Dibenzyl ether

Endpoint summary

Description of key information

Based on the physicochemical data, the metabolism simulator of the OECD QSAR Toolbox Vers 3.2 and analogy observations with chemically related ether compounds, an assumption for the toxicokinetik and metabolism of dibenzylether was generated.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Additional information

Dibenzyl ether

(CAS-No. 103-50-4)

Information/Assumptions Regarding Toxicokinetics and metabolism

Toxicokinetic:

The toxicokinetic behaviour and metabolism of dibenzy ether can be assumed based on available physicochemistry- and toxicological data. ADME assumptions will be discussed within this statement and the criteria outlined in the “Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance” will be applied throughout this statement. Compound specific data are taken from the dibenzyl ether IUCLID Dossier 2015 if not otherwise indicated.

Dibenzyl ether is a colourless liquid with a boiling point of 298 °C by ambient atmospheric pressure. The vapour pressure of dibenzylether is 0.00137 hPa at 25°C.

Dibenzyl ether is moderately soluble in water (42 mg/l at 20°C at pH 6.1). The molecular mass of 198.3 g/mol and the n-octanol/water coefficient (log Pow of 3.31) suggest favourable intestinal absorption subsequent to oral ingestion. This assumption is supported by acute oral toxicity studies. In an acute oral toxicity study rats received by gavage 0.64, 1.6, 2.5, 4 and 6.4 ml dibenzyl ether/kg bw and were observed during a post-observation period of 14 days. Signs of reaction to treatment observed shortly after dosing included pilo-erection, abnormal body carriage (hunched posture) and abnormal gait (waddling). Pilo-erection was also observed in controls animals. Lowest dosed rats exhibited lethargy, increased salivation and decreased respiratory rates increasing with test materials concentrations. Diuresis and diarrhoea was observed in high dosed rats. Ataxia, loss of righting reflex, fine body tremors and ptosis were observed amongst treated rats. Three rats appeared in a comatose like condition.

Bodyweight of rats treated at 4 ml/kg bw exhibited signs of depressed body weight gains during first week but returned normal afterwards. All other surviving treated rats gained bodyweight similarly to controls rats.

Autopsy revealed congestion and hemorrhage of the lungs, pallor of the liver, kidneys and spleen. Opacity of the eyes was observed. Terminal autopsies of sacrificed animals returned normal. The calculated LD50 was 3.7 ml/kg bw (3.86 mg/kg bw).

In another study a LD50 = 4807 mg/kg bw was found. As clinical signs a bad general condition was stated.

In a subchronic toxicity study dibenzyl ether was given in the diet to rats at a rate of 62, 196 or 620 mg/kg/day for 91 consecutive days. Body weights and food consumption were measured weekly; haematological, clinical chemistry and urinalysis values were obtained at wk 6 and 12. Gross and microscopic pathological changes were observed and organ weights recorded. The high-dose females had increased absolute and relative liver weights; this was considered to be related to dose. Other statistically significant events that occurred sporadically within the test groups were unrelated to dose and were considered to be normal adaptive change. No toxicological or pathological effects were noted at any of the dose levels after 91 consecutive days of feeding dibenzyl ether. The observations on liver weight at 620 mg/kg/day are not regarded as adverse based on the lack of histopathological correlates, the NOAEL was 620 mg/kg bw/day.

In relation to the NOAEL = 620 mg/kg bw/d, the acute LD50 is 3.86 mg/kg. Therefore the LD50 ( 3.86 mg/kg bw) is about six fold higher than the NOAEL (620 mg/kg bw/d). As during 91 day of application no toxicological or pathological effects were noted (with the exception of increased liver weight) a bioaccumulations is not evident.

Dibenzyl ether shows mild irritating properties on the skin and is a weak sensitizer. In an acute dermal study a LD50 for rabbits higher than 5.15 ml/kg bw after an exposure of 24 hours under occlusive conditions were found. Based on these results only a limited dermal absorption is assumed.

Metabolism:

QSAR:

The rat liver metabolism simulator of the QSAR toolbox Version 3.2 (structural formula see attached IUCLID document, Basic toxicokinetics, Schlecker, 2014) suggests 5 metabolites. The metabolites have one hydroxylgroup in meta or para position in one or both aromatic rings or two hydroxyl-groups in meta/para-position to the ether bound in one aromatic ring.

The autoxidation and hydrolysis simulator of the QSAR toolbox Version 3.2 proposes benzylalkohol, benzaldehyde and benzoic acid as metabolites (structural formula see attached IUCLID document, Basic toxicokinetics, Schlecker, 2014).

Analogy to structurally related ethers:

In the WHO Food Additives Series n° 52, the metabolism of aliphatic and aromatic ethers is discussed. According to this review, for biotransformation several metabolic options are available for aliphatic and aromatic ethers:

One pathway for aliphatic and aromatic ethers is O-dealkylation to form the corresponding aldehydes and alcohols, if a suitable alkyl substituent (methyl or ethyl) is attached to the ether oxygen. The resulting alcohols may be further oxidized and then conjugated and excreted, while the aldehydes (i.e. acetaldehyde and formaldehyde) are oxidized to carboxylic acids that participate in fundamental biochemical pathways, including the fatty acid pathway and tricarboxylic acid cycle. In a second pathway, the aliphatic acyclic or aromatic moiety may undergo CYP450-induced C-oxidation (ring hydroxylation) or side-chain oxidation, followed by conjugation with sulfate or glucuronic acid, and then excretion.

