Morpholinium toluene-4-sulphonate

Endpoint summary

Additional information

No data are available for morpholinium toluene-4-sulphonate. But information is available for morpholine and p-toluene sulphonic acid. 

Kinetics and metabolism of morpholine

The pharmacokinetic profile, protein binding and metabolism of morpholine were studied in different species after single administration. The available studies in rat demonstrate that morpholine is rapidly and quantitatively absorbed. Morpholine has been reported to be resistant to metabolism in the rat (Tanaka et al., 1978, Sohn et al., 1982) and rabbit (Van Stee et al., 1981). In contrast, Sohn et al. (1982) also reported that morpholine is metabolized by N-methylation and N-oxidation in the guinea pig whereas it is metabolized to a much smaller extent by N-methylation in the rat and hamster (Sohn et al., 1982). Reports also suggested that morpholine is preferentially distributed to the rabbit kidney (Van Stee et al., 1981) and the rat kidney and intestine (Tanaka et al., 1978). Morpholine is primarily excreted unchanged in the urine.

 

Absorption

Toxicity experiments on rodents have shown that morpholine is absorbed after oral, dermal and inhalation exposure (BASF, 1967;Shea, 1939; Smyth et al., 1954).

 

Distribution

Tanaka et al. (1978) determined the distribution of 14C-labelled morpholine in male Wistar rats (3 animals/group, 250 to 300 g) after oral (200 mg/kg bw) and intravenous administration (150 mg/kg bw). The radioactivity was determined in the dried, powdered organs. Large amounts of 14C morpholine were only found in muscle and intestine regardless of route of administration. In rats sacrificed 2 hours after oral administration of morpholine-HCl, 29% of the radioactivity was found in the intestine and 26% in muscle tissue. Similarly, 2 hours after intravenous injections, 19 and 27 % of the dose was found in the intestine and muscle tissue, respectively. Elimination of radioactivity from other organs, tissues and blood was very rapid in cases of both oral and i.v. administration.

Female New Zealand White rabbits were exposed to morpholine (905 mg/m³) for 5 hours by nose-only inhalation (Tombropoulos, 1979). At the end of the exposure, the animals were sacrificed and the tissue and body fluids analysed. Concentrations of morpholine were highest in urine (324 mg/L) and kidney (118 mg/kg bw), the other tissues having concentrations below 50 mg/kg bw.

Van Stee et al. (1981) injected six male New Zealand White rabbits intravenously with 5 mmol [14C]-labelled morpholine/kg bw (435 mg/kg bw). The distribution of radioactivity after 30 min showed the highest concentrations in the renal medulla (36 mmol/kg bw) and cortex (15.4 mmol/kg bw), followed by lung (5.1 mmol/kg bw), liver (4.7 mmol/kg bw) and blood (2.3 mmol/L). Morpholine was not bound to serum proteins. Furthermore, the subcellular binding interactions of morpholine were investigated (Naylor Dana Institute, 1983). Uniform distribution of 14C in TCA-insoluble fractions indicated a non-specific binding and/or incorporation of morpholine. No significant amounts of covalently bound 14C were detected in the subcellular fractions of the liver.

 

Metabolism

Morpholine is eliminated mainly in a non-metabolized form in the urine of the rat, hamster and rabbit (Tanaka et al., 1978; Van Stee et al., 1981; Sohn et al., 1982). However, Sohn et al. (1982) reported that morpholine is metabolized by N-methylation followed by N-oxidation in the guinea-pig. After an intraperitoneal injection of 125 mg/kg bw [14C]-labelled morpholine in guinea-pigs, 20 % of the radioactivity was found in the urine as N-methylmorpholine- N-oxide. The morpholine ring can be cleaved in mammalian systems.  

 

Elimination and excretion

Expired air:

Following intraperitoneal injection, the elimination of 14C from labelled morpholine through expired air is minimal. In rats, only about 0.5 % of the dose of radioactively labeled morpholine was exhaled as 14C carbon dioxide (Sohn et al., 1981). In rabbits, only 0.0008 % of the administered morpholine dose was 14C carbon dioxide (Van Stee et al., 1981).

