Tosyl chloride

Endpoint summary

Description of key information

Due to lack of quantitative data, absorption rates of 100% are indicated for all three routes. Available studies do not indicate a concern for bioaccumulation.

Key value for chemical safety assessment

Bioaccumulation potential:

no bioaccumulation potential

Absorption rate - oral (%):

100

Absorption rate - dermal (%):

100

Absorption rate - inhalation (%):

100

Additional information

Tosyl chloride(CAS 98-59-9) is in this dossier also referred to as p-Toluenesulfochloride (PTSC).

 

1. Physical-chemical properties

Tosyl chloride (PTSC) is an almost odourless, white, hygroscopic crystalline solid, of low dustiness. Light microscopic examination revealed that the Tosyl chloride contains particles < 100 µm. The shape of the product is non-fibrous. This observation is confirmed by sieving the sample. In total 1.9 %m/m is < 100 µm and the respirable fraction (≤ 4 µm) is below 0,04%.

PTSC is a very reactive substance.Sulfonyl halides are known to undergo nucleophilic (S_N2) substitution reactions. Use is generally in organic synthesis for the conversion of a hydroxyl function into a good O-tosyl leaving group via the formation of a reactive alkyl tolsylate intermediate. Its chemical reactivity is also driving it toxicological profile.

 

PTSC has a molecular weight of 191. The substance is a hygroscopic crystalline solid, with a melting point about 68 ºC. No boiling point can be determined as it starts to decompose at temperatures from 160°C. A vapour pressure of 0.72 Pa at 20 °C has been established for PTSC.The water solubility and octanol-water partition coefficient are estimatedby QSARs at around 0.123 g/L and 2.28 respectively. However, as the substance readily hydrolysis in water to p-Toluenesulfonic acid, it is better to take this information on this substance into consideration. The water solubility of p-Toluenesulfonic acid is over 1000 g/L and the logPow is -0.96, both as actually measured values. The pH is not considered to have a modulating effect on these properties and p-Toluenesulfonic acid is considered to be neutral at the whole physiological pH range.

 

2. Data from toxicity studies

PTSC is of low acute toxicity. There are two reasonably high validity studies available resulting to an oral LD50 of 4680 mg/kg bw and LD50 > 5000 mg/kg bw. An available dermal LD50 > 5010 mg/kg bw indicates also low acute toxicity via dermal route.

Available data from different studies shows consistent results indicate that PTSC is irritating, but not corrosive to skin, and corrosive to the eyes. As stated before, PTSC readily hydrolysis in contact with water to p-Toluenesulfonic acid and HCL, which in turn are both corrosive substances. Probably the higher moisture content in eyes explains the more severe reactions compared to the skin.

PTSC was positive in the LLNA test which is consistent with its chemical profile indicating a possibility to react with protein. The hydrolysis productp-Toluenesulfonic acid has not found to be sensitising in a Guinea pig maximisation test.

Performed studies, covering in vitro bacterial mutagenicity, mammalian mutagenicity and clastogenicity by means of an in vivo micronucleus study, support the conclusion that although chemical profiling indicate a possible reactivity to DNA the rapid hydrolysis into the non-genotoxic p-toluenesulfonic acid precluding to exert its activity in the in vivo situation. The in vitro mutagenicity study (MLA) resulted to a positive response in one of the repeats performed with S9 at the maximum possible concentration in view of toxicity. An in vivo micronucleus showed negative results, following i.p. dosing and showing toxicity in bone marrow. A complication in the testing for genotoxicity is that the substance can react with solvents. In the case of DMSO this leads to the formation of a reactive sulfoxomium.

 

Data from repeated dose toxicity studies:

Oral:

As result of the rapid hydrolysis intop-Toluenesulfonic acidand HCl, both strong acids, the most important and dose limiting effect is local irritation in the stomach. At testing with PTSC this resulted to a LOAEL of 150 mg/kg bw in a 28-day study. At this level however, no systemic effects occurred. Effects have been shown to be reversible following a 14-day recovery in the 750 mg/kg dose group.

