4-nitrobenzenesulphonyl chloride

Endpoint summary

Description of key information

The key physicochemical characteristics of the powder 4-nitrobenzene-1-sulfonylchloride are: a moderate molecular weight (221.6 g/mol), low particle size (mass median diameter 823.6 μm MMAD), very low water solubility (0.839 mg/L), moderate partition coefficient (log Kow 2.1 at 20°C and neutral pH) and low volatility (vapour pressure 0.02 Pa at 25°C). The water solubility of 4-nitrobenzene-1-sulfonylchloride could not be determined as it is consideredhydrolytically unstable at pH 4, 7 and 9. The test item, degrades too quickly in water to be analysed.

Based on its molecular weight is < 500 g/mol and its log Kow value between -1 and 4, oral absorption is expected. However,due to its rapid degradation in water, it can be inferred that the parent compound may only be present in the gastrointestinal fluid for a limited period of time. The combined 28-days repeated dose oral toxicity study with the reproduction/developmental toxicity screening test confirms the low to moderate oral absorption rate as no adverse parental effects were observed up to the highest dose level tested but some adverse effects were observed in reproductive parameters (lower number of implementation sites). The respiratory absorption factor is set at 50%. The aerodynamic diameter of the powder powder 4-nitrobenzene-1-sulfonylchloride is larger than 100 µm thus have a lower potential to be inspired. Also 4-nitrobenzene-1-sulfonylchloride can diffuse/dissolve into the mucus lining of the respiratory tract but considering its rapid degradation in fluids, it can be inferred that the parent compound may only be present in a limited period of time. The dermal absorption factor is set to 50% based on the fact that the substance is a solid and its log Kow is moderate. Furthermore, 4-nitrobenzene-1-sulfonylchloride was not considered to be a corrosive nor irritating substance which implies that no enhanced penetration can be caused by damage to the skin.

Key value for chemical safety assessment

Absorption rate - oral (%):

50

Absorption rate - dermal (%):

50

Absorption rate - inhalation (%):

50

Additional information

4-nitrobenzene-1-sulfonylchloride(CAS 98-74-8) is a light-yellow powder with a moderate molecular weight (221.6 g/mol), a moderate partition coefficient (log Pow of 2.1 at 20°C and pH 7), a low volatility (vapour pressure of 0.02 Pa at 25°C) and a particle size of 823.6 µm (Mass Median Aerodynamic Diameter or MMAD). A water solubility test could not be performed with4-nitrobenzene-1-sulfonylchloride as it is consideredhydrolytically unstable at pH 4, 7 and 9. In the course of the determination of the physical-chemical properties of the test item, it was already observed that the test item degraded too quickly in water to be analysed.

The backbone of4-nitrobenzene-1-sulfonylchlorideis a benzene ring with sulfonyl chloride and nitrogen dioxide as substituents. The presence ofthe positively charged nitrogen leads to a higher water solubility.

No toxicokinetic data (animal or human studies) are available on this substance. The data present in this dossier are based on physicochemical and toxicological parameters and will allow a qualitative assessment of the toxicokinetic behaviour of4-nitrobenzene-1-sulfonylchloride.

Absorption

Oral/GI absorption:

4-nitrobenzene-1-sulfonylchlorideis considered favorable for absorption since its molecular weight is < 500 g/mol and its log Pow value is between -1 and 4.However, the determination of its water solubility and hydrolysis behaviour was rendered impossibledue to its rapid degradation in water, it can be inferred that the parent compound may only be present in the gastrointestinal fluid for a limited period of time. Hence, toxicokinetic predictions based on the characteristics of the parent compound may be of limited relevance.

An acute oral toxicity study with4-nitrobenzene-1-sulfonylchloridewas performed on female Wistar rats (OECD 423 and EU Method B.1 tris; van Sas 2018). The test item was administered by oral gavage to two subsequent groups of three female rats at 2000 mg/kg body weight. Animals were subjected to daily observations and weekly determination of body weight. Macroscopic examination was performed after terminal sacrifice (Day 15).

No mortality occurred. Some of the clinical signs observed on Day 1 and Day 2 included hunched posture, uncoordinated movements and piloerection. The mean body weight gain of all the animals over the study period was normal. No abnormalities were found at macroscopic post mortem examination of all animals.

The oral LD50 value of 4 -nitrobenzene-1 -sulfonyl chloride in Wistar rats was established to exceed 2000 mg/kg body weight.

In an oral combined repeated dose toxicity study with reproduction/developmental toxicity screening test, the test substance was administered by daily oral gavage to male and female Wistar Han rats at dose levels of 10, 30 and 100 mg/kg/day (10 rats/sex/dose level) (OECD 422; Van Otterdijk, 2018).

Noadverse parental effects were observed up to the highest dose level tested(100 mg/kg) leading to a NOAEL above 100 mg/kg bw/day.

