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Description of key information

Ethylene Brassylate is bioavailable via oral route. Limited systemic absorption via inhalation and dermal route is anticipated. The substance will cross cellular barriers or will be distributed into fatty tissues. Ethylene Brassylate is expected to undergo hydrolysis and to be mainly excreted in urine. 

Key value for chemical safety assessment

Bioaccumulation potential:
low bioaccumulation potential

Additional information

There is no specific requirement to generate toxicokinetic information in REACH. Therefore, the toxicokinetic profile of Ethylene Brassylate (i.e. absorption, distribution, metabolism and elimination) was derived from the relevant available information. The physical chemical characteristics of the substance, the results obtained from acute and repeated-dose toxicity studies, as well as information gained from genotoxicity assays were used to predict the toxicokinetic behaviour of Ethylene Brassylate.

Physico chemical characteristics:

Ethylene Brassylate is a liquid substance having a relatively low molecular weight of 270.37 g/mol. The substance is slightly water soluble (14.8 mg/L), highly lipophilic based on the octanol/water partition coefficient (log Kow = 4.3) and not volatile according to its vapour pressure (0.017 Pa at 20°C).

Absorption:

The physical chemical characteristics described above suggest that Ethylene Brassylate is of adequate molecular size to participate in endogenous absorption mechanisms within the mammalian gastrointestinal tract. Being lipophilic, Ethylene Brassylate may be expected to cross gastrointestinal epithelial barriers even if the absorption may be limited by the inability of the substance to dissolve into gastro-intestinal fluids and hence make contact with the mucosal surface. Moreover, the absorption will be enhanced if Ethylene Brassylate undergoes micellular solubilisation by bile salts. Substances absorbed as micelles will enter the circulation via the lymphatic system, bypassing the liver. In an acute oral gavage study, one death and clinical signs of toxicity such as lethargy were observed at 5000 mg/kg bw. However, no significantly adverse effects were observed at the highest practicable & biologically-relevant concentration (i.e. 1000 mg/kg bw/day) in a 90-day a 28-day repeated dose and the prenatal developmental toxicity studies performed on read-across substances using the oral route (gavage). In the 90-day study, effects observed in the kidney of high-dose male rats were consistent with well-documented sex and species-specific responses to the administration of hydrocarbons. The lack of significant adverse findings following repeated oral dosing may be due to limited gastrointestinal absorption of the test material and/or its metabolites, or due to a very low inherent toxicity of Ethylene Brassylate. However, the observation of systemic effects, even if of very low toxicological concern, indicates the oral bioavailability of Ethylene Brassylate and/or its metabolites.

Regarding the dermal absorption, Ethylene Brassylate being lipophilic (log Kow = 4.3), the rate of uptake into the stratum corneum is expected to be high while the rate of penetration is likely to be limited by the rate of transfer between the stratum corneum and the epidermis. Moreover, it is assumed that the dermal uptake is also limited by the slight water solubility of Ethylene Brassylate. These assumptions are supported by the absence of systemic effects following single-dose dermal application of Ethylene Brassylate up to 5000 mg/kg bw which would suggest a limited systemic absorption through cutaneous barriers. Moreover, enhanced skin penetration is not expected since Ethylene Brassylate is not a skin irritant or corrosive.

The potential for inhalation toxicity was not evaluated in vivo. However, the vapour pressure of Ethylene Brassylate (0.017 Pa at 20°C) indicated an absence of volatility and therefore no exposure by inhalation is anticipated. Thus, at ambient temperature, no respiratory absorption is expected under normal use and handling of the substance

Distribution:

Systemic distribution of Ethylene Brassylate can be predicted from its physical chemical characteristics. Considering that the substance is highly lipophilic (log Pow >4) and slightly water soluble, it is suggested that, upon systemic absorption, Ethylene Brassylate may be transported through the circulatory system in association with a carrier molecule such as a lipoprotein or other macromolecule. Afterwards, based on its lipophilic character, the substance will readily cross cellular barriers or will be distributed into fatty tissues with a low potential to accumulate.