Urine:

Elimination studies on male Wistar rats (200-350 g) were carried out by administering morpholine HCl (500 mg/kg bw) or [14C]-labelled morpholine HCl (200 mg/kg bw) orally and morpholine-HCl (250 mg/kg bw) intravenously. In all cases, over 85 % of the total dose was excreted in urine within 24 hours. A further portion, up to 5 %, was excreted during the next three days. 14C morpholine palmitate was eliminated slightly slower, but the urinary excretion within 3 days following oral administration amounted to 90 % of the dose (Tanaka et al., 1978). The time-course of urinary excretion of 14C by Sprague-Dawley rats, Syrian golden hamsters, and strain II guinea pigs treated with 14C morpholine was compared by Sohn et al. (1982). In all three species over 80 % of the dose was excreted in 3 days, while the rate of urinary excretion within the first 6 hours was greatest in the hamster and least in the guinea pig.

Van Stee et al. (1981) infused rabbits intravenously with 14C morpholine (5 mmol/kg bw) which had been neutralized with HCl. After 4 hours, 18.5 % of the dose was excreted in the urine. When the pH of the urine was lowered from 7.8 - 7.9 to 7.1 - 7.2 by administration of ammonium chloride (10 g/L) in drinking-water prior to the morpholine injection, the urinary excretion more than doubled (to 43 %). These data suggest that the urinary excretion of morpholine is enhanced by its neutralization with acid.

Faeces:

Rats dosed orally or intravenously with morpholine HCl excreted not more than 1.7 % of the dose in the faeces (Tanaka et al., 1978). However, when dosed orally with morpholine palmitate (Tanaka et al., 1978), up to 7% was excreted in faeces.

 

Retention and turnover

Plasma concentration-time curves of 14C after intraperitoneal injections of 14C morpholine (125 mg/kg bw in 0.9% NaCl) in Sprague-Dawley rats, Syrian golden hamsters, and strain II guinea pigs declined biexponentially. Marked differences were noted between the guinea pig and the other two species with respect to plasma levels (as well as the metabolism of morpholine). Whereas rates of the first phase of elimination from plasma in rats and hamsters were similar (half-lives of 115 and 120 min, respectively), the half-life in guinea-pigs was significantly longer (300 min) (Sohn et al., 1982).

 

Additional information on morpholine – nitrosation

In the presence of nitrite, morpholine can be nitrosated to the carcinogenic N-nitrosomorpholine (NMOR). For instance, NMOR was found in the stomach of rodents whose feed contained nitrite and morpholine (Sander et al., 1968; Kitano et al., 1979). Hecht & Morrison (1984) developed a method to monitor the in vivo formation of NMOR by measuring N-nitroso(2 -hydroxyethyl)glycine, its major urinary metabolite. The formation of NMOR was measured in F-344 rats over wide range of doses of morpholine (38.3 - 0.92 µmol) and sodium nitrite (191 - 4.8 µmol). According to estimates by the authors, 0.5 to 12 % of the administered morpholine, depending on the dose, was nitrosated. Furthermore, in vitro experiments have demonstrated that nitrosation of morpholine is also possible in human saliva and in gastric juices (Ziebarth, 1997; Ziebarth, 1973; Boyland et al., 1971).

 

Kinetics and metabolism of p-toluene sulphonic acid

Following oral administration, p-toluene sulphonic acid is rapidly absorbed. In dogs were given 17.4 mg of radiolabelled 35S sodium tosylated/kg body weight, maximum radioactivity was measured in the blood after just 30 minutes (Dreyfuss et al., 1971).