Low systemic toxicity is supported by information on the hydrolysis productp-Toluenesulfonic acid, where a 28-day study resulted to a NOAEL of 500 mg/kg bw. Evaluation of further data obtained from cross-reading from other Aromatic Sulphonic Acids (ASA) involving longer duration studies of 90-days (but also 2 year studies) show a comparable low toxicity and high NOAEL. (See additional document on category of Aromatic Sulphonic Acids (ASA))

Based on this information it is justified to take 150 mg/kg bw as NOAEL for systemic toxicity, as systemic exposure will only be top-Toluenesulfonic acid having showing a much higher NOAEL of 500 mg/kg bw.

 

Inhalation:

There are no data available following testing via inhalation. Exposures by inhalation are unlikely in view of the low vp of 0.13 Pa at 20°C, its low dustiness (the respirable fraction (≤ 4 µm) of the hygroscopic, crystalline solid is below 0,04%) and low likelihood of exposures by aerosols with uses limited to chemical intermediate in industrial settings. Furthermore Tosyl chloride readily hydrolyses to toluene sulfonic acid and HCL which are both corrosive acids. Inhalation of dust particles will therefore lead to respiratory irritation/corrosion rather than expected to result in systemic toxicity.

 

Dermal:

Also data on repeated dose toxicity via dermal route is lacking.Tosyl chloride is used as a chemical intermediate in industrial or professional setting, where due to its corrosive/irritant and sensitising properties adequate protection is applied. Exposures are consequently limited. Testing by the dermal route is therefore not appropriate.

 

3. Absorption, distribution, metabolism, excretion

Both PTSC isneutral at environmental relevant pH range. Absorption is therefore expected to occur by all routes of exposure. However, it can be expected that the substance is hydrolysed to p-Toluenesulfonic acid before taken up from Gastro-Intestinal tract.The Human Intestinal absorption (HIA) is estimated (QSAR toolbox v. 3.1) to be comparable for both substances at around 91%.

Considering its high polarity and water solubility, p-Toluenesulfonic acidis expected to be rapidly excreted and minimally absorbed into systemic circulation. Information from kinetic studies with labelled p-Toluenesulfonic acid confirms rapid distribution and very rapid excretion mainly in urine with highest concentrations seen in urine about half hour following intravenous injection. Following oral administration of 34.8 mg of PTSAcid/kg body weight to rats, 82% was excreted in the urine and 13% in the faeces within four days, the largest part already within one day.

 

At this stage no data are available on dermal absorption. Based on the irritant/corrosive properties of PTSC and even more p-Toluenesulfonic acid dermal absorption as a consequence of facilitated penetration through damaged skin can be anticipated. QSARs for dermal absorption indicate low levels. Due to the lack of quantitative absorption data, 100% absorption is taken as a conservative approach.

 

Also for inhalation no data are available on absorption, but similar as oral absorption seems reasonable and 100% is proposed. Exposures by inhalation are unlikely in view of the low vp of 0.13 Pa at 20°C, its low dustiness (the respirable fraction (≤ 4 µm) of the hygroscopic, crystalline solid is below 0,04%) and low likelihood of exposures by aerosols with uses limited to chemical intermediate in industrial settings.

 

Considering the low octanol/water partitioning coefficient and the rapid excretion ofp-Toluenesulfonic acid, the potential for bioaccumulation of Tosyl chloride is considered to be low.

 

Below are molecular chemical profile and estimated properties of PTSC compared to those of its hydrolysis product p-Toluenesulfonic acid and its salt.