Metabolism:

The WHO International Programme on Chemical Safety has made a safety evaluation of certain food additives and contaminants. This report describes the likely metabolic route for various aliphatic primary alcohols, aldehydes, carboxylic acids, acetals, and esters containing additional oxygenated functional groups, including Ethylene Brassylate. Esters or diesters are expected to undergo hydrolysis to their corresponding alcohol, which would be further metabolized. Hydrolysis of Ethylene Brassylate is expected to occur in most tissues but predominantly in the intestinal tract, blood and liver and is catalysed by carboxylesterases or esterases. The presence of a second oxygenated functional group has little if any effect on hydrolysis of these esters. This report indicates that hydrolysis of the cyclic diester Ethylene Brassylate would be expected to occur on the basis of the hydrolysis of structurally related lactones like omega-6-hexadecenlactone. In simulated intestinal fluid, omega-6-hexadecenlactone underwent nearly complete hydrolysis (92%) to its open-chain form within 15 minutes.

Elimination:

Ethylene Brassylate having a molecular weight lower than 300, it is expected to be mainly excreted in urine and no more than 5-10% may be excreted in bile. Any substance that is not absorbed from the gastro-intestinal tract, following oral ingestion, will be excreted in the faeces. Following dermal exposure, highly lipophilic substances, such as Ethylene Brassylate, that have penetrated the stratum corneum but not penetrated the viable epidermis may be sloughed off with skin cells.

Reference:

- JECFA (2000) ALIPHATIC PRIMARY ALCOHOLS, ALDEHYDES, CARBOXYLIC ACIDS, ACETALS, AND ESTERS CONTAINING ADDITIONAL OXYGENATED FUNCTIONAL GROUPS. WHO food additives series 44.

Justification for Read-Across of Toxicity data from Globalide/Habanolide (reaction mass of: (E)-oxacyclohexadec-12-en-2-one (E)-oxacyclohexadec-13-en-2-one a) (Z)-oxacyclohexadec-(12)-en-2-one and b) (Z)-oxacyclohexadec-(13)-en-2-one; EC 422-320-3; CAS 111879 -80 -2) and 1,4-dioxacyclohexadecane-5,16-dione (EC 259-423-6; CAS 54982 -83 -1) to Ethylene Brassylate.

Hypothesis for the analogue approach:

This report addresses the use of a read-across by analogue approach on:

- Globalide/Habanolide, to fill the sub-chronic repeated dose toxicity data gap of Ethylene brassylate

- 1,4-dioxacyclohexadecane-5,16-dione, to fill the sub-acute repeated dose toxicity data gap of Ethylene brassylate

- Globalide/Habanolide, to fill the pre-natal developmental toxicity data gap of Ethylene brassylate.

This read across is based on the hypothesis that source and target substances have similar toxicological properties because they have structural similarity and are anticipated to follow the same metabolism pathway. This prediction is supported by common physico-chemical and toxicological data on the three substances.

Target substance and source substance:

Ethylene Brassylate (EINECS 203-347-8) is considered the target substance and Globalide/Habanolide & 1,4-dioxacyclohexadecane-5,16-dione are the source substances. All three compounds are cyclic esters (macrocyclic musks) containing long chains in the ring, Ethylene brassylate and 1,4-dioxacyclohexadecane-5,16-dione contains two ester groups whereas Globalide/Habanolide contains one ester-group.

Therefore, the source and the target substances share structural similarities with common functional groups, esters, and chains in the ring having the same length.

 

Target substance

Source substance 1

Source substance 2

Chemical name

1,4-dioxacycloheptadecane-5,17-dione

Reaction mass of: (E)-oxacyclohexadec-12-en-2-one (E)-oxacyclohexadec-13-en-2-one a) (Z)-oxacyclohexadec-(12)-en-2-one and b) (Z)-oxacyclohexadec-(13)-en-2-one

1,4-dioxacyclohexadecane-5,16-dione

Common name

Ethylene Brassylate

Globalide/Habanolide

1,4-dioxacyclohexadecane-5,16-dione

EC number

203-347-8

422-320-3

259-423-6

CAS number

105-95-3

111879-80-2

54982-83-1

Formula

C15H26O4

C15H26O2

C14H24O4

Table 1

Purity / Impurities:

Macrocyclic musks are typically very pure (> 95%) and it is not expected that any of the impurities will affect the physico-chemical parameters, environmental fate, ecotoxicological and toxicological properties. Therefore, it is concluded that the impurities will not affect the read-across.

