Morpholinium toluene-4-sulphonate

Endpoint summary

Additional information

Repeated dose toxicity oral:

In a subchronic study performed similar to OECD 408, Morpholine oleic acid salt (MOAS) was applied to mice for 13 weeks (Shibata, 1987). The dose levels of MOAS used were 0, 0.15, 0.3, 0.6, 1.25, and 2.5 % in drinking water (approximately 0, 70, 140, 200, 400 and 700 mg/kg). It seems that a dose equivalent to approx. 200 mg/kg impaired renal activity, as evidenced by the rise in kidney weights, increase in BUN-levels, and the specific gravity of the urine. Approximately 700 mg/kg bw/day caused swelling of the proximal renal tubules. No further treatment-related histopathological alterations were observed in organs of either sex. Due to the given data, a NOAEL of 140 mg/kg is derived for oral repeated toxicity.

In a repeated dose toxicity study on Sprague-Dawley rats, morpholine was added to feed for eight weeks (Sander & Buerkle, 1969). Seven rats took in a daily average of 500 m/kg. No mortality could be observed. After 270 days had elapsed, the only effect that was noted was moderate adiposis of the liver. The NOAEL was set at 500 mg/kg.

 

A 28 -day oral study of toluene-4-sulphonic acid was performed similar to OECD 408 (Habrinol Decin s.r.o., 1990).Tested concentrations were 4, 20, 100, and 500 mg/kg. Salivation and acidic pH-values were noted at 500 mg/kg, probably contributed to the acidity of the test substance. Altogether, no adverse effects were found at the highest tested concentration of 500 mg/kg. The NOAEL was set at 500 mg/kg. To support the assessment, a further read-across was included using hydrotropes - the salt form of the sulphonic acids.

The studies with the salts (hydrotropes) provide valid read-across for the acids. The specific cation is not expected to have an appreciable effect on fate, ecotoxicity or mammalian toxicity and therefore the dataset for the hydrotropes category can be added to the assessment (see read-across statement in section13).

There are a total of 6 oral repeated dose studies for the hydrotrope sodium xylene sulphonate (CAS No. 1300-72-7). Three 14-day range-finding studies were conducted resulting for mice in a NOAEL of higher than 1 % (The Soap and Detergent Association, 1979). For rats, a NOAEL of > 1% < 2% was achieved in the one study and a NOAEL of approximately 1 % in the second study (The Soap and Detergent Association, 1979 and 1980).

In the 90-day study, groups of 30 young rats (15/gender) were exposed by diet for 90 days to concentrations of 0.2 %, 1 %, and 5 % (Huntsman, 1969). This study was conducted comparable to the OECD 408 guideline study. Based on haematology effects (decreased red blood cells, decreased activity of a transaminase in serum), urinalysis (decreased specific gravity of urine), decreased spleen weight, and histopathology (minimal changes in the liver), the NOAEL was set at > 763 < 3534 mg/kg (93 % active ingredient). In another study, five groups of ten mice of each sex were exposed for 13 weeks to 5 doses in the diet (The Soap and Detergent Association, 1980). These concentrations were for males 152, 305, 610, 1220 and 2439 mg/kg and for females 154, 308, 617, 1234 and 2467 mg/kg (assuming 100% purity). No treatment-related findings could be detected. For that reason, the NOAEL was set at higher than 2439 mg/kg. In addition, a study was conducted resembling OECD 408 (The Soap and Detergent Association, 1980). Here, young male and female rats (10 per sex per dose) were exposed by diet for 13 weeks to 0.125, 0.25, 0.50, 1.0 and 2.0 % of Xylene Sufonic Acid Sodium Salt. The NOAEL was set > 1% < 2 %.

Repeated dose toxicity: inhalation

 

In a two-year chronic inhalation study (Huntsman, 1983), male and female rats that inhaled morpholine at concentrations of 0, 10, 50, or 150 ppm (0, 36, 181 or 543 mg/m³), 6 hours/day, 5 days/week for 104 weeks showed normal growth, survival, hematology, and clinical chemistry. The incidence of neoplasia in morpholine-exposed rats was not altered significantly compared to the concurrent controls. Rats exposed at the 150 ppm concentration developed focal erosion and focal squamous metaplasia of the epithelium of the anterior nasal cavity. Obvious evidence of chronic nasal irritation and inflammation with neutrophilic infiltration was documented in these same tissues. Ocular injury, including retinal degeneration, corneal irritation, uveitis, and corneal damage, were demonstrated only in rats exposed at 150 ppm. The distribution of ocular changes recorded in the groups exposed at 10 or 50 ppm morpholine was similar to that seen in the controls. Chronic exposure of rats to morpholine for 2 years at concentrations of 150 ppm or less revealed no carcinogenic potential or chronic systemic toxicity. Consistent with its known irritating properties, morpholine produced only local irritation, which was limited almost exclusively to high-dose animals. The systemic NOEC was set at higher than 50 ppm, the local NOEC was 36 ppm.

In a previous subchronic inhalation study (Conaway et al., 1984), rats inhaled morpholine at concentrations of 0, 25, 100, and 250 ppm. None of the animals died or were sacrificed in extremis during the study. No treatment-related trends or findings were apparent in either sex for haematology, clinical chemistry and gross pathology. Exposure to morpholine at 250 ppm for 13 weeks confirmed the result, seen at week 7, of focal erosion of the maxillary turbinates accompanied by the presence of necrotic cell debris and focal squamous metaplasia. Lesions were then noted involving the nasal septum and anterior nasal cavities. Lesions of chronic murine pneumonia were also increased in severity in rats of the high-level group. A maximum tolerated dose (MTD) of 150 ppm was established on the basis of the nasal irritation.

Repeated dose toxicity: dermal

No studies are available for morpholinium tuluene-4 -sulphonate.

Since reliable oral and inhalative toxicity data are available for the dissociation products morpholine and toluene-4-sulphonic acid and it´s salts, no additional repeated dose study for the dermal route is required. Nevertheless one study was performed with morpholine.

Shea (1939) assessed the dermal toxicity and skin absorption of morpholine in one investigation using rabbits. Unneutralized, diluted morpholine (1 part morpholine, 2 parts water) was applied at a daily dose of 900 mg/kg bw to the clipped skin. All rabbits (7/7) died before the eleventh dose. Necrosis of the treated skin, and inflammation and congestion of the underlying organs were evident upon gross examination due to corrosivity of the test substance. Microscopic lesions of the liver and effects on kidneys and spleen were observed. No assessment of systemic effects is possible.

Justification for classification or non-classification

Based on the current weight-of-evidence, Morpholinium toluene-4-sulphonate is not subject to classification according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (GHS/CLP).