For dibenzylether an O-demethylation and ring hydroxylation is predicted in this WHO Food Additives Series.

This means, that benzoic acid or p-hydroxybenzoic acid can be assumed as main metabolites, because dibenzyl ether has an activated aliphatic methylene group between the aromatic ring system and the ether bound.

Experimental data for a structurally related ether:

The proposed metabolites correspond with the metabolism of di-(3,5-di-tert.-butyl-4-hydroxy-benzyl)ether (Ionox 201) in the rat (Wright AS et al. (1967)), the metabolism. This compound is a higher homologue of dibenzyl ether with 2 chemically stable tert.-butyl groups in m-position and a hydroxyl-group in para position in each aromatic ring, which is also present in dibenzyl ether after metabolic ring hydroxylation. The results of the study is as follows:

l. Up to one-third of a single oral dose (6.78 mg; 1,82 µC/mg in 1.0 ml olive oil by gavage) of Ionox 201 was absorbed in rats.

2. In rats dosed with (14C]Ionox 201 86.8-97.2% of the label is excreted in the faeces in 24 days (much of this is eliminated in the first 4 days after dosage), 5.6% in the urine and not more than 0.8% in the exhaled air; 5.0% of 14C is present in the carcass and viscera after removal of the gut, and most of this is in the fatty tissues.

3. About 65.0% of l4C in the faeces is due to unchanged antioxidant, 30.0% to 3,5-d.i-tert.butyl-4-hydroxy-benzoic acid, 3.5% to unidentified polar constituent(s), 1•4% to 3,5-d.i-tert.-butyl-4-hydroxybenzaldehyde and 0.1% to 3,3',5,5'-tetra-tert.-butyl-4-,4'-stilbenequinone. A variable proportion of 14C in the urine is due to 3,5-di-tert.-butyl-4-hydroxybenzoic acid (40-60%) and the remainder (60-40%) to the ester glucuronide, when the animals were treated with different doses of antioxidant.

In eight individual animals dosed with 6.78 mg of [14C]Ionox 201, one•third of 14C in the bile is due to the free acid, 45% to the ester glucuronide, 20% to an unidentified constituent and 2% to unchanged antioxidant, and, in two animals dosed with 13,56 mg, there is a small proportion of free acid and a larger proportion of ester glucuronide. About 80% of 14C in the body fat is due to unchanged antioxidant, 19% to the free acid and 1% to 3,5-di-tert.-butyl-4-hydroxybenzaldehyde. 4. At least 36.2% of a single oral dose of Ionox 201 is metabolized:

3,5-di-tert.-butyl-4-hydroxybenzoic acid accounts for 30.2% of a dose, (3,5-di-tert.-butyl-4-hydroxybenzoyl ß-n-glucopyranosid)uronic acid for 1.4%, 3,5-di-tert.-butyl-4-hydroxy-benzaldehyde for 1.3 %, 3,3',5,5' -tetra-tert.-butyl-4,4'-stilbenequinone for 0.1% and unidentified polar metabolite(s) for 3.2 %• 5. The metabolism of Ionox 201 in vivo is closely related to its antioxidant action in vitro.

The water solubility of di-(3,5-di-tert.-butyl-4-hydroxy-benzyl)ether is 0.00031 mg/l and the log Pow is 8.64 (predicted EPI-suite values). http://www.chemspider.com/Chemical-Structure.73389.html

Compared with di-(3,5-di-tert.-butyl-4-hydroxy-benzyl)ether the water solubility of dibenzyl ether is much higher and the log Pow much lower.

Therefore it is expected, that dibenzyl ether is absorbed to a higher extend from the gastro-intestinal tract and also excreted to a higher extend via the urine compared with di-(3,5-di-tert.-butyl-4-hydroxy-benzyl)ether. The accumulation in body fatty tissues is expected for dibenzyl ether to be lower in comparison with di-(3,5-di-tert.-butyl-4-hydroxy-benzyl)ether due to lower lipophilicity.

Synopsis:

Overall, the molecular structure of dibenzyl ether suggests that partly a ring hydroxylation occurs in phase I metabolism. Additionally, cleavage of the methylene ether (O-de-methylation) is predicted, followed to form the corresponding aldehydes and alcohols which are oxidized to benzoic acid or hydroxyl-benzoic acid. In phase II glucoronidation takes place.

The metabolites will be substantially more hydrophilic and rapidly cleared from systemic circulation by renal elimination.

The existing experimental data on repeated dose toxicity to not indicate bioaccumulation (no toxicological or pathological effects were noted at any of the dose levels after 91 consecutive days of feeding dibenzyl ether). Furthermore, effects observed in acute toxicity studies were found to be reversible at the end of the recovery period or at least show a clear tendency towards reversibility (body weight gain and terminal autopsies of sacrificed animals returned normal). Therefore, in spite of the favourable log Pow for absorption, there is no indication of an accumulation potential of dibenzyl ether from mammalian toxicity data.

References:

Wright AS, Crowne RS, Hathway DE, The metabolism of di-(3,5-di-tert.-butyl-4-hydroxy-benzyl)ether (Ionox 201) in the rat, Biochem J 102, 351-361 (1967)

WHO Food Additives Series n° 52: http://www.inchem.org/documents/jecfa/jecmono/v52je16.htm

Water solubility and log Pow:

http://www.chemspider.com/Chemical-Structure.73389.html