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Carcinogenicity

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Description of key information

Combined chronic toxicity and carcinogenicity study (OECD 453): oral, 2 years, rat
NOAEL (carcinogenicity), males/females = 159/220 mg/kg bw/day
NOAEL (systemic toxicity), males/females = 39/56 mg/kg bw/day
Carcinogenicity study (OECD 451): oral, 1.5 years, mouse
NOAEL (carcinogenicity) male/females = 506/354 mg/kg bw/day
NOAEL (systemic toxicity), males/females = 50/354 mg/kg bw/day

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Dose descriptor:
NOAEL
159 mg/kg bw/day

Justification for classification or non-classification

The available data on carcinogenicity do not meet the criteria for classification according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.

Additional information

There are data available from a combined chronic toxicity and carcinogenicity study according to OECD 453 in rats and a carcinogenicity study according to OECD 451 in mice, both conducted under GLP conditions.

According to OECD 451, the test substance was administered for 18 months via the diet to groups of mice at concentrations of 350, 2000 and 3500 ppm, corresponding to 50, 287 and 506 mg/kg bw/day for males and to 63, 354 and 616 mg/kg bw/day for females, respectively (Langrand-Lerche, 2006). In addition, an interim sacrifice was performed after 52 weeks of treatment to assess chronic toxicity.

Groups of 60 male and 60 female mice were initially intended to be fed a diet containing 350, 2000 or 7000 ppm of the test substance. Since the Maximum Tolerated Dose was exceeded in females at 7000 ppm during the first weeks of treatment, an additional treatment group (60 animals/sex) at 3500 ppm was added to the study approximately one month after the start of treatment. The high rate of mortality observed in both sexes at 7000 ppm led to the early termination of this treatment group.

The mortality incidence in males was higher at 3500 ppm than in the control group after 12 and 18 months of treatment, largely due to the presence of stones within the urinary tract, causing acute or chronic renal failure or due to secondary treatment-related nephropathy following product administration.

At the 18-month haematology determination, a tendency towards lower red blood cell count was noted in both sexes. This change was associated with slightly lower haemoglobin concentration, haematocrit and mean corpuscular haemoglobin concentration and slightly higher mean corpuscular volume. Histopathological treatment-related changes were mainly attributed to the presence of urinary stones or to treatment-related nephropathy. These changes were located in the urinary bladder and to a lesser extent in the kidney at the 12-month interim sacrifice.

At the carcinogenicity phase (18-month) sacrifice, changes due to treatment-related nephropathy were seen in the kidney, urinary bladder, prostatic urethra and ureters. In the liver, minimal to slight centrilobular to panlobular hepatocellular hypertrophy and an increased incidence of hepatocellular single cell necrosis were observed in males. All the effects seen in the urinary tract were considered to be due to a chronic irritative mechanism, resulting from the formation of stones or crystals. In addition, indirect treatment-related findings were observed in the lymphoid system in males and were considered to be secondary to the stress induced by the stone deposition and/or the treatment-related nephropathy. In the heart, a higher incidence of epicardial mixed cell infiltrates was noted in 5/50 males at 3500 ppm, compared to no cases in controls. This minimal change only observed in males was considered to be an indirect and non-adverse response to the treatment.

Neoplastic changes comprised transitional cell papilloma in the urinary bladder of 2/49 females at 3500 ppm. This finding was considered to be secondary to the chronic hyperplastic changes due to the presence of calculi. Analysis of urinary bladder stones taken from one male and one female at terminal sacrifice revealed that the composition of the stones consisted of approximately 90 to 95% of test material.

In conclusion, dietary administration of the test substance over an 18-month period to the mouse, at dose levels up to 3500 ppm (corresponding to 506 mg/kg/day in males and 616 mg/kg/day in females), produced transitional cell papilloma in the urinary bladder of 2 females. The incidence of these tumours was very low and was considered to be secondary to the chronic hyperplastic changes resulting from chronic irritation due to the presence of calculi. The NOEL was 350 ppm for males (equivalent to 50 mg/kg/day) and 2000 ppm for females (equivalent to 354 mg/kg/day).

According to OECD 453, the test substance was administered to groups of 60 male and 60 female rats by continuous dietary treatment at 1000, 4000 and 8000 ppm, corresponding to 39, 159 and 321 mg/kg/day in males and 56, 220 and 447 mg/kg/day in females, respectively, over a 24-month period (Langrand-Lerche, 2006).

