Dimethylamine-borane (1:1)

Basic toxicokinetics

Administrative data

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

4 (not assignable)

Rationale for reliability incl. deficiencies:

abstract

Data source

Reference

Reference Type:

publication

Title:

Metabolism and disposition of [14C]dimethylamine borane in male Harlan Sprague Dawley rats following gavage administration, intravenous administration and dermal application.

Author:

Mathews J.M. et al.

Year:

2013

Bibliographic source:

Xenobiotica - the fate of foreign compounds in biological systems Volume 44, 2014 - Issue 1, p. 36-47

Materials and methods

Objective of study:

metabolism

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

The objective of the study was to evaluate the metabolism and disposition of DMAB in male Harlan Sprague Dawley (HSD) rats and in in human skin.

Test material

Test material information

Constituent 1

Reference substance name:

Dimethylamine-borane (1:1)

EC Number:

200-823-7

EC Name:

Dimethylamine-borane (1:1)

Cas Number:

74-94-2

Molecular formula:

C2H10BN

IUPAC Name:

N-Methylmethanamine-borane (1:1)

Radiolabelling:

yes

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

Further, DMAB was applied in fresh human skin (in vitro)

Sex:

male

Details on test animals or test system and environmental conditions:

no data

Administration / exposure

Route of administration:

other: oral (gavage), dermal and intravenous

Vehicle:

not specified

Details on exposure:

no data

Duration and frequency of treatment / exposure:

no data

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

1.5 mg/kg bw/day

Remarks:

oral

Doses / concentrations 2

Dose / conc.:

1.5 mg/kg bw/day

Remarks:

intravenous

Doses / concentrations 3

Dose / conc.:

0.15 mg/kg bw/day

Remarks:

dermal

Doses / concentrations 4

Dose / conc.:

1.5 mg/kg bw/day

Remarks:

dermal

Doses / concentrations 5

Dose / conc.:

15 mg/kg bw/day

Remarks:

dermal

No. of animals per sex per dose / concentration:

no data

Control animals:

not specified

Positive control reference chemical:

no data

Details on study design:

no data

Details on dosing and sampling:

no data

Statistics:

no data

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on absorption:

Dermal application:
The absorption of [14C]DMAB following dermal application was moderate; percent dose absorbed increased with the dose, with 23%, 32% and 46% of dose absorbed at 0.15, 1.5 and 15 mg/kg, respectively.
Absorption of DMAB in fresh human skin in vitro was ca. 41% of the applied dose: the analysis of the receptor fluid shows that the intact DMAB complex can be absorbed through the skin.

Details on distribution in tissues:

Dermal application:
Tissue retention of the radiolabel was low ca. 1%, but was higher than following the gavage or intravenous administration.

Oral/Intravenous application:
After 72 hours, 0.3-0.4% of radioactivity was recovered in tissues.

Details on excretion:

Oral/intravenous application:
Disposition of radioactivity was similar between gavage and intravenous administration of 1.5 mg/kg [14C] DMAB, with nearly 84%–89% of the administered radioactivity recovered in urine 24 h post dosing. At 72 h, only 1% or less was recovered in feces, 0.3% as CO2, and 0.5%–1.4% as volatiles.

Dermal application:
Urinary and fecal excretion ranged from 18%–37% and 2%–4% of dose, respectively, and 0.1%–0.2% as CO2, and 1%–3% as volatiles

Metabolite characterisation studies

Metabolites identified:

not specified

Any other information on results incl. tables

Following co-administration of DMAB and sodium nitrite by gavage, N-nitrosodimethylamine was not detected in blood or urine above the limit of quantitation of the analytical method of 10 ng/mL.

Applicant's summary and conclusion

Conclusions:

In conclusion, the study provides information on the metabolism and disposition of dimethylamine-borane in Harlan Sprague Dawley rats. The disposition of radioactivity was similar between oral and intravenous administration. Tissue retention of the radiolabel was low 1% for dermal application, but higher than the gavage or intravenous administration. For oral, intravenous and dermal application Dimethylamine-borane will be mainly excreted via urine.

Executive summary:

In a study conducted by the National Toxicology Program, the metabolism and disposition of dimethylamine-borane (DMAB) in male Harlan Sprague Dawley rats and in human skin was evaluated .

Disposition of radioactivity was similar between gavage and intravenous administration of 1.5 mg/kg [14C] DMAB, with nearly 84%–89% of the administered radioactivity recovered in urine 24 h post dosing. At 72 h, only 1% or less was recovered in feces, 0.3% as CO2, and 0.5%–1.4% as volatiles and 0.3%–0.4 % in tissues.

The absorption of [14C]DMAB following dermal application was moderate; percent dose absorbed increased with the dose, with 23%, 32% and 46% of dose absorbed at 0.15, 1.5 and 15  mg/kg, respectively. Urinary and fecal excretion ranged from 18%–37% and 2%–4% of dose, respectively, and 0.1%–0.2% as CO2, and 1%–3% as volatiles. Tissue retention of the radiolabel was low ∼1%, but was higher than following the gavage or intravenous administration.

Following co-administration of DMAB and sodium nitrite by gavage, N-nitrosodimethylamine was not detected in blood or urine above the limit of quantitation of the analytical method of 10 ng/mL.

Absorption of DMAB in fresh human skin in vitro was ∼41% of the applied dose: the analysis of the receptor fluid shows that the intact DMAB complex can be absorbed through the skin.