Registration Dossier

Administrative data

Link to relevant study record(s)

Reference
Endpoint:
basic toxicokinetics, other
Remarks:
Assessment of the toxicokinetic behaviour of isobutylamine to the extent that can be derived from relevant available information
Type of information:
other: Supporting Document for Submission
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Justification for type of information:
According to Annex VIII REACH: Assessment of the toxicokinetic behaviour to the extent that can be derived from relevant available information.
Objective of study:
absorption
distribution
excretion
metabolism
toxicokinetics
GLP compliance:
no
Details on absorption:
Iso-butylamine is polar in it’s nature (as indicated by a Log Kow of 0.73 with an aqueous solubility of 1000 mg/mL at 25°C) and low molecular weight (73.1 g/mol) and is, therefore, expected to be readily absorbed through the skin, the respiratory tract via inhalation and across the gastro-intestinal tract.
For the animals dosed iso-butylamine via oral gavage administration, clinical signs of centrally mediated effects of central nervous system (CNS) depression were reported, indicating systemic exposure to iso-butylamine. At the higher doses, convulsions and death were observed, providing evience of a dose related increase in absorption across the GI tract. Time to the death for male rats dosed with iso-butyamine and iso-propylamine ranged between 1-3 hours and 7 minutes-4 hours, respectively, suggesting oral absorption was rapid.
Absorption into the systemic circulation via the lungs has been demonstrated in the 90 day repeat dose and developmental toxicity studies where the animals were exposed to a vapour of iso-propylamine and where treatment related clinical signs including changes in body weight and clinical chemistry (mild) were observed.
In the acute dermal toxicity studies with butylamine and iso-propylamine, treatment related findings such as dyspnoea, apathy, staggering, spastic gait, tremor, piloerection, exophthalmos, poor general state and death, provides evidence of absorption into the systemic circulation via the skin. For the animals exposed to iso-propylamine, the systemic effects were observed on the day of application, suggesting absorption through the skin was rapid.
Following the “read-across” approach to iso-propylamine, it would be reasonable to assume that absorption into the systemic circulation via the lungs or the skin would also be routes of absorption for iso-butylamine
Details on distribution in tissues:
Due to the physico-chemical properties described for iso-butylamine, the substance would be expected to distribute into tissues. Confirmation of distribution into tissues following oral administration (iso-butylamine), inhalation and dermal exposure (iso-propylamine) was indicated by the clinical observations observed during the toxicity studies, suggestive of centrally mediated effects indicating penetration into the brain, and CNS. The times (1-3 hours) to the first mortalities of the animals in the acute oral toxicity study (Section 3.1) demostrates that distribution to the tissues following oral administration is likely to be rapid. Therefore, based on the “read-across” approach it would not be unreasonable to assume a rapid and general distribution of iso-butylamine into highly perfused tissues throughout the body.
Details on excretion:
Excretion studies have not been cited in the literature for iso-buylamine or the structurally similar amines iso-propylamine and butylamine.
Since iso-butylamine is a highly polar molecule with low molecular weight (73.1 g/mol), the major route of exretion for iso-butylamine and metabolites is likley to be via the kidneys, significant excretion in bile would not be expected. It is also reasonable to assume that phase 2 metabolism (i.e. conjugation) would not play a major role in the elimination of iso-butylamine or it’s metabolites.
Details on metabolites:
Metabolism studies have not been cited in the literature for iso-buylamine or the structurally similar amines iso-propylamine and butylamine. Therefore, based on the structure of iso-butylamine and following absorption through the GI tract wall to the liver, metabolism would likely proceed via phase 1 metabolism, mediated by cytochrome P450s, monooxygenases and flavine monooxygenases. The biotransformation9,10 of iso-butylamine in is likely to proceed by 3 concurrent pathways; hydroxylation of the aliphatic carbons to iso-butylhydroxylamine (preferencial on the secondary or tertiary sites), N-oxidation to N-isobutylhydroxylamine and oxidative deamination, forming the corresponding aldehyde and ammonia. The aldehyde would further metabolise via hydrolysis to the corresponding carboxylic acid and the ammonia would be available as a substrate for urea synthesis in the liver.
Since iso-butylamine is a highly polar molecule with low molecular weight (73.1 g/mol), the major route of exretion for iso-butylamine and metabolites is likley to be via the kidneys, significant excretion in bile would not be expected. It is also reasonable to assume that phase 2 metabolism (i.e. conjugation) would not play a major role in the elimination of iso-butylamine or it’s metabolites.
Conclusions:
Iso-butylamine would be rapidly absorbed following oral and dermal administration and the same would be expected following exposure via inhalation. Once absorbed into the systemic circulation a general and rapid distribution of iso-butylamine into highly perfused tissues throughout the body would be expected as indicated by clinical observations suggestive of penetration into the brain, CNS and lungs. The biotransformation of iso-butylamine is likely to proceed via 3 concurrent pathways: hydroxylation of the aliphatic carbons, N-oxidation and oxidative deamination. Since iso-butylamine is a higly polar molecule with low molecular weight the major route of exretion for iso-butylamine and metabolites is likelyto be via the kidneys, significant excretion in bile would not be expected. It is also reasonable to assume that phase 2 metabolism (i.e. conjugation) would be unlikely to play a major role in the elimination of iso-butylamine or it’s metabolites.
Executive summary:

According to Annex VIII REACH an assessment of the toxicokinetic behaviour of isobutylamine was performed to the extent that can be derived from relevant available information.

An assessment of the toxicokinetics of iso-butylamine was undertaken to obtain a consensus on the in vivo toxicokinetic behaviour of the aliphatic amine in terms of its absorption, distribution, metabolism and excretion. This assessment was made on the basis of physical chemical properties and relevant data in the scientific literature. Data generated in a number of iso-propylamine and butylamine toxicity studies will be used to “read-across” to iso-butylamine.

Description of key information

Iso-butylamine would be rapidly absorbed following oral and dermal administration and the same would be expected following exposure via inhalation. Once absorbed into the systemic circulation a general and rapid distribution of iso-butylamine into highly perfused tissues throughout the body would be expected as indicated by clinical observations suggestive of penetration into the brain, CNS and lungs. The biotransformation of iso-butylamine is likely to proceed via 3 concurrent pathways: hydroxylation of the aliphatic carbons, N-oxidation and oxidative deamination. Since iso-butylamine  is a higly polar molecule with low molecular weight the major route of exretion for iso-butylamine and metabolites is likelyto be via the kidneys, significant excretion in bile would not be expected. It is also reasonable to assume that phase 2 metabolism (i.e. conjugation) would be unlikely to play a major role in the elimination of iso-butylamine or it’s metabolites.

Key value for chemical safety assessment

Bioaccumulation potential:
no bioaccumulation potential

Additional information