Analogue approach justification:

Empirical structure similarity between Ethylene brassylate and Globalide/Habanolide / 1,4-dioxacyclohexadecane-5,16-dione:

Globalide/Habanolide is a cyclic aliphatic ester, Ethylene brassylate and 1,4-dioxacyclohexadecane-5,16-dione are cyclic aliphatic di-esters. All three compounds have a similar molecular weight (see Table 2) and have a structural similarity (see Attachment).

Toxicokinetic aspects:

Common name

Ethylene Brassylate

Globalide/Habanolide

1,4-dioxacyclohexadecane-5,16-dione

Molecular weight

270.37

238.4

256.3

Log Kow

4.3

5.5

3.65

Water solubility

14.8 mg/L

1.2 mg/L

75 mg/L (20°C)

Vapour pressure

0.017 Pa (20°C)

0.039 Pa (20°C)

0.028 Pa (25°C)

Table 2

The physico-chemical properties relating to toxicokinetics of Ethylene Brassylate, Globalide/Habanolide and 1,4-dioxacyclohexadecane-5,16-dione are relatively similar. All three substances are highly lipophilic, only slightly water soluble and are not volatile. Due to these similar physico-chemical properties it is anticipated that the toxicokinetic behaviour of Ethylene brassylate, Globalide/Habanolide and 1,4-dioxacyclohexadecane-5,16-dione is alike.

Metabolism similarity:

In addition to the structural similarity, the metabolism of the three substances is also anticipated to be similar, with hydrolysis to their corresponding alcohols and acids. The WHO report indicates that studies on the absorption, metabolism, and elimination of esters and diesters show that they are readily hydrolysed and absorbed and are completely metabolized. Many of these substances or their metabolites are endogenous in humans. Furthermore, the presence of a second oxygenated functional group has little if any effect on the hydrolysis of these esters.

Toxicity profile similarity:

The toxicity profiles for Ethylene Brassylate, Globalide/Habanolide and 1,4-dioxacyclohexadecane-5,16-dione are compared below for those endpoints for which data of the source and target chemical are available.

Name 

Ethylene Brassylate

Globalide / Habanolide

1,4-dioxacyclohexadecane-5,16-dione

Skin irritation

Not irritating

Not irritating

Not irritating

Eye irritation

Not irritating

Not irritating

Not irritating

Skin sensitisation

Not sensitising

Not sensitising

Not sensitising

Genotoxicity

Not mutagenic

Not clastogenic

Not mutagenic

Not clastogenic

Not mutagenic

Not clastogenic

Acute oral toxicity

LD 50 ≥ 5000 mg/kg bw

LD 50 ≥ 2000 mg/kg bw

LD50 = 4500 mg/kg bw

Acute dermal toxicity

LD 50 ≥ 5000 mg/kg bw

LD 50 ≥ 2000 mg/kg bw

LD 50 ≥ 5000 mg/kg bw

28-day repeated dose toxicity

-

-

NOAEL = 1000 mg/kg bw/day

90-day repeated dose toxicity

-

NOAEL = 1000 mg/kg bw/day

-

Prenatal developmental toxicity study

-

NOAEL = 1000 mg/kg bw/day

-

The results of the available toxicological data for Ethylene brassylate, Globalide/Habanolide and 1,4-dioxacyclohexadecane-5,16-dione are identical for acute toxicity, irritation, sensitisation and mutagenicity end-points. Furthermore, the similarity of the structural and physico-chemical properties is pronounced. On this basis it is considered appropriate and scientifically justified to read-across the data of the:

- Repeated dose (28-day) toxicity study on 1,4-dioxacyclohexadecane-5,16-dione to Ethylene brassylate. In this case the NOAEL for repeated dose toxicity is 1000 mg/kg bw/day in an OECD 407, 28-day oral toxicity study in the rat.

- Repeated dose (90-day) toxicity study on Globalide/Habanolide to Ethylene brassylate. In this case the NOAEL for repeated dose toxicity is 1000 mg/kg bw/day in an OECD 408, 90-day oral toxicity study in the rat.

- Reproductive and pre-natal developmental toxicity study on Globalide/Habanolide to Ethylene brassylate. In this case the NOAEL for developmental toxicity is 1000 mg/kg bw/day in an OECD 414 pre-natal developmental study.