Dimethylamine-borane (1:1)

Endpoint summary

Link to relevant study record(s)

Reference

Reference 1

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

Objective of study:

metabolism

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.

Radiolabelling:

yes

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

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

Dose / conc.:

1.5 mg/kg bw/day

Remarks:

oral

Dose / conc.:

1.5 mg/kg bw/day

Remarks:

intravenous

Dose / conc.:

0.15 mg/kg bw/day

Remarks:

dermal

Dose / conc.:

1.5 mg/kg bw/day

Remarks:

dermal

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

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

Metabolites identified:

not specified

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.

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.

Reference 2

Endpoint:

basic toxicokinetics, other

Remarks:

review article

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

data from handbook or collection of data

Objective of study:

other: Review article about the toxicology of boranes

Qualifier:

no guideline followed

Principles of method if other than guideline:

Review article

GLP compliance:

no

Radiolabelling:

no

Conclusions:

In conclusion, the review article provides information on the chemistry and elimination of boranes. According to this review paper, dimethylamine borane will be eliminated rapidly in the body.

Executive summary:

The review article provides information about the toxicology of boranes. In this review article, Roush describes that amine boranes are very stable and hydrolyse very slowly, are selective reducing agents and have variable solubility in water.

It is further reported that dimethylamine borane will be eliminated rapidly in the body. In a study from Levinska, cited by Roush, dimethylamine borane was injected intravenously in a dog. It has been shown that the compound rapidly disappeared from the blood stream, and over 80% was recovered in the urine in the first 24 hours.

Levinskas suggests that the boranes may exert their toxic effects by different metabolic pathways. This approach was suggested by the apparent separation of LD50 for the boranes into two distinct groups based on the milligrams of boron per kilogram rather than on the basis of milligrams of borane per kilogram.

 In a study cited from Hill, Levinskas and Merrill, it has been compared the toxicity of the boranes with their reducing power and found that for the known boranes the reducing power paralleled the toxicity considered boranes may interfere with the oxidation-reduction mechanism.

Description of key information

In a review paper of Roush, it is described that boranes are very stable and hydrolyse very slowly, are selective reducing agents and have variable solubility in water. Furthermore, dimethylamine-borane will be eliminated rapidly in the body. After intravenous application in the dog, 80% of dimethylamine-borane was recovered in the urine in the first 24 hours.

Moreover, in the publication by Levinskas, the toxicity of several borane compounds was compared by comparing the LD50 values from different routes of administration (oral, inhalative, intraperitoneal) and species (rats and mice). Levinskas suggested, that the boranes may exert their toxic effects by different metabolic pathways. This approach was suggested by the apparent separation of LD50 for the boranes into two distinct groups based on the milligrams of boron per kilogram rather than on the basis of milligrams of borane per kilogram.

A study reported by Mathews et al. provides information on the metabolism and disposition of dimethylamine-borane in Harlan Sprague Dawley rats. Disposition of radioactivity was similar between gavage and intravenous administration of 1.5 mg/kg [14^C] 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 [14^C] DMAB following dermal application was moderate. The percent dose absorbed increased with the applied 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.

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.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential

Additional information

No studies, which were performed according to internationally accepted guidelines (e.g. OECD Test Guideline 417) for evaluation of the toxicokinetics [i.e. Absorption, Distribution, Metabolism and Elimination (ADME)] of dimethylamine-borane, were found in the public domain or in the archives of the applicants. However, existing literature has been identified in the public domain and reviewed for the ADME properties of dimethylamine-borane.

 

In a review paper of Roush, it is described that Boranes are very stable and hydrolyse very slowly, are selective reducing agents and have variable solubility in water. Further, dimethylamine-borane will be eliminated rapid in the body. After intravenous application in dog, 80% of dimethylamine-borane was recovered in the urine in the first 24 hours.

A rapid elimination has been also seen in a study reported by Mathews et al.. In this study, the metabolism and disposition of dimethylamine-borane 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 bw, 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.

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.

Based on these studies it can be concluded, that oral, intravenous and dermal applied dimethylamine-borane will be eliminated mainly and rapid via urine. A small part will be excreted via feces and low amounts (ca. 1 % or below) will retend in tissues. It has also been shown for dermal application that percent dose absorbed increased with the dose.

 

Another aspect was shown in a study conducted by Levinskas. Levinskas suggests that the boranes may exert their toxic effects by different metabolic pathways. This approach was suggested by the apparent separation of LD50 for the boranes into two distinct groups based on the milligrams of boron per kilogram rather than on the basis of miligrams of borane per kilogram.