N-butylbenzenesulphonamide

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1997

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Objective of study:

toxicokinetics

Guideline:

other: no data

GLP compliance:

no

Radiolabelling:

yes

Remarks:

[13C6] NBBS

Species:

rat

Strain:

Wistar

Sex:

female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: /
- Age at study initiation: /
- Weight at study initiation: ca. 200g
- Fasting period before study: 12h
- Housing: metabolic cages
- Individual metabolism cages: yes
- Diet (e.g. ad libitum): fasted for a 12 hour period
- Water (e.g. ad libitum):ad libitum
- Acclimation period: 4 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): no data
- Humidity (%): no data
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light):no data


IN-LIFE DATES: From: no data

Route of administration:

oral: feed

Vehicle:

other: sweetened condensed milk

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
Unlabelled NBBS was administrated orally (1mg/kg; dissolved in sweetened condensed milk).
[13C6] NBBS was administrated intravenously via the lateral tail vein (1 mg/kg; dissolved in 0,9% saline)

DIET PREPARATION
- Rate of preparation of diet (frequency):1
- Mixing appropriate amounts with (Type of food): sweetened condensed milk
- Storage temperature of food:/


VEHICLE
- Justification for use and choice of vehicle (if other than water): feed
- Concentration in vehicle: /
- Amount of vehicle (if gavage):
- Lot/batch no. (if required):
- Purity:


HOMOGENEITY AND STABILITY OF TEST MATERIAL:

Remarks:

Doses / Concentrations:
Unlabbeled NBBS: 1mg/kg; dissolved in sweetened condensed milk
[13C6] NBBS: 1 mg/kg; dissolved in 0,9% saline

No. of animals per sex per dose / concentration:

4

Control animals:

no

Details on dosing and sampling:

METABOLITE CHARACTERISATION STUDIES
- Tissues and body fluids sampled (delete / add / specify): urine, blood, plasma, serum or other tissues, cage washes, bile
- Time and frequency of sampling:24 hours
- From how many animals: 4 (samples pooled or not): not
- Method type(s) for identification (GC-MS
- Limits of detection and quantification: Standard for GC-MS were prepared by serial dilution of a solution of either [13C6] NBBS (1 mg/ml in ethyl acetate) or native NBBS (1mg/ml in ethyl acetate) to give solutions with final amounts of between 10 ng/ml and 1 µg/ml ([13C6] NBBS; 1 ng injected) or 100 ng/ml (native NBBS; 100 pg injected). A fixed amount of internal standard, [2H9] NBBS (corresponding to 50pg injected on column), was added to each solution. Standard or calibration curves were typically established with 6 standards (including a zero standard), spanning the analytical range.
- Other:


TREATMENT FOR CLEAVAGE OF CONJUGATES (if applicable):

Details on absorption:

BBSA is not accumulated by tissues of the periphery:examination of (13C6) BBSA levels eight hours following administration revealed concentrations in all tissues were only a fraction of that in plasma

Details on distribution in tissues:

>95% of the dose is distributed throughout the body within the first minute following intravenous administration of (13 C6) BBSA

Metabolites identified:

yes

Details on metabolites:

In vitro studies of biotransformation of BBSA in the rabbit, rat and human enabled the identification of one phase I metabolite common to all three
species: 2-hydroxyn-butylbenzenesulfonamide (BBSA-OH). Phase II metabolites were not identified

Conclusions:

