showed elevated serum bilirubin levels at 30 days until termination. Two of the dogs receiving the lowest dose showed elevated serum bilirubin levels at 30 days which returned to normal at later timepoints. Microscopically, changes were noted in the livers of dogs receiving 250 mg/kg bw/day ethyl maltol. The change was distinguished by a few to moderate number of Kupffer cells containing hemosiderin with small amounts of intracellular bilirubin. At the 125 mg/kg bw/day level, a few to moderate number of hemosiderin-laden Kupffer cells, but no hepatocellular bilirubin, was observed.  As the observed abnormal cells were few to moderate, the change is considered adaptive. The NOAEL (male/female) was 250 mg/kg bw/day.

 

Based on the physicochemical data and available in vivo toxicological data, there is systemic absorption after oral administration. For chemical safety assessment purposes, an oral absorption rate of 50% is accepted.

 

Absorption – dermal

Ethyl Maltol is not a skin irritant or skin sensitiser. The ECHA guidance criteria (Chapter R.7C) state that 10% dermal absorption is used when the molecular weight of the substance is >500 and the log Pow is <-1 or >4, otherwise 100% dermal absorption is used. In general, dermal absorption will not be higher than oral absorption, so for chemical safety assessment purposes a dermal absorption rate of 50% is accepted.

 

Absorption – inhalation

There is no data on inhalation available. For chemical safety assessment purposes, an inhalation absorption rate of 100% is accepted, based on the most conservative approach.

 

Distribution/Metabolism/Excretion

Based on the expert opinion and available in vivo toxicological data, Ethyl Maltol will be distributed throughout the body. The JECFA indicate that as the γ-pyrone ring contains a 3-hydroxy substituent, it is expected that ethyl maltol will be readily conjugated with glucuronic acid or sulfate and excreted in the urine.

 

[1] JECFA (2006). Safety evaluation of certain food additives. Who Food Additives Series:56. Prepared by the Sixty fifth meeting of the Joint FAO/WHO Expert Committee on Food Additives (JECFA). World Health Organization, Geneva.