Acetonitrile, 2,2',2'',2'''-(1,3-propanediyldinitrilo)tetrakis-

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics

Type of information:

other: review

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Review of existing information.

Data source

Reference

Reference Type:

other: review

Title:

Unnamed

Year:

1998

Report date:

1998

Materials and methods

Objective of study:

other: Assessment of toxicokinetic behaviour

Test material

Test material information

Constituent 1

Reference substance name:

-

EC Number:

429-330-7

EC Name:

-

Cas Number:

110057-45-9

Molecular formula:

C11H14N6

IUPAC Name:

2-({3-[bis(cyanomethyl)amino]propyl}(cyanomethyl)amino)acetonitrile

Applicant's summary and conclusion

Conclusions:

Interpretation of results (migrated information): no bioaccumulation potential based on study results

Executive summary:

The acute oral and dermal toxicity of PDTN is low, with the LD50 being higher than 2000 mg/kg body in both cases. The 28 -day toxicity study also revealed that PDTN has a low toxicity. Therefore, an extensive toxicokinetic assessment is considered of limited value. Below, an assessment of the anticipated toxicokinetic behaviour of PDTN is given.

The water solubility of PDTN is relatively high (1.66 g/l), and therefore not considered a rate-limiting factor for the absorption of the compound from the gastro-intestinal tract. Generally, the bioavailability of PDTN from the gastrointestinal tract is anticipated to be high (1). However, bioavailability (systemic exposure) may be decreased because of extensive first-pass metabolism. After absorption of PDTN, dealkylation of the tertiary nitrogens is anticipated. This metabolic route is mediated by the P450 enzyme system (2). Conjugation of the dealkylated nitrogen with glucuronide is an expected next step in the metabolism of PDTN.

Another possibility for the metabolism of PDTN is that one or more of the cyano groups are displaced by glutathione (3).

Extensive metabolism of the compound might lead to enzyme induction, which might cause the observed increase in alanine aminotransferase activity and the increased Iiver:body weight ratio as well as the centrilobular hepatocyte hypertrophy after the 1000 mg/kg body weight dose in the 28-day toxicity study.

Generally, this phenomenon is more considered an adaptation mechanism rather than a toxic effect. Glutathion conjugates formed in the liver can be excreted intact in bile, or they can be converted to mercapturic acids in the kidney and excreted in urine.

PDTN will probably show a small volume of distribution because of its low partition coefficient. Accumulation in fatty tissues is not anticipated.

Since it is generally accepted that substances with log po/w ranging from 0.1 to 6 penetrate the skin easily (4), it is to be expected that PDTN will not penetrate the skin.

Based on the expected kinetic behaviour in the body, as described above, PDTN accumulation in the body during prolonged exposure is not anticipated.

1. L.S. Schanker et al. Absorption of drugs from the rat small intestine. J. Pharmacol. Exp. Ther. 123 (1958) pp 81-88.

2. A. Parkinson. In: Casarett and Doull's Toxicology, The basic science of poisons, fifth edition. Eds. C.O. Klaassen, M.O. Amdur and J. Doull. Chapter 6: Biotransformation of xenobiotics. McGraw-Hili, New York (1996), p 144.

3. A. Parkinson. In: Casarett and Doull's Toxicology, The basic science of poisons, fifth edition. Eds. C.D. Klaassen, M.O. Amdur and J. Doull. Chapter 6: Biotransformation of xenobiotics. McGraw-Hili, New York (1996), p 178.

4. T.G. Vermeire et al., Estimation of consumer exposure to chemicals: application of simple models. The Science of the Total Environment 136 (1993) 155-176.