In rats and dogs which were given oral doses of p-toluene sulphonate as sultamicillin tosylate (100 mg/kg and 50 mg/kg body weight, respectively), maximum serum concentrations were measured 2 hours after administration (Kano et al., 1985)

In situ studies of intestinal absorbtion with Sprague-Dawley rats showed that at pH 7.5 /thus, in dissociated form) PTSA was not absorbed after 10 minutes (Ho et al., 1982)

The distribution of PTSA in the tissues also occurs rapidly. Its half life in the plasma of both dogs and rats was found to be 75 minutes (Dreufuss et al., 1971; Ho et al., 1982). Studies with sultamicillin tosylate produced a half life value in dogs of 60 minutes and in ratd of 100 minutes (Kano et al., 1985).

The distribution of PTSA in the tissues following intravenous injection (no information on dose size) has been studies.. The highest concentration after 35 minutes was found in urine and kidneys (Ho et al., 1982). Following adinistration as Sultamicillin tosylate to rats, its concentration was measured after 2 and 6 hours. After 6 hours, p-toluene sulphonate was no longer detectable in any tissues apart from the kidney (1.2 ug/g), heart (0.1 ug/g) and serum (0.3 ug/ml) (Kano et al., 1985)

As can be seen from these studies, elimination is very rapid and occurs mainly via the kidneys. Within four days, following oral administration of 34.8 mg of PTSA/kg body weight to rats, 82% was escreted in the urine and 13% in the faeces. For dogs, which were given 17.4 mg PTSA/kg body weight, the respective values were 84,5% and 17.5%. In both cases by far the greater part of the administerd dose was eliminated after just one day (Dreyfuss et al., 1971).

In rats, within 24 hours sultamicillin tosylate (200 mg/kg bw) was eliminated to 87% in the animal's urine and to 1.2% in the faeces (Kano et al., 1985). Analyses of urine and faeces showed that in both cases the substance had been eliminated unaltered. The excretion profiles for dogs which were administerd 17.4 mg sodium tosilate-35S/kg bw i.p. or p.o. and for rats which where administerd 34.8 mg/kg of the same substance p.o. were found to be very similar (Dreyfuss et al., 1971) . After 5 days, excretion of labelled sodium tosilate in the dogs was below the detection limit. In rats, too, even at a dose of 200 mg/kg, after 4 days 95% of the dose has been excreted (Dreyfuss et al., 1971).

Also when p-toluene sulphonate was administerd to rats in the form of sultamicillin tosylate in daily doses of 100 mg/kg bw over a period of 21 days, no accumulation of p-toluene sulphonate in the animal was found. The highest p-toluene suklphonate concentrations were found in the kidneys (14 ug/g) and serum (2.9 ug/ml) 4 hours following administration of the last dose, while the concentration in other tissues was under 1 ug/g. These concentrations were of the same order of magnitude as those found 4 hours after administration of a single dose of the substance. 24 hours after administration of the final dose, p-toluene sulphinate was no longer detectable in the animals' organs (Kano et al., 1985)

Regarding dermal adsorption a model was built to evaluate the dermal penetration for hydrotopes.

A multiple homogeneous layer model was used to derive an estimate of dermal penetration for hydrotropes. The mathematical model simulates the uptake of a chemical substance through the skin into a central sink compartment below the skin. The model uses the substance's diffusion and partitioning coefficients and calculates the total (cumulative) fraction of the substance that enters the stratum corneum for a specific exposure duration. The model does not include any metabolism and the model is believed to represent an upper bound estimate of the potential uptake of the substance through the skin.

Dermal penetration simulations based on a mechanistic model of the process of uptake of chemical substances in skin predicts that the dermal penetration of a generic hydrotrope is less than 0.6% of the applied amount (over a wide range of exposure scenarios). Simulations show that for an exposure extending to 23 hours, the dermal uptake does not exceed 2.8% of the applied amount, regardless of the applied amount (concentration) within the range of 0.0002% to 10%. 10% is considered an upper bound of the concentration of hydrotropes in consumer products.

 

Although polarity of the aromatic sulfonic acids is less than hydrotopes, the low Kow can help in supporting a very low penetration of acids too. The dermal pathway is in any case not included in the exposure scenarios because of the corrosivity of the substance.