1,6-Bis(methoxybenzoyloxy)hexane

Endpoint summary

Description of key information

In accordance with COLUMN 1, Annex VIII Section 8.8.1 of REACH a in order to fulfill the requirements for

submission of a REACH dossier according to Annex IX of REACH Regulation (EC) No.1907/2006 (for substances 100 - 1000 tones/year) and in absence of data on the toxicokinetics and dermal absorption, an assessment of toxicological behaviour is required. No studies are available on the toxicokinetics, metabolism and distribution of 1,6-Bis(methoxybenzoyloxy)hexane. The available physico-chemical and toxicological information of the substance has been evaluated and used to assess the toxicological behaviour. An expert statement is provided.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

ASSESSMENT OF THE TOXICOKINETIC BEHAVIOUR OF 1,6-BIS (METHOXYBENZOYLOXY) HEXANE (SETAFIX 1077)

 

GENERAL INFORMATION

In order to fulfil the requirements for submission of a REACH dossier according to Annex IX of REACH Regulation (EC) No.1907/2006 (for substances >100 tones/year) and in the absence of data on the toxicokinetics and dermal absorption, an assessment of toxicological behaviour based on available data is required. No studies are available on the toxicokinetics, metabolism and distribution of 1,6-Bis (methoxybenzoyloxy) hexane. There is no specific requirement to conduct studies to generate Toxicokinetic Information under REACH Regulation (EC) No.1907/2006. The ECHA “ Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance May 2008” document provides guidance on how physico-chemical properties commonly determine oral, inhalatory and dermal absorption, distribution, metabolism and elimination of substances (Link: http://echa.europa.eu/documents/10162/13632/information_requirements_r7c_en.pdf) 

 

Structure of 1,6-Bis(methyoxybenzoyloxy)hexane

 

IUPAC Name	1,6-Bis(methoxybenzoyloxy)hexane
Common Name	SETAFIX 1077
CAS Number	390359-18-9
Molecular weight	386g/mol
Appearance	Yellow crystalline solid at 20°C and 1013 hPa
Purity	> 95 %
Impurities	p-anisic acid (CAS# 100-09-4, EC# 202-818-5) and a monoester

 

PHYSICO-CHEMICAL PROPERTIES

Melting Point	85°C – 87°C (358K - 360K)
Boiling Point	Decomposition at 243°C (516K) prior to boiling
Density	1.25g/cm³
Particle Size	Median (μm.): 509.2 μm;  < 10 % of material: 212.1 μm;  < 90 % of material:  811.2 μm.
Vapour Pressure	0.019 Pa at 20°C
Partition Coefficient Octanol/water (log Pow)	5.2 at 24.5°C
Water Solubility	0.0018 mg/L (< 0.1 mg/L)
Surface tension	Not measured
Hydrolysis	Not measured

 

TOXICOKINETIC ASSESSMENT OF 1,6-BIS(METHOXYBENZOYLOXY)HEXANE (SETAFIX 1077)

 

The available physico-chemical and toxicological information of the substance has been evaluated and is used to assess the Toxicokinetic behaviour (TK) of the substance 1,6-Bis(methoxybenzoyloxy)hexane (SETAFIX 1077). The results of this analysis will address the question on how the chemical will react in the body.

Skin and Eye irritancy	Not an irritant
Skin sensitisation	Not a sensitizer
Acute oral toxicity	LD50 > 2000 mg/kg bw
Acute dermal toxicity	LD50 > 2000 mg/kg bw
Genotoxicity	Not mutagenic (Ames test), Not clastogenic (human lymphocytes), Not mutagenic (mouse lymphoma)
Bioaccumulation Potential	Low (Bioaccumulation test in fish: Carp (Cyprinus carpio)

 

The acute oral toxicity of SETAFIX 1077 is low; the oral LD50, rat is higher than 2000 mg/kg in the total absence of any clinical signs, symptoms or effects. The dermal LD50 > 2000 mg/kg, with signs of skin irritation and lethargy in most animals, diarrhoea and ptosis in some males. The 28-day toxicity study revealed that SETAFIX 1077 has an NOAEL of 150 mg/kg./day, At 1000 mg/kg/day slight deviations in blood biochemistry in females and possibly higher motor activity in males, in the absence of any concurrent histopathology. The substance is not irritative to eyes or skin, not a sensitizer and not mutagenic or clastogenic.

 

The bioaccumulation potential of SETAFIX 1077 is low (Bioconcentration: Flow-through Fish Test). The substance cannot be considered readily biodegradable although it has been found to be inherently biodegradable and no hydrolysis study was performed due to poor solubility in water. There are also no measurements to determine breakdown products.

 

The available physico-chemical and toxicological information of the substance has been evaluated and is used to assess the Toxicokinetic behaviour (TK) of the substance 1,6-Bis(methoxybenzoyloxy)hexane (SETAFIX 1077). The results of this analysis will address the question on how the chemical will react in the body.

 

ABSORPTION

The major routes by which chemicals/toxicants enter the body are via the lungs, the gastrointestinal tract (both being absorption surfaces by nature), and the skin. To be absorbed, substances must transverse across biological membranes.

