N-butylbenzenesulphonamide

Basic toxicokinetics

Administrative data

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

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1997

Report date:

1997

Materials and methods

Objective of study:

toxicokinetics

Test guideline

Guideline:

other: no data

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

N-butylbenzenesulphonamide

EC Number:

222-823-6

EC Name:

N-butylbenzenesulphonamide

Cas Number:

3622-84-2

Molecular formula:

C10H15NO2S

IUPAC Name:

N-butylbenzenesulfonamide

Details on test material:

- Name of test material (as cited in study report): N-n-butyl benzenesulphonamides (NBBS)
- Substance type: mono constituent substance-organic
- Physical state: liquid
- Analytical purity: no data
- Impurities (identity and concentrations): no data
- Composition of test material, percentage of components: N-n-butyl benzenesulphonamides
- Isomers composition: no data
- Purity test date: no data
- Lot/batch No.: no data
- Expiration date of the lot/batch: no data
- Stability under test conditions: no data
- Storage condition of test material: no data
- Other: NBBS was obtained from Pfaltz & Bauer (Waterbury, CT, USA) and used without additional purification.

Radiolabelling:

yes

Remarks:

[13C6] NBBS

Test animals

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

Administration / exposure

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:

Doses / concentrations

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):

Results and discussion

Toxicokinetic / pharmacokinetic studies

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

Metabolite characterisation studies

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

Applicant's summary and conclusion

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.