Diallylamine

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics, other

Remarks:

Assessment of toxicokinetic behaviour

Type of information:

other: In accordance with REACH Annex VIII (8.8) an assessment of toxicokinetic behavior has been conducted to the extent that can be derived from the relevant available information.

Adequacy of study:

key study

Study period:

September 2017

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Relevant studies were reviewed by a qualified toxicologist with a view to fulfilling the requirements of Annex VIII (8.8).

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2017

Materials and methods

Objective of study:

absorption

distribution

excretion

metabolism

toxicokinetics

Test guideline

Qualifier:

no guideline required

Principles of method if other than guideline:

Summaries of studies and literature were reviewed by a qualified toxicologist with a view to fulfilling the requirements of Annex VIII, point 8.8 of REACH. The assessment of the likely toxicokinetic behaviour of the substance was provided to the extent that can be derived from the relevant available information at the time of the assessment. The assessment is based on the Guidance on information requirements and chemical safety assessment Chapter R.7c: Endpoint specific guidance (ECHA, June 2017 (v 3.0)).

Test material

Test material information

Constituent 1

Reference substance name:

Diallylamine

EC Number:

204-671-2

EC Name:

Diallylamine

Cas Number:

124-02-7

Molecular formula:

C6H11N

IUPAC Name:

diallylamine

Results and discussion

Any other information on results incl. tables

Toxicokinetic behaviour:

The substance is a transparent liquid and has a relatively low molecular weight (97.16).

The relatively high vapour pressure (3.5 x 10³ Pa at 25ºC), and low flash point shows that the substance is relatively volatile and therefore inhalation is a potential significant route of exposure.

The substance has a low log octanol/water partition coefficient (Log Pow -0.65) and high water solubility (81 g/l).

The substance is considered to be corrosive to both skin and eye.

An oral repeated dose reproductive screening study (OECD 422) showed evidence of absorption and did not show evidence regarding metabolism or excretion.

An in vivo micronucleus assay in mice showed evidence of absorption following oral exposure based on measured concentrations of substance being detected in plasma samples.

Acute and repeat dose inhalation test data showed evidence of absorption following inhalation exposure.

The substance was non-mutagenic in bacteria (Ames test) in either the absence or presence of an auxiliary metabolising system. The substance was non-clastogenic in mammalian cells in vitro (human lymphocytes) in non-activated treatment but positive (for structural aberrations) in activated treatment. The substance was non-clastogenic (negative) in an in vivo micronucleus study.

Absorption:

The main evidence supporting absorption following oral exposure comes from the In Vivo Micronucleus Assay in Mice study and the oral repeated dose reproductive screening study (OECD 422).

In the In Vivo Micronucleus Assay mice were administered the substance by oral gavage and plasma samples taken for analysis. Measurable concentrations of the substance were detected in the analysed plasma samples of the substance dosed groups, showing that absorption of the substance through the gastro-intestinal tract occurred and that the substance had been distributed.

Results from acute oral toxicity studies (which showed mortalities and dose-dependent depression (lethargy) in all exposed groups) and oral repeated dose reproductive screening study (OECD 422) showed evidence to support the gastric absorption of the substance. The high water solubility and small molecular size of the substance should allow absorption through the gastro-intestinal tract via passive diffusion. This would suggest that the gastro-intestinal tract provides a route of absorption, following oral administrative, thereby facilitating systemic distribution via the circulatory system. Evidence from the OECD 422 study supporting absorption includes the histopathology findings of increased hyaline droplets in the kidneys (in males at 75 mg/kg bw/day) and other signs of substance uptake.

Results from acute dermal toxicity studies showed evidence to support potential dermal absorption. The small molecular size (mw <100) of the substance favours dermal uptake. However, based on the water solubility and log Pow of the substance it is considered that dermal uptake will be low and the substance will not readily cross the skin barrier. The substance is corrosive to skin and therefore damage to the skin surface may allow for increased penetration of the substance through the skin. It is therefore likely that the systemic effects seen in acute dermal toxicity studies, which showed local corrosive effects, were due to increased penetration due to skin damage.

The high vapour pressure (3.5 x 10³Pa at 25ºC), and low flash point shows that the substance is relatively volatile and that the substance may be available as a vapour and therefore inhalation is a potentially significant route of exposure.Results from acute inhalation studies and repeat dose inhalation exposures show evidence to support absorption. Substances with log Pow values between -1 and 4 are generally favourable for absorption directly across the respiratory tract epithelium by passive diffusion. Therefore absorption may be a relatively simple process in terms of passage across biological membranes. Vapours of hydrophilic substances may be retained within the mucous lining of the respiratory, which would therefore likely cause irritancy.

Distribution:

As the substance is of low molecular weight and is water soluble, it can be assumed that any absorbed substance can be readily distributed in the water fraction of circulatory fluids. The systemic distribution is likely to occur from either oral or inhalation exposure of substance based on systemic toxicity findings in studies from either route. Thelow log octanol/water partition coefficient and high water solubility would suggest the substance is not lipophilic and would not accumulate in body fat.

Further evidence supporting the distribution of the substance comes from theIn VivoMicronucleus Assay in Mice. In this study mice were administered the substance by oral gavage and plasma samples taken for analysis. Measurable concentrations of the substance were detected in the analysed plasma samples of the substance dosed groups, showing that absorption of the substance through the gastro-intestinal tract occurred thereby facilitating systemic distribution in circulatory fluids.

Metabolism:

The results of the repeat dose toxicity/screening reproduction study shows no significant evidence of enhanced hepatic metabolism (only effect on liver was an increased weight) and the fact that the substance is already freely water soluble suggests that metabolism may not be required to enhance excretion.

 

The negative result (non-mutagenic in bacteria) in an Ames test showed no evidence that genotoxicity is either enhanced or diminished in the presence of a metabolising system. A chromosome aberration (in human lymphocytes) study did show a negative result without the presence of a metabolising system and a positive result with the presence of a metabolising system. However, there is no evidence as to whether this effect may be due to a cytotoxic mode of action or a true genotoxic mechanism but some metabolism cannot be ruled out.

Excretion:

There is no evidence to indicate the route of excretion but high water-soluble substance are not favourable for biliary excretion and therefore urinary excretion may well be the significant route for this substance. In addition to the high water solubility, a molecular weight of below 300 g/mol is also a characteristic favourable for urinary excretion in the rat. Any substance that is not absorbed will be excreted in the faeces.

 

Applicant's summary and conclusion

Conclusions:

The substance is a low molecular weight liquid that is water soluble and has a low log octanol/water partition coefficient. The available information suggests that absorption of the substance from the gastro-intestinal tract can take place. Dermal uptake of the substance will be low but local damage to the skin surface may allow for increased penetration of the substance. Inhalation may also be a route of exposure and absorption may occur. Absorbed substance is likely to be distributed in the water fraction of circulatory fluids. The substance is unlikely to be metabolised and excretion is most likely to be via the kidney in urine.