Butylamine

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Meets generally accepted scientific standards, limited documentation, acceptable for assessment

Objective of study:

excretion

Principles of method if other than guideline:

Biochemical/physiological model study on the mechanism of ammonia and amine excretion in acidosis and alkalosis:
Excretion into urine of rats after i.p. injection of the HCl salts of various amines under artificially alkalotic or acidotic metabolic conditions.
Identification and quantification of the urinary amines after derivatisation with dinitrophenol by reverse-phase HPLC.

GLP compliance:

no

Radiolabelling:

no

Species:

rat

Strain:

Sprague-Dawley

Sex:

not specified

Details on test animals or test system and environmental conditions:

ca. 250 g body weight

Route of administration:

intraperitoneal

Vehicle:

physiological saline

Duration and frequency of treatment / exposure:

12 hour(s)

Remarks:

Doses / Concentrations:
100 mg/kg bw (related to free base) in 5 mL saline

No. of animals per sex per dose / concentration:

6

Control animals:

not specified

Metabolites identified:

no

n-Butylamine was easily excreted into the urine within 8 h, 4.2 times 

higher under acidotic conditions (urinary pH 5.4 - 6.0) than under 

alkalotic conditions (urinary pH 7.7 - 8.7).

No mass balance or quantitative data are documented.

It can concluded that the un-ionised, more lipohilic n-butylamine partitions rapidly across membranes by diffusion, and excretion into urine is favoured by ionisation under acidotic conditions, thus the amine (like ammonia) serving as vehicle to get rid of excess H+ (compensation of acidosis).

   ---------------

Reference 2

Endpoint:

basic toxicokinetics in vivo

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Acceptable, study meets basic scientific principles. Early human metabolism study. Analytical procedure outdated. Documentation of test conditions sufficient. limited documentation, acceptable for assessment

Objective of study:

excretion

Qualifier:

no guideline required

Principles of method if other than guideline:

Metabolism /excretion study: The excretion of unchanged amine in urine was examined 24 hours after ingestion of the hydrochloric acid salts
of various primary (methyl, ethyl-, propyl, butyl, isobutyl) and secondary (dimethyl, diethyl) amines by one human volunteer.
The amines - if found in substantial amounts in the urine- were characterized as their salts of picrolonic acid from the urine, otherwise the volatile alkylamine fraction excreted in urine served as indicator for excretion of unchanged test substance.

GLP compliance:

no

Radiolabelling:

no

Species:

human

Strain:

other: Caucasian white

Sex:

male

Route of administration:

oral: unspecified

Vehicle:

not specified

Duration and frequency of treatment / exposure:

24 hour(s)

Remarks:

Doses / Concentrations:
Males: 3.5 g n-butylamine HCl (= 0.446 g N)

No. of animals per sex per dose / concentration:

Males: 1

Control animals:

no

Details on study design:

24-hour urine was collected and measured. Unchanged n-butylamine in urine was quantified as volatile alkylamine fraction.

Details on excretion:

Only about 2 % (1.95 %) of the dose was excreted into the urine within 24 h, based on excess volatile alkylamine in the urine. The respective picronolate was not produced for further characterisation.

Metabolites identified:

no

Details on metabolites:

It is concluded that most of the butylamine was metabolised.

The oral ingestion of a single dose of 3.5 g n-butylamine was well tolerated.

Reference 3

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
n-Butylamine hydrochloride (NBA-HCl) has been used in the experimental studies investigating toxicokinetic behaviour (Rechenberger, 1940; Bourke et al., 1972).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Source chemical
Chemical name: Butan-1-aminium chloride
Synonym: n-Butylamine hydrochloride, n-butylammonium chloride
CAS number: 3858-78-4
EINECS number: 223-369-1
Chemical formula: C4H12ClN

Purity
n-Butylamine has a purity in the range > 99.5 to ≤ 100% with a typical purity of 99.8%.
Toxicokinetic studies in section 7.1.1 have been performed with n-butylamine hydrochloride of unknown purity. However, this is not regarded as relevant, as these studies have been performed to study the fate of the source chemical in the mammalian organism, and impurities are not expected to alter this metabolism to a relevant extent.


3. ANALOGUE APPROACH JUSTIFICATION
n-Butylammonium chloride has been tested in toxicokinetic studies as a surrogate for n-butylamine. The high corrosivity of the latter strongly restricts testing in vivo. Application of the test material n-Butylammonium chloride was in buffered solutions, i.e. n-butylammonium ion would have been generated in situ anyway. Therefore, the study results are considered valid for the evaluation of n-butylamine toxicokinetics.

