Registration Dossier

Diss Factsheets

Toxicological information

Basic toxicokinetics

Currently viewing:

Administrative data

Endpoint:
basic toxicokinetics, other
Type of information:
other: Expert review and assessment
Adequacy of study:
key study
Reliability:
other: Not assignable as the result is from expert assessment.

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2017
Report date:
2017

Materials and methods

Objective of study:
other: Basic toxicokinetic assessment to support REACH Annex VIII registration.
Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Expert review and assessment of toxicokinetic behaviour of the substance derived from available data as required by REACH Annex VIII.
GLP compliance:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Ethylidynetrimethanol
EC Number:
201-063-9
EC Name:
Ethylidynetrimethanol
Cas Number:
77-85-0
Molecular formula:
C5H12O3
IUPAC Name:
2-(hydroxymethyl)-2-methylpropane-1,3-diol
Test material form:
solid: particulate/powder

Results and discussion

Any other information on results incl. tables

INFORMATION BASED ON PHYSICO-CHEMICAL PROPERTIES

Trimethylolethane is a low molecular weight (MW = 120.15) substance and is a solid at room temperature with a melting point of 198°C. It is very soluble in water with a solubility of 350 g/l at 20 °C and it has a log Pow is -1.26 at 20°C which indicates that the substance will lack solubility in lipids.  

In its solid form Trimethylolethane is a granular powder.  Particle size analysis found that 23.8% of the particles are inhalable (particle size <100 µm) and that 5.45% were < 5.5 µm and therefore classed as potentially respirable particles.

Trimethylolethane is hydrolytically stable with an estimated half-life of > 1 year at 25 °C at pH 4, pH 7 and pH 9.  No ready biodegradability test has been conducted on Trimethylolethane; however, by read-across to Trimethylolpropane it is considered that it will not be readily biodegradable.

ABSORPTION, DISTRIBUTION AND EXCRETION

Absorption

Trimethylolethane in solid form contains < 23.8% particles that could be inhaled following exposure to airborne dusts. Much of this dose can be expected to be transferred to the stomach via mucocilliary action and swallowing; however, 5.45% of particles are < 5.5 µm and can be classified as respirable and if inhaled could reach the alveoli where absorption directly into the blood stream could take place.

Trimethylolethane is a low molecular weight molecule and therefore its size is unlikely to present a significant barrier to absorption across the gastrointestinal mucosa, hence, uptake as it passes through the gastrointestinal tract may occur. However, uptake is likely to be limited as Trimethylolethane has a log P value of -1.26 at 20°C and therefore the non-ionised form is unlikely to have sufficient lipid solubility to easily pass across biological membranes.  It is unlikely that active transport mechanisms will be a significant uptake route due to a lack of similarity with endogenous molecules.

Overall, it can be expected that absorption of the intact molecule across the gastrointestinal mucosa will occur, but a proportion of an oral dose is likely to not be absorbed and subsequently be excreted in the faeces.

Evidence for Absorption

An oral repeated dose reproductive toxicity with developmental toxicity screening study (OECD 422) has been conducted on a read-across substance Trimethylolpropane using doses of 12.5, 50, 200 and 800 mg/kg/bw/day. No effects on reproductive performance were observed during the study.  General toxicity effects observed which were attributable to test item were a reduction in body weight in both males and females and in male’s significant increases in absolute liver weight with some histopathological changes. The study NOAEL for general toxicity was 200 mg/kg bw/day. The results indicate that Trimethylolpropane was absorbed and it, and/or its metabolites were at a sufficient concentration to exert effects. Based on these results it is expected that given its structural similarity, Trimethylolethane will be absorbed and have a similar profile following repeat dosing.  

Trimethylolethane is a small molecule (MW 120.15) and given its molecular weight it is conceivable that a dermal absorption could occur.   In an acute dermal toxicity study on the read-cross substance, Trimethylolpropane, there was evidence of absorption following dermal exposure as histopathological changes occurred in the kidneys from a dose of 2150 mg/kg bw (study top dose 10,000 mg/kg bw).  It is expected that Trimethylolethane will show a similar dermal absorption profile.  