 

Dermal absorption: The low molecular weight (386g/mol) of the substance means it is favourable for absorption. However, due to the low water solubility (< 0.10 mg/L) the substance will not be sufficiently soluble in water to partition from the stratum corneum into the epidermis. Therefore, based on the log Pow of 5.2 and the very low water solubility (0.0088 mg/L), the substance cannot be expected to be absorbed through the intact skin to a significant extent. The substance is not irritating to skin and increased absorption due to damaged skin is therefore not likely. Once absorbed, there is no information on the actual breakdown products formed. However, a review of the molecular structure shows that the substance is a diester and likely to undergo hydrolytic decomposition to its corresponding alcohol and acid under physiological conditions. There is no information on the actual breakdown products formed.

 

The default value of 100% skin absorption has been assumed as the molecular weight is less than 500 g/mol.

 

Inhalation absorption: Based on the low vapour pressure 0.019 Pa at 20°C and high boiling point 243°C (516K) the substance is expected to have low volatility and therefore unlikely to be available for inhalation as a vapour. Therefore, inhalation is not expected to be a major route of exposure. Although the substance can be ground into a coarse powder (as was done for particle size determination for notification purposes), it is not manufactured or marketed as such. Thus, dust inhalation and/or skin contamination with dust is considered irrelevant and hence not considered here. There is no information on the actual breakdown products formed.

 

The default value of 100% inhalation absorption has been assumed.

 

Oral Absorption: At present, absorption from the alimentary tract cannot be determined or confirmed with certainty. The clinical signs and biochemical changes observed in the high dose group during the 28-day oral gavage study are minimal, of a statistical nature, not consistent, have no histopathological equivalent and are therefore not necessarily due to absorbed test material. Based on the very low water solubility, direct absorption is not expected. Whether other mechanisms, such as co-absorption with oils or fatty materials are operant remains to be established. There is no information on the actual breakdown products formed. However, the presence of ester groups in the molecular structure suggest that, upon oral intake, the substance is likely to undergo hydrolytic breakdown to its corresponding alcohol and acid, thereby minimising oral/GI absorption of the substance.

 

The default value of 100% oral absorption has been assumed.

 

DISTRIBUTION

Once the chemical has entered the blood stream, it may exert its toxic action directly in the blood or in any target tissue or organ to which the circulatory system transports or distributes it. It is the blood flow through the organ, the ability of the substance to cross membranes and capillaries, and its relative affinity for the various tissues that determine the rate of distribution and the target tissues.

 

Assuming absorption into the bloodstream, the substance is likely to partition into fatty tissues because of the high partition coefficient (log Pow = 5.2) which suggests that the substance is highly lipophilic enough (log Pow > 4) to allow bioaccumulation in the body fat. The high lipophilicity of the substance also suggests that it can readily penetrate the lipid rich stratum corneum of the skin though it is not well absorbed systemically. The substance, however, has low bioaccumulation potential based on the Bioaccumulation test in fish: Carp (Cyprinus carpio). In addition, assuming absorption, it is unlikely the substance as such will survive enzymatic hydrolysis due the presence of ester functional groups in its molecular structure.

 

Therefore, considering its low water solubility, the expected very low absorption through all routes of access, possible enzymatic hydrolysis and low bioaccumulation potential, the substance is unlikely to found widely distributed in the body and unlikely to be of any toxicological concerns.

 

METABOLISM

It is very difficult to predict the metabolic changes a substance may undergo on the basis of physico-chemical information alone. Although it is possible to look at the structure of a molecule and identify potential metabolites, it is by no means certain that these reactions will occur in vivo (e.g. the molecule may not reach the necessary site for a particular reaction to take place).

 

No data are available on the metabolism of the substance. In view of the chemical structure, enzymatic hydrolysis to the mono-ester and subsequently to the hexane-1,6-diol (CAS# 629-11-8; EC# 211-074-0) and the p-anisic acid (CAS# 100-09-4; EC# 202-818-5) is possible. In that case, toxicity would be determined by the metabolites. The toxicity of hexanediol is probably comparable to other glycols and relatively low. In fact, hexane-1,6-diol (CAS# 629-11-8; EC# 211-074-0) is not classified as hazardous according to Regulation (EC) No. 1272/2008. No data are available for the p-anisic acid. The acute oral LD50 of >2,000 mg/kg has been predicted. However, considering the SETAFIX 1077 low water solubility, it is unlikely that metabolites will reach sufficient levels to cause serious effects or any toxicological concerns.

 

EXCRETION 

Chemicals can be excreted via various routes and mechanisms. The relative importance of the excretion processes depends on the physical and chemical properties of the compound and its various metabolites.

 

No data are available on the excretion of the substance. However, assuming absorption, and considering its low water solubility it is unlikely that the parent compound will survive enzymatic hydrolysis. Hence, much of the excretory products are likely to consist of metabolic products of the parent compound.

 

CONCLUSION

While toxicokinetic data is not available on 1,6-Bis(methoxybenzoyloxy)hexane (SETAFIX 1077)., if absorbed, it is not expected to bioaccumulate but rather to breakdown under normal physiological conditions. There is no information on the actual breakdown products formed. However, considering its low water solubility, it is unlikely that metabolites will reach sufficient levels cause serious effects or any toxicological concerns.