Toluenesulphonamide

Endpoint summary

Description of key information

Rapid and complete oral uptake followed by rapid excretion mainly with urine. Overall dermal absorption is about 20%.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

20

Absorption rate - inhalation (%):

100

Additional information

Information is based on profiling, available data in database and cross-reading between o-TSA, p-TSA and o/p-TSA (For justification see document Justification in support of cross-reading between Toluenesulphonamides).

 

Full ADME study is available on p-TSA, which is based on dosing with Chloramine-T. It is shown that [14C]-Chloramine-T is almost instantaneously converted to p-TSA in contact with stomach and intestinal contents of rat, and therefore results are fully applicable to p-TSA. Similarly, also an in-vitro dermal absorption study demonstrated the conversion of Chloramine-T, resulting to only p-TSA to pass the skin. Therefore the available ADME data on Chloramine-T is directly applicable in p-TSA.

 

Oral absorption:

These ADME studies show that p-TSA is rapidly and almost completely absorbed after oral administration, and relatively fast completely excreted again, mostly via the urine, as a benzoic acid derivative (4-sulfamoylbenozic acid, CAS 138-41-0). At termination, only about 1% of the activity remained in the body. About 78-87% is excreted in the urine, and 13-16% via the faeces. About 4-6% passes with the bile.

The tissue concentration of Chloramine-T equivalents (measured radiolabel) were below the concentration observed in blood in all groups indicating that there is no potential for accumulation. The available information from acute oral toxicity on p-TSA confirms this assessment. Clinical signs appear quick and at not too high dose levels resolve again within a day. At high dose levels specifically involvement of the urinary tract is observed.

Dermal absorption:

In-vitro dermal penetration studies with 0.5% aq Chloramine-T solution show that approximately 12% passed the skin completely and about 8% of the applied dose passed the stratum corneum but remained fixed in the skin after 24 hours. This results to an overall absorption of about 20%. Dermal absorption is thus lower then oral absorption. The amount of 20% can be regarded as worst case, as the level of absorption decreases with increasing concentrations: At a concentration of 3% only 4% passed the skin and total absorption was about 10%.

 

Information available from profiling the molecular structures indicate for p-TSA an estimated dermal penetration coefficient of 0.006 cm/h comparable to that of water (0.0005 cm/hr). The Maximal dermal absorption: 0.0016 mg/cm²/hr (IH Skin Perm v1.03 from AIHA). [0.0016 mg/cm²/hr equals 3.21 mg/hr over 2000 cm², approximate skin surface of the hands and forearms]. For o-TSA the value for Maximal dermal absorption differs slightly with a lower value compared to p-TSA, which is related to lower water solubility (p-TSA: 3100 mg/L, o-TSA: 1600 mg/L ).

Inhalation:

There is no information in uptake following inhalation. Due to the very low vp any relevant uptake has to be by means of aerosols or particles. These will deposit mainly on upper airways, and will be subsequently swallowed following mucociliary transportation to pharynx. This results to no principal difference in absorption compared oral route.

 

 

Metabolism:

In the urine samples from Chloramine-T studies, one major radioactivity peak was observed. This peak was identified as benzoic acid derivative (4-sulfamoylbenozic acid, CAS 138-41-0).

An older study from literature on p-TSA confirms the identity of the major metabolite (Ball, L.M., et al., 1978). Female albino Wistar rats were given a single low and high oral dose (29 mg/kg bw in 1ml 20% ethanol in water and 200 mg/kg bw in 50% aq. propylene glycol (1ml)). This study also identified the small amounts of other metabolites found next to a remaining small amount of parent compound p-TSA (1.5-2.3%). Other identified metabolites were 4-sulphamoylbenzyl alcohol (2.0-3.9%), 4-sulphamoylbenzaldehyde (0-1.5%) and at high dose N-acetyltoluene-4-sulphonamide (2.1-2.3%). Other studies reported in literature on metabolism were largely qualitative and confirm the metabolite4-sulfamoylbenozic acid in urine of dogs and rats (Flaschenträger B., et al., 1934; Minegishi, K. I., et al., 1972).

 

Similar information on kinetics and metabolism on o-TSA is available from literature (Renwick et al., 1987). O-TSA is rapidly absorbed and subsequently eliminated via urine in rat (92% in 24 hr). Excretion in man is slower (80% in 48h) but still relatively rapid. Most is excreted as conjugated oxidation metabolites of 2-sulphamoylbenzyl alcohol and saccharin.