[No public or meaningful name is available]

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert review and assessment

Adequacy of study:

key study

Study period:

Report Issued 07-Jan-2019

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Not assignable as the result is from expert assessment.

Data source

Reference

Reference Type:

other company data

Title:

Unnamed

Year:

2018

Report date:

2019

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 of available data at REACH Annex VIII tonnage level.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Fatty acids, C14-C18 and C18 unsaturated, amides with 2,2’-iminodiethanol

Molecular formula:

not applicable as UVCB

IUPAC Name:

Fatty acids, C14-C18 and C18 unsaturated, amides with 2,2’-iminodiethanol

Test material form:

liquid

Results and discussion

Any other information on results incl. tables

INFORMATION BASED ON PHYSICO-CHEMICAL PROPERTIES

KOMAD 710 is a reddish-brown viscous liquid, although it may sometimes appear yellowish. It has a boiling point of 177°C. It is poorly soluble in water with a solubility of 2.807 mg/L at 21°C. Due to its chemical nature it is not possible to experimentally determine a Log P_ow; however, a calculated Log P_ow of 5.51 is available which indicates that it is likely to be very lipid soluble. 

 

No hydrolysis information is available as the test was waivered because KOMAD 710 is classified as readily biodegradable having attained 100% biodegradability after 28-days in a ready biodegradability test.

 

Absorption

 

Potential for Absorption

 

KOMAD 710 a viscous liquid at room temperature (18°C). No vapour pressure is available as the test was not technically possible as when a determination was made a true boil could not be achieved. However, given its viscous nature it is anticipated that KOMAD 710 will not be able volatise easily and therefore exposure and absorption via the inhalation route is considered unlikely.

 

KOMAD 710 has a low water solubility but a high calculated Log P_ow of 5.51 and it can therefore be expected to be very lipid soluble and that absorption across the gastrointestinal mucosa will occur as it passes through the gut. Cell membranes walls contain a family of fatty acid active transport proteins (SLC27); however, given that KOMAD 710 lacks direct similarity with endogenous molecules, it is not possible to confirm if these transport proteins will be able to transport KOMAD 710.

 

There is no information with which to assess the dermal absorption of KOMAD 710. Given its high Log P_ow and likely lipid solubility it is conceivable that dermal absorption could occur.

 

Given that KOMAD 710 is a UVCB it is likely that different components may be absorbed to different degrees, or not at all.

 

 

2,2'-iminodiethanol

 

KOMAD 710 contains 2,2'-iminodiethanol as an identified component. It is not free within the product, but believed to be bound by physical forces to the fatty acid chains. What its absorption profile will be and how it may be affected by being bound to the KOMAD 710 fatty acids and /or other components is not known. 

 

 

Evidence for Absorption

 

An acute oral toxicity study on KOMAD 710 gave an LD50 values female rats of > 2000 mg/kg bw. There were no deaths, clinical signs or abnormalities at necropsy. Because of the lack of observations it is not possible to draw any conclusions as to whether the dose of KOMAD 710 was absorbed.

 

 

An OECD 422 oral repeated dose reproductive developmental toxicity screening study has been conducted on KOMAD 710 at doses of 100, 330 and 750 mg/kg bw/day. A significant number of effects were noted on this study indicating that KOMAD 710 was absorbed during the dosing period. Organs affected included kidneys, lungs, stomach, mammary gland and liver. Changes were also seen in body and organ weights along with changes in liver enzymes, haematological parameters and changes to some reproductive parameters. The study NOAEL for both general systemic toxicity and reproductive effects was 100 mg/kg bw/day.

 

The wide ranging effects demonstrate that KOMAD 710 or its components can be absorbed following repeated oral exposure. It is not possible to assess if all components are absorbed to an equal degree.

 

It should be noted that the identified component of KOMAD 710,2,2'-iminodiethanol, has shown significant toxicity in repeated dose studies and it is not possible to excluded the scenario that it is wholly or in part responsible for the toxicity observed. Hence the absorption profile for KOMAD 710 fatty acid components may be different from that suggested by the toxicological observations.

 

 

DISTRIBUTION

 

 

It is not possible to determine the distribution of systemically absorbed KOMAD 710 with available studies.

 

A significant number of toxicological effects were observed in the OECD 422 repeated dose study; however, it is not possible to establish if these were direct effects of KOMAD 710, individual components, or the effects of metabolites.

 

 

METABOLISM

There is no data on the mammalian metabolism of KOMAD 710. Given it is made up of fatty acid chains it could be expected that it will in part be metabolised by bacteria in the gut and any absorbed material, be it KOMAD 710, or products from its metabolism by gut bacteria will subsequently undergo fatty acid catabolism in cell mitochondria (excluding red blood cells which do not contain mitochondria and possibly the central nervous system as long chain fatty acids cannot cross the blood brain barrier).

 

In the ready biodegradability test using sludge organisms, KOMAD 710 underwent 100% degradation indicating that all components are readily metabolised by bacteria and other organisms found in the environment.

 

In vitro bacterial Ames, Chromosome Aberration and Mouse Lymphoma assays conducted on KOMAD 710 gave negative responses in both the presence and absence of an S9 metabolising system. No conclusions about the potential of KOMAD 710 to undergo metabolic change can be drawn from these studies given that negative responses were observed both in the presence and absence of S9.

 

 

EXCRETION

 

No route or details of excretion of KOMAD 710 can be deduced from the studies available. Material that is not absorbed from the gut or metabolised by gut bacteria can be expected to be excreted in the faeces. Given its fatty acid composition it is likely that after entering the fatty acid catabolism pathways component parts will be incorporated into other molecules. Excretion may therefore be limited, but where it does occur a proportion is likely to be via the urine as this is a route of excretion for fatty acids.

 

Applicant's summary and conclusion

Conclusions:

Observations from repeated dose oral toxicity studies demonstrate that KOMAD 710 or components of it can be absorbed from the gastrointestinal system and exert systemic effects.

Systemically absorbed KOMAD 710 will probably enter fatty acid catabolism pathways and be metabolised; however, it is not possible to determine if metabolism will be similar for all components.

Executive summary:

Introduction

An expert review of toxicokinetic data on KOMAD 710 was undertaken to provide a basic toxicokinetic asessment as required for REACH Annex VIII registration. The assessment was based on available data from toxicological studies studies and some literature references. No specific toxicokinetic studies were undertaken.

Conclusion

Observations from repeated dose oral toxicity studies demonstrate that KOMAD 710 or components of it can be absorbed from the gastrointestinal system and exert systemic effects. 

 

Systemically absorbed KOMAD 710 will probably enter fatty acid catabolism pathways and be metabolised; however, it is not possible to determine if metabolism will be similar for all components.