Trimethylenediamine

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: Expert statement

Adequacy of study:

key study

Study period:

2013-03-14

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Expert statement in the absence of toxicokinetic studies.

Data source

Reference

Reference Type:

other: Expert statement

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

Expert statement

GLP compliance:

yes (incl. QA statement)

Test material

Test material information

Constituent 1

Reference substance name:

Trimethylenediamine

EC Number:

203-702-7

EC Name:

Trimethylenediamine

Cas Number:

109-76-2

Molecular formula:

C3H10N2

IUPAC Name:

propane-1,3-diamine

Test material form:

other: liquid

Test animals

Species:

other: Expert statement

Strain:

other: Expert statement

Administration / exposure

Route of administration:

other: Expert statement

Vehicle:

other: Expert statement

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

After oral administration the substance is assumed to dissolve in the gastrointestinal fluids and absorption via aqueous pores or carriage across membranes with the bulk passage of water might occur as indicated by the high water solubility. In addition, absorption of the substance via passive diffusion might be favoured due to the log Pow value of -1.05. The LD50 evaluated in an oral acute toxicity study and the pathological and histopathological findings after repeated oral administration indicate that the compound becomes bioavailable after oral administration.
The test items volatility is considered to be low as the vapour pressure is less than 0.5 kPa at 20 °C. Therefore, inhalation of vapour is unlikely. However, if the test item becomes available for inhalation as under the conditions of an acute inhalation toxicity study, it might cross the respiratory tract epithelium by passive diffusion or active transport via aqueous pores as indicated by the small molecular weight and the physic-chemical properties of the substance. This assumption is supported by the results of the acute inhalation toxicity study in which signs of systemic toxicity were observed.
Dermal absorption of trimethylenediamine is suspected to be low as uptake into the stratum corneum is limited by very high water solubility and a log Pow value below 0. But mortality was observed in the available acute dermal toxicity study. This may be ascribed to the highly corrosive potential of the substance as damage to the skin surface enhances the penetration of the substance. Further, the test substance was identified as a skin sensitiser supporting the assumption of a dermal uptake of the substance.

Taken together, experimental data indicate bioavailability of the test substance via oral, dermal and possibly also via inhalation route.

Details on distribution in tissues:

A wide distribution of the test substance in the organism is expected due to its low molecular weight and high water solubility. In the available chronic and sub-chronic studies on reproduction toxicity, the liver was identified as a target organ.
Based on the low log Pow value, no bioaccumulation of the test substance is expected.

Details on excretion:

Due to the low molecular weight (74.13 g/mol), the high water solubility (>500 g/L) and the presumed metabolism, trimethylenediamine and/or its metabolites are expected to be excreted via urine.

Metabolite characterisation studies

Details on metabolites:

A metabolism similar to ethylenediamine can be assumed. Resorbed ethylenediamine is quickly released from blood plasma and excreted via urine, mainly as acetylated metabolite N-acetylethylenediamine and to a minor extent as unchanged substance. This information is supported by respective animal studies.
Thus, N-acetylpropylenediamine is expected as the main metabolite of trimethylenediamine.
There are no indications of genotoxicity of the test item and its metabolites from the present mutation assays (Zeiger, 1987; BASF, 2012) conducted in bacteria and mammalian cells. Thus, trimethylenediamine and its metabolites are expected not to be genotoxic and metabolic activation is unlikely to occur.
This assumption is further supported by a carcinogenicity study in rats. No evidence of carcinogenic effects was exhibited.

Bioaccessibility (or Bioavailability)

Bioaccessibility (or Bioavailability) testing results:

Taken together, experimental data, as well as phys.-chem. properties and structure indicate bioavailability of the test substance via oral, dermal and possibly also via inhalation route.