The pharmacokinetics, oral bioavailability, cerebrovasculair permeability and biotransformation of the neurotoxic compound NBBS were studied in order that the human health risk due to environmental exposure to NBBS could be evaluated.
Pharmocokinetics of NBBS was determined in Wistar rats, following intravenous administration of the isotopomer 13C-NBBS. 13C-NBBS is rapidly cleared from plasma by the liver. The compound has a short distribution phase (t1/2 of upto 47 seconds) and a long terminal phase (t1/2 of upto 17 hours). Plasma 13C-NBBS concentrations, 24 hours after administration, only represented 0,04% of the administered dose. These data indicated rapid uptake into tissue, which was confirmed upto 8 hours following administration. 13C-NBBS was not, however, accumulated by any of the tissues studied.
Oral bioavailability was determined by similtaneously administering native NBBS orally and 13C-NBBS intravenously to Wistar rats. The compound was found to be absorbed erratically and subject to first pass metabolism. Plasma concentrations of orally administred NBBS fluctuated over the duration of the experiment. This precluded estimation of areas under the oral NBBS-curves to infinity, hence the mean for absolute bioavailability (62%) is a minimum value.
Cerebrovascular permeability of NBBS was determined with 13C-NBBS, in Sprague-Dawley rats, using the in-situ brain perfusion technique of Takasato et al. (1984). The uptake of 13C-NBBS into brain was very rapid and flow limited. Assuming an average cerebral perfusion fluid flow rate of 0,11 ml/s/g, the calculated single pass extraction value for 13C-NBBS is 99,95% with a K in of 0,1099 ml/s/g. This is in close agreement with experimental values for the 15 second saline perfusion (extraction = 98% - 125% and K in = 0,108 - 0,137). No differences in regional brain distribution of NBBS were found.
In-vitro biotransformation studies revealed one phase I metabolite in incubates of NBBS containing human, rabbit and rat post-mitochondrial supernatant (S-9 in fraction). This metabolite is 2-hydroxy-n-butylbenzenesulfonamide (NBBS-OH; hydroxylated in the omega-1 position). Other species specific cytochrome P-450 dependent metabolites were not detected and neither were phase II metabolites.
Based on these data, environmental exposure to NBBS does not pose a significant human health risk.

Executive summary:

The pharmacokinetics, oral bioavailability, cerebrovasculair permeability and biotransformation of the neurotoxic compound NBBS were studied in order that the human health risk due to environmental exposure to NBBS could be evaluated.

Pharmocokinetics of NBBS was determined in Wistar rats, following intravenous administration of the isotopomer 13C-NBBS. 13C-NBBS is rapidly cleared from plasma by the liver. The compound has a short distribution phase (t1/2 of upto 47 seconds) and a long terminal phase (t1/2 of upto 17 hours). Plasma 13C-NBBS concentrations, 24 hours after administration, only represented 0,04% of the administered dose. These data indicated rapid uptake into tissue, which was confirmed upto 8 hours following administration. 13C-NBBS was not, however, accumulated by any of the tissues studied.

Oral bioavailability was determined by similtaneously administering native NBBS orally and 13C-NBBS intravenously to Wistar rats. The compound was found to be absorbed erratically and subject to first pass metabolism. Plasma concentrations of orally administred NBBS fluctuated over the duration of the experiment. This precluded estimation of areas under the oral NBBS-curves to infinity, hence the mean for absolute bioavailability (62%) is a minimum value.

Cerebrovascular permeability of NBBS was determined with 13C-NBBS, in Sprague-Dawley rats, using the in-situ brain perfusion technique of Takasato et al. (1984). The uptake of 13C-NBBS into brain was very rapid and flow limited. Assuming an average cerebral perfusion fluid flow rate of 0,11 ml/s/g, the calculated single pass extraction value for 13C-NBBS is 99,95% with a K in of 0,1099 ml/s/g. This is in close agreement with experimental values for the 15 second saline perfusion (extraction = 98% - 125% and K in = 0,108 - 0,137). No differences in regional brain distribution of NBBS were found.

In-vitro biotransformation studies revealed one phase I metabolite in incubates of NBBS containing human, rabbit and rat post-mitochondrial supernatant (S-9 in fraction). This metabolite is 2-hydroxy-n-butylbenzenesulfonamide (NBBS-OH; hydroxylated in the omega-1 position). Other species specific cytochrome P-450 dependent metabolites were not detected and neither were phase II metabolites.

Based on these data, environmental exposure to NBBS does not pose a significant human health risk.

