Benzenesulfonamide, N-[2-[[(phenylamino)carbonyl]amino]phenyl]-

Endpoint summary

Link to relevant study record(s)

Reference

Endpoint:

basic toxicokinetics, other

Type of information:

other: Expert Statement

Adequacy of study:

key study

Study period:

2022-02-28

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Expert Statement

Details on absorption:

Generally, absorption is favoured for molecular weights below 500 g/mol and log Pow values between -1 and 4. Therefore, it can be concluded that NKK-1304 is likely to become bioavailable following the oral route, as indicated by its physico-chemical properties. Some clinical effects have been observed in the acute oral toxicity study at 2000 mg/kg bw like hunched posture and piloerection indicating some systemic bioavailability. However, no adverse effects have been observed in acute or repeated dose toxicity studies up to the highest doses tested.
Absorption via the respiratory route depends on physico-chemical properties like vapor pressure, log Pow and water solubility. Decomposition of the compound at high temperatures and the low vapor pressure indicate that the substance will not be available for inhalation as a vapor under standard environmental conditions. However, the substance is a powder and inhalation of dust might occur. Generally, particles with an aerodynamic diameter below 100 µm have the potential to be inspired, particles below 50 µm may reach the thoracic region and those below 15 µm are able to pass into the alveolar region of the respiratory tract. Since 50 % (by mass) of the particles are smaller than 43.53 µm a significant amount of the substance is expected to reach the thoracic region upon exposure to dust. However, no adverse effects have been observed in a 4 h acute inhalation toxicity study in rats at the limit concentration of 5.23 mg/L, indicating no toxic potential of the substance after inhalation of the aerosol.
In general, dermal absorption is favoured by log Pow values between 1 and 4, particularly if water solubility is high. As the water solubility is low, dermal uptake for NKK-1304 is expected to be moderate. No skin effects were observed in mice upon exposure during an LLNA test. The substance is not irritating to skin. Therefore, only minimal damage to enhance the penetration of the stratum corneum is expected upon exposure to the target substance.

Details on distribution in tissues:

In general, the smaller the molecule, the wider the distribution. Based on the physico-chemical properties the substance will be distributed by systemic circulation. Bioaccumulation is not likely to occur based on the compound’s physical-chemical characteristics, particularly water solubility and octanol-water partition coefficient

Details on excretion:

In general, urinary excretion in favored by low molecular weight (below 300 g/mol in the rat) good water solubility, and ionization of the molecule. Substances that are excreted in the bile tend to have higher molecular weights or may be conjugated as glucuronides derivates. Therefore, NKK-1304 is expected to be excreted partially via urine but also via faeces

Details on metabolites:

Based on the results obtained in the hydrolysis study performed with NKK-1304 the substance is considered as hydrolytically stable at physiological pH (no degradation observed) and also at acidic and alkaline pH values (half- life times between 600 and 765 days at pH 4 and 9 and 50°C). Thus, hydrolysis in the GI tract is not expected.

Metabolic transformation of the substance may occur in the liver and may partially be catalysed by cytochrome P-450 enzymes. Phase I reactions may include oxidation or hydroxylation. Most probably metabolism will not render the parent compound more toxic. This assumption is supported by results obtained in the in vitro genotoxicity tests. The assays show that there is no significant difference in toxicity, in absence or presence of a rodent microsomal S9-fraction. This clearly indicates that the formation of reactive metabolites is rather unlikely. Phase II reactions may include sulfatation and glucuronidation as well as other conjugation reactions. It is likely that metabolism of the substance will render the molecule more polar, leading to faster excretion via urine and bile (following conjugation).

Conclusions:

Based on physico-chemical properties, oral absorption and distribution through-out the body is expected. Some clinical signs have been reported after acute oral administration to rats. However, no adverse effects have been observed in acute or repeated dose toxicity studies up to the highest doses tested. Dermal absorption is expected to be low. Absorption as vapor via the inhalation route is, due to physico-chemical properties of the test item, is not expected. Based on the particle size, particles could reach the alveolar region of the respiratory tract after inhalation of dust. However, no adverse effects have been observed in a 4 h acute inhalation toxicity study in rats at the limit concentration of 5.23 mg/L, indicating no toxic potential of the substance after inhalation. Bioaccumulation of the substance is not expected after continuous exposure. The test substance is expected to be excreted via faeces and urine.

Description of key information

Based on physico-chemical properties, oral absorption and distribution through-out the body is expected. Some clinical signs have been reported after acute oral administration to rats. However, no adverse effects have been observed in acute or repeated dose toxicity studies up to the highest doses tested. Dermal absorption is expected to be low. Absorption as vapor via the inhalation route is, due to physico-chemical properties of the test item, is not expected. Based on the particle size, particles could reach the alveolar region of the respiratory tract after inhalation of dust. However, no adverse effects have been observed in a 4 h acute inhalation toxicity study in rats at the limit concentration of 5.23 mg/L, indicating no toxic potential of the substance after inhalation. Bioaccumulation of the substance is not expected after continuous exposure. The test substance is expected to be excreted via faeces and urine.

Key value for chemical safety assessment

Bioaccumulation potential:

low bioaccumulation potential