Reason / purpose for cross-reference:

read-across source

Executive summary:

The study used as sourceinvestigated n-butylamine hydrochloride (butan-1-aminium chloride).The study results of the source compound were considered applicable to the target compound.

Reference 4

Endpoint:

basic toxicokinetics in vivo

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

supporting study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
n-Butylamine hydrochloride (NBA-HCl) has been used in the experimental studies investigating toxicokinetic behaviour (Rechenberger, 1940; Bourke et al., 1972).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Source chemical
Chemical name: Butan-1-aminium chloride
Synonym: n-Butylamine hydrochloride, n-butylammonium chloride
CAS number: 3858-78-4
EINECS number: 223-369-1
Chemical formula: C4H12ClN

Purity
n-Butylamine has a purity in the range > 99.5 to ≤ 100% with a typical purity of 99.8%.
Toxicokinetic studies in section 7.1.1 have been performed with n-butylamine hydrochloride of unknown purity. However, this is not regarded as relevant, as these studies have been performed to study the fate of the source chemical in the mammalian organism, and impurities are not expected to alter this metabolism to a relevant extent.


3. ANALOGUE APPROACH JUSTIFICATION
n-Butylammonium chloride has been tested in toxicokinetic studies as a surrogate for n-butylamine. The high corrosivity of the latter strongly restricts testing in vivo. Application of the test material n-Butylammonium chloride was in buffered solutions, i.e. n-butylammonium ion would have been generated in situ anyway. Therefore, the study results are considered valid for the evaluation of n-butylamine toxicokinetics.

Reason / purpose for cross-reference:

read-across source

Executive summary:

The study used as source investigated n-butylamine hydrochloride (butan-1-aminium chloride).The study results of the source compound were considered applicable to the target compound.

Description of key information

see below

Additional information

Toxicokinetics, Metabolism and Distribution

n-Butylammonium chloride has been tested in toxicokinetic studies as a surrogate for n-butylamine. The high corrosivity of the latter strongly restricts testingin vivo. Application of the test material n-Butylammonium chloride was in buffered solutions, i.e. n-butylammonium ion would have been generatedin situanyway. Therefore, the study results are considered valid for the evaluation of n-butylamine toxicokinetics.

No experimental data on absorption have been located.

The substance is assumed to be readily bioavailable by all potential routes of exposure; main potential exposure may occur by inhalation and by skin contact.

There is limited experimental data about excretion of n-butylamine (oral, human: Rechenberger 1940; i.p., rat: Bourke et al. 1972).The findings suggest that the substance easily passes cellular membranes and rapidly disappears from the body by direct excretion or metbolism.

In general, it can be assumed that n-butylamine as a primary aliphatic amine will be a substrate of mitochondrial monoamine oxidases (MAO) and undergoes ready metabolism in the mammalian organism (Cavender et al. 2000; Abbott et al. 2006):

Monoamine oxidase (MAO) catalyses the deamination of primary, secondary, and tertiary amines (Beard and Noe, 1981):

       2 RCH₂NR’R’’    + O₂+ 2 H₂O  -->  2 RCHO +   2 NHR’R’’ + H₂O   + H₂O₂

After initial oxidative deamination by wide-spread monoamine oxidases (MAO), mainly located in liver, kidney and the intestinal mucosa, the resulting aldehyde is further oxidised chiefly by NAD⁺-dependent aldehyde dehydrogenases to form the respective fatty acids, in this case butyric acid, which may directly enter the ß-oxidation pathway to be degraded to C2 bodies and finally to carbon dioxide.

____________________________

Reviews:

Abbott PJ, Mattia A, Renwick AJ, and DiNovi M (2006): Aliphatic and aromatic amines and amides (first draft).

WHO Food Additives Series Vol. 56 (2006), pp 327-397 [http://www.inchem.org/documents/jecfa/jecmono/v56je13.pdf]

[T04518]

Cavender FL, Bingham E, Cohrssen B, Powell CH (2000): Aliphatic and Alicyclic Amines. Patty´s Industrial Hygiene and Toxicology, J. Wiley & Sons [T02713]

Beard RR and Noe JT (1981): Aliphatic and Alicyclic Amines, in: Patty's Industrial Hygiene and Toxicology, Vol. 2 (Toxicology), chapter 44, pp. 3135-3173, John Wiley & Sons [T01289]

JECFA (2006): Evaluation of Certain Food Additives: 65the report. WHO Technical Report Series 934, Genf [ T04510]