Description of key information

Pharmacokinetics of NBBS was determined in Wistar rats, following intravenous administration of the isotopomer 13C-NBBS. 13C-NBBS is rapidly cleared from plasma by the liver. The compound has a short distribution phase (t1/2 of up to 47 seconds) and a long terminal phase (t1/2 of up to 17 hours). Plasma 13C-NBBS concentrations, 24 hours after administration, only represented 0,04% of the administered dose. These data indicated rapid uptake into tissue, which was confirmed up to 8 hours following administration. 13C-NBBS was not, however, accumulated by any of the tissues studied.

Oral bioavailability was determined to be 62% as a minimum value; since this value is close to the default value of 50% the conservative default value was used for the risk assessment. The uptake of 13C-NBBS into brain was very rapid and flow limited. Assuming an average cerebral perfusion fluid flow rate of 0,11 ml/s/g, the calculated single pass extraction value for 13C-NBBS is 99,95% with a K in of 0,1099 ml/s/g. This is in close agreement with experimental values for the 15 second saline perfusion (extraction = 98% - 125% and K in = 0,108 - 0,137). No differences in regional brain distribution of NBBS were found.

In-vitro biotransformation studies revealed one phase I metabolite in incubates of NBBS containing human, rabbit and rat post-mitochondrial supernatant (S-9 in fraction). This metabolite is 2-hydroxy-n-butylbenzenesulfonamide (NBBS-OH; hydroxylated in the omega-1 position). Other species specific cytochrome P-450 dependent metabolites were not detected and neither were phase II metabolites. Based on these data, environmental exposure to NBBS does not pose a significant human health risk.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

50

Additional information

The pharmacokinetics, oral bioavailability, cerebrovascular permeability and biotransformation of NBBS were studied in order that the human health risk due to environmental exposure to NBBS could be evaluated (Ganesh Kumar Samiayah, 1997).

Pharmacokinetics of NBBS was determined in Wistar rats, following intravenous administration of the isotopomer 13C-NBBS. 13C-NBBS is rapidly cleared from plasma by the liver. The compound has a short distribution phase (t1/2 of up to 47 seconds) and a long terminal phase (t1/2 of up to 17 hours). Plasma 13C-NBBS concentrations, 24 hours after administration, only represented 0,04% of the administered dose. These data indicated rapid uptake into tissue, which was confirmed up to 8 hours following administration. 13C-NBBS was not, however, accumulated by any of the tissues studied.

Oral bioavailability was determined by simultaneously administering native NBBS orally and 13C-NBBS intravenously to Wistar rats. The compound was found to be absorbed erratically and subject to first pass metabolism. Plasma concentrations of orally administered NBBS fluctuated over the duration of the experiment. This precluded estimation of areas under the oral NBBS-curves to infinity; hence the mean for absolute bioavailability (62%) is a minimum value.

Cerebrovascular permeability of NBBS was determined with 13C-NBBS, in Sprague-Dawley rats, using the in-situ brain perfusion technique of Takasato et al. (1984). The uptake of 13C-NBBS into brain was very rapid and flow limited. Assuming an average cerebral perfusion fluid flow rate of 0,11 ml/s/g, the calculated single pass extraction value for 13C-NBBS is 99,95% with a K in of 0,1099 ml/s/g. This is in close agreement with experimental values for the 15 second saline perfusion (extraction = 98% - 125% and K in = 0,108 - 0,137). No differences in regional brain distribution of NBBS were found.

In-vitro biotransformation studies revealed one phase I metabolite in incubates of NBBS containing human, rabbit and rat post-mitochondrial supernatant (S-9 in fraction). This metabolite is 2-hydroxy-n-butylbenzenesulfonamide (NBBS-OH; hydroxylated in the omega-1 position). Other species specific cytochrome P-450 dependent metabolites were not detected and neither were phase II metabolites.

Based on these data, environmental exposure to NBBS does not pose a significant human health risk.