 

 

Molecular chemical profile and estimated properties:

	Tosyl chloride	Toluene-4-sulphonic acid	Toluenesulfonic acid, sodium salt
CAS	98-59-9	104-15-4 (6192-52-5 hydrate)	657-84-1 / 12068-03-0 (16722-51-3 anion)
Physical state	Crystalline solid	Solid	Solid
SMILES	c1(S(=O)(=O)Cl)ccc(C)cc1	S(c1ccc(C)cc1)(O)(=O)=O	S(c1ccc(C)cc1)(=O)(=O)[O-].[Na+]
Molecular formula	C7H7ClO2S	C7H8O3S	C7H7NaO3S
Molecular weight	190.647	172.202	194.183
Solubility:    avgLogS                           (g/L)	-3.19 (0.123 g/L)	-1.22 (10.4 g/L)	-1.11 (15.1 g/L)
Solubility (meas)	n.a.: hydrolyses	1154 g/L (pH=0)	818 g/L (pH 9.2)
Density	1.492	1.3453	1.5445
pKa:               neutral:	No ionisable atoms	pKa = -2.14	pKa = -2.14
logPow(ALOGPS 2.1)         (KOWWIN v1.68)	2.28 (±0.55) 3.4886	0.41 (±0.92) -0.6177	0.26 (±1.61) -2.4047
logPow (meas)	n.a.: hydrolyses	-0.96	-3.18
logD (Chemaxon)	pH      logD All       2,433	pH       logD 1,700   -0,694 4,600   -0,709 5,500   -0,709 7,400   -0,709	pH       logD1 1,700   -0,694 4,600   -0,709 5,500   -0,709 7,400   -0,709
Mp (EPIWIN)	75.29 °C	101.76 °C	532.98 °C *
bp (EPIWIN)	290.16 °C	331.69 °C	228.00 °C *
Vp (EPIWIN) (25°C)	0.161 Pa	0.000386 Pa	3.51E-009 Pa *
Mp (meas)	68.1 °C (Avg Lit.)	30±1 °C	> 400 °C
bp (meas)	Decomp.≥160°C	223.4 °C	> 400 °C
Vp (meas)	0.13 Pa at 20°C	Ca 2 Pa (IUCLID)	< 1.331E-8 Pa at 20°C
Reactivity	DNA: nucleophilic (SN2) substitution; Protein: Adduct formation	No alerts	No alerts
HOMO (eV) LUMO (eV) difference	-10.7(-10.7;-10.7)  -1.95(-1.95;-1.95) 8.75	-10.4(-10.4;-10.4) -0.881(-0.884;-0.878) 9.519	-10.4(-10.4;-10.4)  -0.879(-0.886;-0.873) 9.299
Dermal penetration coefficient Kp (est)	0.00437 cm/hr	0.000039 cm/hr	0.000000981 cm/hr
Max. dermal absorption	7.00E-7 mg/cm²/hr	7.29E-2 mg/cm²/hr	2.75E-2 mg/cm²/hr
Human Intestinal absorption (HIA)	91%	90.5%	90.5%

Molecular formula, molecular weight, pKa and logD were all calculated using ChemAxon MarvinSketch (v.5.4.0.1).

Melting point, boiling point, vapour pressure and logPow were estimated by EPI Suite (v4.1).

* EPI Suite indicates a covalent binding of Sodium to oxygen.

Solubility and logPow are estimated using ALOGPS 2.1 (VCCLAB, Virtual Computational Chemistry Laboratory,http://www.vcclab.org, 2005)

Reactivity: QSAR Toolbox v.3.0: profiling: DNA binding (OASIS v1.1; OECD); Protein binding (OASIS v1.1; OECD)

HOMO/LUMO Energy, [eV], quantum-chemical descriptor (the energy of the highest occupied resp. lowest unoccupied molecular orbital), calculated in OASIS software, based on MOPAC 7.

(a large difference between HOMO and LUMO energies implies high stability and thus low reactivity)

Absorption properties:

- dermal: EpiSuite v. 4.1 (Pow used measured or ALOGPS value); (water:0.0005 cm/hr):

- intestinal: HIA (Human Intestinal Absorption, QSAR toolbox v.3.1)

Max. dermal absorption: IH Skin Perm v1.03 from AIHA