5,7-di-tert-butyl-3-[4-(2-hydroxyethoxy)phenyl]-1-heteropolycycl-2(3H)-one

Endpoint summary

Description of key information

An assessment of the toxikokinetics of the substance was conducted based on the readily available information.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

100

Additional information

Introduction

The physico-chemical properties and the results of in vitro studies and acute and repeat dose toxicity studies with animals for Lactone 1EO have been used to determine a toxicokinetic profile. 

 

Physicochemical properties

The substance 5,7-di-tert-butyl-3-[4-(2-hydroxyethoxy)phenyl]-1-benzofuran-2(3H)-one (IUPAC) or 2(3H)-Benzofuranone, 5,7-bis(1,1-dimethylethyl)-3-[4-(2-hydroxyethoxy)phenyl]- (CAS) and henceforth identified using its trade name, “Lactone 1EO” is an off-white powder and has the molecular formula C₂₄H₃₀O₄with a molecular weight of 382 g/mol. 

 

It is considered to be insoluble to poorly water soluble, with a measured water solubility of 0.114 mg/L at 20 °C with a log Pow value of 5.09 at 25°C. No information is available on the hydrolytic behaviour of the substance.

 

SeeTable 1. 

Table 1: Chemical Properties

Property
MW	382
State	Solid (powder)
Melting Range	80.3 to 129°C
Boiling Point	Decomposition from 201 °C
Density	1.17 at 24.0 ± 0.5°C
Particle Size Distribution	<100µm: 32.7% <10.0µm: 10.8%
Vapour Pressure	<0.00043 Pa at 25 °C
Water Solubility	≤ 0.114 mg/L
Log Pow	5.09
Hazardous Physico-Chemical Properties	None known

 

Absorption

Oral absorption

The oral absorption of a chemical is influenced strongly by its molecular weight and size, its water solubility and its lipid solubility. The molecule in question is considered to be sufficiently small, with a molecular weight of 382 g/mol, so as not to have its size impede its absorption. However, the material’s low water solubility (≤ 0.114 mg/L) and relatively high log P_owvalue (5.09) are considered to considerably reduce the likelihood of the material’s absorption.

 

The result of the acute oral toxicity study, performed in the rat to OECD Guideline 420, indicates that there are no toxicologically significant effects seen following a single acute dose of the material up to levels of 2000 mg/kg bodyweight. However, in a 28-day repeated dose study also conducted in the rat, there were adverse toxicological signs noted in all groups dosed from 100 mg/kg bw/day up to 1000 mg/kg bw/day. Whilst reduction of the top level dose group to 500 mg/kg bw/day and subsequently early termination of this group for ethical reasons meant that limited data on the top dose level group were available, it was not possible to derive a NOAEL from the results of the study. Gross necropsy of these animals supports the hypothesis that the material had properties making it irritant to the administration site, (the substance was determined to be irritating to the eye) evidenced by inflammatory gastric changes. 

 

There were several notable histopathological changes seen in the liver, thyroid, and pituitary glands as well as changes to male reproductive tissues. These signs were considered to increase in severity in line with an increase in dose and it was not considered possible to conclude that these were all secondary signs of toxicity. Given that systemic toxicity is considered to have occurred, absorption of the substance has been concluded to take place.

 

Given the lack of quantitative data, and as a worst-case assumption for risk assessment purposes a first tier approach, 50% oral absorption is assumed.

 

Dermal absorption

The physical state, high log Pow value (>5), together with the low water solubility (<0.114 mg/L) indicate very low potential for dermal absorption. Given the molecular size of the substance and relative lipophilicity, deposition in the stratum corneum to some extent may occur. According to EFSA guidance (2012) a dermal absorption value of 25% might be assumed for risk assessment purposes, however in accordance with REACH guidance (R.8, 2012), given oral absorption is not fully quantifiable, the same value adopted for oral absorption (50%) must be adopted for dermal absorption.

 

Inhalation absorption

The registered substance has a low vapour pressure and therefore is unlikely to be available for inhalation as a vapour. Furthermore, particle size distribution indicates that the proportion of test item having an inhalable particle size (<100 µm) is 32.7%, that having a thoracic particle size (<10.0 µm) is 10.8% while the proportion of test item having a respirable particle size (<5.5µm) account to only 2.02% and there were too few particles of a size less than 10.0 µm to allow accurate assessment of the mass median aerodynamic diameter.

In absence of any data, and as a worst-case assumption, for risk assessment purposes absorption by inhalation will be assumed to be 100 %.

 

Distribution

Whilst a molecule of this size would typically be considered to have a wide distribution , there is the potential for preferential partition to fatty/adipose tissues upon repeated exposure given the high log Pow of the material. 

 

Metabolism

Little specific information is available on the potential metabolism of the substance; however cleavage of the ester bond might be anticipated .

 

Elimination

A molecular weight of >300 indicates that excretion is more likely to occur via the bile.

 

Conclusion

In the absence of quantitative data, but indications from in vivo studies that oral absorption did occur, values of 50%, 50% and 100% are adoption for oral, dermal and inhalation exposure in accordance with ECHA guidance.

 

Distribution within the body would be considered to be wide with preferential partitioning to fatty tissues.

There is no data on the metabolism of the substance; however cleavage at the ester bond might be anticipated. The molecular weight of >300 suggests elimination via the bile.