Registration Dossier

Administrative data

Endpoint:
basic toxicokinetics
Type of information:
other: Assessment report
Adequacy of study:
key study
Study period:
2009
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: fully documented summary report about TK data obtained from relevant in vivo studies

Data source

Reference
Reference Type:
other company data
Title:
Unnamed
Year:
2009
Report Date:
2009

Materials and methods

Objective of study:
toxicokinetics
Test guideline
Qualifier:
no guideline available
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent

Results and discussion

Applicant's summary and conclusion

Conclusions:
Interpretation of results (migrated information): no bioaccumulation potential based on study results
In summary: it is not possible for N-butylpyridinium heptachlorodialuminate to reach the internal body environment because contact with water/water media leads to immediate production of the breakdown products HCI, aluminium oxide and N-butylpyridinium chloride with an exothermic reaction and consequent corrosivity action. All these breakdown products are relatively poorly absorbed, and fairly rapidly eliminated by the body and therefore no potential for accumulation is foreseen.
Executive summary:
No toxicology or toxicokinetic data are available for N-butylpyridinium heptachlorodialuminate.
The substance is strongly reactive: in contact with water an exothermic reaction occurs and HCl gas, aluminium oxide and N-butylpyridinium chloride are produced.

It was therefore not possible to test the substance in vivo, and only a Buhler test could be performed, applying the Hilltop chambers only after an
appropriate time to allow the exothermic reaction to complete. A package of in vitro genotoxicity testing was also performed, again allowing the exothermic reaction to complete before adding the relevant bacteria and/or cell line: all the studies failed to reveal any genotoxic potential.

Toxicokinetic evaluation for N-butylpyridinium heptachlorodialuminate should therefore be based on the fate of each of its breakdown products i.e. HCl, aluminium oxide and N-butylpyridinium chloride.

Although likely to completely evaporate during the exothermic reaction, as an inorganic salt HCl dissolves in water to form hydrogen and chloride ions, both of which are physiological electrolytes. Due to its high solubility and immediate dissociation properties, an aqueous solution of hydrochloric acid is not expected
to be systemically available, and no accumulation of hydrogen chloride per se is expected in living organisms. Chloride ions and hydrogen ions, which combine with water to form the hydronium ion, are both normally present in the body and are also habitually found in the environment. Chloride ions are a normal constituent of the blood, its body pool is large (approx. 100-115 mEq/L in most animal species) and the excess is physiologically excreted into urine. The production of hydronium ions is not expected to affect the pH in the blood or body fluids as this is regulated within a narrow range to maintain homeostasis, and
body buffers will instantaneously take up (or release) protons in response to changes in acidity of the body. Via urinary excretion and exhalation of carbon dioxide the pH will be maintained.

Aluminium oxide is not considered a skin or an eye irritant. Health and medical applications include aluminium oxide as a material in hips replacements and it is also used in toothpaste formulations.

Neurotoxic effects, osteomalacia and adverse effects on haematopoiesis are known toxic effects of aluminium intoxication, but animals studies with aluminium chloride indicate that oral administration can lead to these effects only when exposure is prolonged, and/or when kidney function is impaired. The fraction absorbed orally was only 0.27% of the administered dose and the half-life was of ca. 5 hours. Plasma protein binding was determined to be nearly 98%. Sixty percent of an intravenous dose was excreted in urine and 40% in the faeces. N-butylpyridinium chloride at dosages of 0.5, 5 or 50 mgJkg bw is readily absorbed by the gastro-intestinal tract of male F-344 rats, with an oral availability of ca. 65% and with 86% of the absorbed dose eliminated in the urine in 12 hours as parent compound. Depending on the vehicle, absorption k om dermal application at 5 mgJkg bw (125 µg/cm2) was 10 to 35% at 96 hours. Urine is the major route of excretion also after intravenous or repeated oral administration in either in male F-344 rats (i.v.: 5 mg/kg bw and oral repeated - 5 days - dose of 50 mg/kg bw) or in female B6C3F1 mice (single oral dose of 50 mg/kg bw). Notably, only the parent compound was detected in all urine and blood samples thus indicating that no
transformation occurs within the body. The systemic clearance was determined to be 6.4-9.0 mL/min. Coadministration of N-butylpyridinium chloride and inulin (i. v. ) revealed that the clearance of N-butylpyridinium chloride exceeded the rat glomerular filtration rate, suggesting organic cation transporters (OCTs) play a role in secretion. An in vitro study using Chinese hamster ovary cells expressing human organic cation transporter 2 (hOCT2) demonstrated that N-butylpyridinium chlonde was effectively transported by hOCT2 (Ki 11-18 µM), and that it was also a potent inhibitor (IC50 1.6 µM) of another substrate (tetraethyl ammonium) transported by hOCT2.

In summary: it is not possible for N-butylpyridinium heptachlorodialuminate to reach the internal body environment because contact with water/water media leads to immediate production of the breakdown products HCI, aluminium oxide and N-butylpyridinium chloride with an exothermic reaction and consequent corrosivity action. All these breakdown products are relatively poorly absorbed, and fairly rapidly eliminated by the body and therefore no potential for accumulation is foreseen. References Aluminium oxide - Wikipedia, the free encyclopedia Bowles A. (2006) N-butylpyridinium heptachlorodialuminate: Salmonella typhimurium and Eschrichia coli/mammalian-microsome reverse mutation assay. Safe Pharm unpublished project No. 0703/ 0349 (Chevron reference No. 06-006) Cheng Y., Wright S.H. , Hooth MJ. and Sipes loG. (2009) Characterization of the disposition and toxicokinetics of N-butylpyridinium chloride in male F-344 rats and female B6C3F1 mice and its transport by organic cation transported 2. Drug Metab. Dispas. 37(4): 909-16 Cheng Y., Kuester R., Knudsen G., Wright S. and Sipes loG. (200B) The in vivo and in vitro characterization of N-ButylPyridinium Chloride transport and elimination. The FASEB 1. 22: 1132.1 Durward R. (200B) N-butylpyridinium heptachlorodialuminate: Chromosome aberration test in human lymphocytes in vitro . SafePharm unpublished project No. 0703/0402 (Chevron reference No. OB-004) European Commission - European Chemicals Bureau (2000) IUCLID Dataset Substance 10: 1344-2B-1, aluminium oxide European Commission - European Chemicals Bureau (2000) IUCLID Dataset Substance 10: 7446-70-0, aluminium chloride Flanders L (200B) N-butylpyridinium heptachlorodialuminate: lS17BY TK +/- mouse lymphoma assay. SafePharm unpublished project No. 0703/0401 (Chevron reference No. OB-005) Integrated laboratory System Inc. (2004) Ionic Liquids 1-Butyl-3-methylimidazolium Chloride (CAS No. 79917-90-1) l-Butyl-l -methylpyrrolidinium Chloride (CAS No. 479500-35-1) N-Butylpyridinium Chloride (CAS No. 1124-64-7) Review of Toxicological Literature Rodabaugh D.O. (2006) A dermal sensitization study in guinea pigs with N-butylpyridinium heptachlorodialuminate - modified Buehler design - Charles River l aboratories unpublished study No. lM00050 (Chevron reference No. 06-005)