Reproductive results showed at 100 mg/kg dose, a lower number of implantation sites (10.6 vs 13.2 in control females) and lower fertility index (78% vs. 100% in the control group). Accordingly, developmental results showed a lower mean number of living pups (8.8 vs 11.9 in the control group). The reproduction NOAEL was, therefore, concluded to be 30 mg/kg.

Based on the above information,the oral absorption factor is considered to be 50%.

 

Respiratory absorption:

Because4-nitrobenzene-1-sulfonylchloridehas a low volatility, the availability of the substance for inhalation as a vapour is limited. Also, its MMAD is significantly larger than 100 µm (823.6 µm); therefore, the solid particles are unlikely to be inhaled and reach the thoracic region.

4-nitrobenzene-1-sulfonylchloridecan diffuse/dissolve into the mucus lining of the respiratory tract but considering its rapid degradation in fluids, it can be inferred that the parent compound may only be present in a limited period of time. The toxicokinetic predictions based on the characteristics of the parent compound may therefore be of limited relevance. Its lipophilic character (log Pow > 0) implies that the product has the potential to be subsequently absorbed directly across the respiratory tract epithelium through passive diffusion. The portion of the product which is not dissolved into the mucus could be coughed or sneezed out of the body or swallowed. As described above, the product has the potential to be absorbed after oral intake.

Based on the physicochemical properties, therespiratory absorption factor is considered to be 50%.

Dermal absorption:

Since4-nitrobenzene-1-sulfonylchlorideis a solid, the product will not be readily taken up by the skin in comparison to liquid products. The dry product will have to dissolve into the surface moisture of the skin before uptake can take place. Because4-nitrobenzene-1-sulfonylchloridedegrades quickly in water,it can be inferred that it may not be present on the skin surface long enough for uptake. On the other hand, considering that uptake occurs,the compound must first penetrate into the (lipid rich) stratum corneum in order to cross the skin. The moderate log Pow value of 2.1 indicates that the substance is lipophilic and therefore easily crosses the lipid rich environment of the stratum corneum leading to dermal uptake.

In anin vitroskin corrosion study (OECD Guideline 431 and EU Method B.40 ), 4-nitrobenzene-1-sulfonyl chloride was not corrosive to the skin based on the criteria of the CLP regulation (EC) No 1272/2008. In addition, according to OECD Guideline 439 and EU Method B.46, 4 -nitrobenzene-1-sulfonyl chloride was not irritating to the skin based on the criteria of the CLP regulation (EC) No 1272/2008.

In a Bovine Corneal Opacity and Permeability (BCOP) test, performed according to OECD Guideline 437, 4 -nitrobenzene-1-sulfonyl chloride induced serious eye damage. It was concluded that the test item should be classified for serious eye damage Category 1 according to the criteria of the CLP regulation (EC) No 1272/2008.

Based on the above, thedermal absorption factor is considered to be 50%.

Distribution

The water solubility and moderate molecular weight predict that4-nitrobenzene-1-sulfonylchloridewill probably distribute through the body due to diffusion through aqueous channels and pores. Since the substance is lipophilic, the substance is likely to distribute into cells leading to a higher intracellular concentration in comparison to the extracellular concentration particularly in fatty tissues.

Accumulation

Based on the physicochemical properties of4-nitrobenzene-1-sulfonylchloride( high particle size, and moderate partition coefficient), no or only limited accumulation is expected within the body.

Metabolism

The determination of its water solubility and hydrolysis behaviour was rendered impossible due to its rapid degradation in water. However, the degradation products are not confirmed analytically.

Based on the structure,4-nitrobenzene-1-sulfonylchloridemight undergo phase I biotransformation such as hydroxylation, reduction and dealkylation followed by conjugation reactions (phase II) such as glucuronidation (by the enzyme glucuronosyltransferase) and sulfation (by the enzyme sulfotransferase). The Phase II conjugation reactions largely increase the hydrophilic character of the product. Metabolism mainly takes place in the liver, causing route specific presystemic (or first pass) effects, especially after oral intake. Other metabolic changes may take place in the gastrointestinal (GI) flora or within the GI tract epithelia (mainly in the small intestine), respiratory tract epithelia (in the nasal cavity, trachea-bronchial mucosa and alveoli and skin), etc.

Excretion

A possible route of excretion of4-nitrobenzene-1-sulfonylchloridefrom the systemic circulation is the urine. In general, conjugated metabolites such as glucuronides and sulfates from Phase II biotransformation reactions, which are more water soluble than the parent compound, are excreted in the urine. Most of them will have been filtered out from the blood by the kidneys, though a small amount can enter the urine directly by passive diffusion. There is also the potential for re-absorption into the systemic circulation across the tubular epithelium. Another route of excretion of4-nitrobenzene-1-sulfonylchloridecan be the bile. Substances excreted in the bile may be conjugated (such as glucuronides). The excretion via the bile is highly influenced by hepatic function since metabolites formed in the liver may be excreted directly into the bile without entering the bloodstream. Products in the bile pass through the intestine before excretion in the feces and can thus undergo enterohepatic recycling which will prolong their half-life.