Distribution

It is unlikely that Trimethylolethane will exhibit any significant distribution within the body between plasma and tissues as its log P value (-1.26) does not indicate it will have a strong affinity for fats.  

Because no reproductive effects were observed for the read-across substance, Trimethylolpropane, it is not possible draw any conclusions about whether the distribution of Trimethylolethane in the body could include the reproductive organs.    

Metabolism

Trimethylolethane contains water solubilising hydroxyl groups which are likely to aid excretion and also metabolism of the molecule by cytochrome P450 enzyme metabolising system. Hence, in organisms such as mammals and fish with significantly developed xenobiotic metabolising systems, Trimethylolethane is expected to undergo a degree of metabolism resulting in breakdown of the molecule and ultimate excretion.

In two in vitro bacterial Ames assays, an in vitro mammalian chromosome aberration assay in Chinese Hamster Ovary cells and an in vitro gene mutation assay in Chinese Hamster Fibroblasts cells on the read-across substance Trimethylolpropane, gave negative results in both the presence and absence of an S9 metabolising system.  Given the negative results, no conclusions about the potential of Trimethylolpropane and concomitantly Trimethylolethane ethane to undergo metabolic change can be drawn from these studies.

Excretion

Due to presence of water solubilising groups present on Trimethylolethane, or added during metabolism, the main route of excretion of absorbed Trimethylolethane and/or its metabolites is likely to be via the kidneys into the urine.

In an acute dermal toxicity study on the read-across substance Trimethylolpropane, histopathological changes were observed in the kidneys suggesting that either Trimethylolpropane and/or its metabolites were excreted via the kidneys. It is expected that Trimethylolethane will have a similar profile.

The molecular weight of Trimethylolethane is below the biliary exclusion limit of circa 325 in the rat and 500 in humans and therefore elimination of any absorbed substance in the bile is not expected to be significant.  

Applicant's summary and conclusion

Conclusions:
Observations from an acute dermal toxicity study on the read-across substance Trimethylolpropane indicate it can be absorbed through the skin and it is expected that Trimethylolethane will similarly be able to penetrate the skin.

In the case of the gastrointestinal system, absorption is likely to be slow and most of an oral dose is expected to be excreted in the faeces. However, a proportion will be systemically absorbed as demonstrated by the observation of treatment related effects in a repeat dose toxicity with reproductive developmental toxicity screening study (OECD 422) conducted on the read-across substance Trimethylolpropane.

The presence of hydroxyl groups on the structure can be expected to aid metabolism of systemically, absorbed Trimethylolethane to water soluble products that will ultimately be excreted via the kidneys.

There is no expectation that Trimethylolethane will preferentially distribute to particular organs or tissues in the body.
Executive summary:

Introduction

An expert review of the toxicokinetic profile of Trimethylolethane was undertaken based on its physico-chemical profile and available data from toxicological studies on a read-cross substance.

Conclusion

Observations from an acute dermal toxicity study on the read-across substance Trimethylolpropane, indicate it can be absorbed through the skin and it is expected that Trimethylolethane will similarly be able to penetrate the skin.

In the case of the gastrointestinal system, absorption is likely to be slow and most of an oral dose is expected to be excreted in the faeces.  However, a proportion will be systemically absorbed as demonstrated by the observation of treatment related effects in a repeat dose toxicity with reproductive developmental toxicity screening study (OECD 422) conducted on the read-across substance Trimethylolpropane.

The presence of hydroxyl groups on the structure can be expected to aid metabolism of systemically, absorbed Trimethylolethane to water soluble products that will ultimately be excreted via the kidneys.  

There is no expectation that Trimethylolethane will preferentially distribute to particular organs or tissues in the body.