The mortality rate was higher in females at 8000 ppm after 24 months of treatment and was largely due to secondary treatment-related nephropathy following product administration. Mean cumulative body weight gain was reduced during the first week of treatment by 7 and 12% in males and females treated at 8000 ppm, respectively, compared to the controls. Urinalysis revealed the presence of sulfonamide-like crystals throughout the study in both sexes, the effect being more pronounced in females than in males. At the 12-month interim sacrifice, treatment-related non-neoplastic findings were seen microscopically in the kidney and the urinary bladder. At the carcinogenicity phase (24-month) sacrifice, treatment-related effects were found in the urinary tract, i. e. kidney, urinary bladder, and ureters. These changes were due to treatment-induced nephropathy, characterized in the kidney by a combination of hyperplastic and inflammatory changes associated with the presence of stones. A slightly higher incidence of the commonly occurring lesion diffuse bilateral tubular degeneration of the testis and bilateral oligospermia of the epididymis was observed at the carcinogenicity phase. Neoplastic changes comprised of a high dose-related transitional cell carcinoma in the kidney of one male and a transitional cell carcinoma in the urinary bladder of one female. These findings, seen only at 8000 ppm, were considered to be secondary to the combination of hyperplastic and inflammatory changes associated with the presence of stones. In conclusion, dietary administration of the test substance over a 24-month period to the rat, at dose levels up to 8000 ppm (corresponding to 321 mg/kg/day in males and 447 mg/kg/day in females), produced a transitional cell carcinoma in the kidney of one male and a transitional cell carcinoma in the urinary bladder of one female. The incidence of these tumours was very low and was considered to be secondary to the chronic hyperplastic changes resulting from chronic irritation due to the presence of stones. The NOAEL for carcinogenicity was159 mg/kg bw/day for males and 220 mg/kg bw/day for females.

The NOAEL for systemic toxicity over a 24month period of dietary administration with the test substance to rats was 1000 ppm in both sexes (equivalent to 39 mg/kg/day in males and 56 mg/kg/day in females).

In summary, Cyprosulfamide induced a very low incidence of bladder tumors in rats and mice. This occurred only at high doses and was associated with the formation of urinary tract calculi. As urinary tract calculi represented a toxicologic response only at high doses in rats and mice, it is consistent with what is known chemically, metabolically and toxicologically for sulfonamide and related compounds (Clayson, 1974; Petri, 2006; Clayson et al., 1967).

In humans, sulfonamides have been used clinically for more that fifty years, and their toxicologic effects are well known (Robinson and MacDonald, 2001). This includes the commonly observed formation of sulfonamide-containing crystals in the urine of patients on sulfonamides, without any adverse toxicologic consequence (Clayson, 1974). Calculi can form from sulfonamides in humans, but this is exceedingly rare and has not been associated with the formation of bladder tumors. In fact, many patients with long standing bacterial cystitis with or without urinary tract calculi are treated with long term sulfonamide antibiotic therapy (Schaeffer and Schaeffer, 2007). Based on this long clinical experience, sulfonamides are not considered carcinogens for humans, and are widely prescribed.

In conclusion, Cyprosulfamide, like many sulfonamides, when ingested at high exposure levels, produces urinary tract solids, including calculi, which lead to cytotoxicity, subsequent inflammatory reaction and regenerative urothelial proliferation, and in the rat and mouse, rarely lead to bladder tumors. Based on the lack of genotoxicity, the well known biology and toxicology of urinary tract calculi, and the lack of carcinogenic effect of sulfonamides in humans, even when significantly high doses leading to the formation of sulfonamidecrystals in the urinary tract are formed, Cyprosulfamide, does not pose a carcinogenic hazard or risk to humans. For further information see the position paper attached.

Literature:

Schaeffer, A.J., and Schaeffer, E.M. Infections of the urinary tract. In: Wein, A.J., Kawanssi, L.R., Novick, A.C., Pantin, A.W., and Peters,(Eds.), Campbell-Walsh Urology, Ninth Ed., Saunders-Elsevier,, Vol 1: 223-303, 2007.

Clayson, D.B. Bladder carcinogenesis in rats and mice: Possibility of artifacts. J. Natl. Cancer Inst., 52:1685-1689. 1974

Petri, Jr, W.A. Sulfonamides, trimethoprim–sulfamethoxazole, quinolones, and agents for urinary tract infections. In: Brunton, L.L., Lazo, J.S., Parker, K.L., Buxton, I.L.O., and Blumenthal, D.K. (Eds.). Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11thedition. Chapter 43: 1111-1126, 2006.

Clayson, D.B., Pringle, J.A.S., and Bonser, G.M. 4- Ethylsulphonylnaphthalene-1-sulphonamide: A new chemical for the study of bladder cancer in the mouse. Biochem. Pharm., 16: 619-626. 1967.

Robinson, D.E., and MacDonald, J.S. Background and framework for ILSI’s collaborative evaluation program on alternative models for carcinogenicity assessment. Toxicol. Pathol., 29: 13-19, 2001.


Carcinogenicity: via oral route (target organ): urogenital: kidneys

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