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Description of key information

Oral (OECD 408), subchronic, rat: NOAEL (systemic), males/females = 58/70 mg/kg bw/day
Oral (OECD 409), subchronic, dog: NOAEL (systemic), males/females = 221/221 mg/kg bw/day
Oral (OECD 408), subchronic, mouse: NOAEL (systemic) males/females = 1110/398 mg/kg bw/day
Oral (OECD 452) chronic, dog: NOAEL (systemic) males/females= 66/67 mg/kg bw/day
Oral (OECD 453) chronic, rat: NOAEL (systemic) males/females = 181/249 mg/kg bw/day

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
58 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Additional information

There are three subchronic studies available addressing repeated dose toxicity via the oral route, conducted in rats, dogs, and mice.

The subchronic study in rats was performed according to OECD 408 (McElligott, 2003). The rats (10/sex/group) received the test substance in their feed for a period of 90 days. The following doses were administered: 1000, 4000 and 12000 ppm of the test substance, corresponding to 58, 240, and 720 mg/kg bw/day for males and 70, 281 and 859 mg/kg bw/day for females. At 12000 ppm, the continuous administration of the test substance induced mortalities in 2 females during week 5. Body weight gain decrease was most pronounced between weeks 4 and 5 in both sexes with reduced food consumption. Urinalysis revealed sulfonamide-like crystals, radially striated sperical structures, in the urine of both sexes. Higher absolute and relative kidney weights were observed at terminal sacrifice in both sexes. Slight centrilobular hepatocyte hypertrophy and thymus involution were observed in males. Hyperplasia of the urothelium in the urinary bladder, of collecting ducts and pelvis epithelium in the kidneys and increased incidence and/or severity of basophilic tubules in the kidneys were observed in both sexes. In the spleen, brown pigment in the red pulp was seen in males and females. As sulfonamide-like crystals and hyperplasia of the urothelium in the urinary bladder were also seen in both sexes at 4000 ppm, this dose level was chosen as LOAEL, corresponding to 240 and 281 mg/kg bw/day for males and females, respectively. No adverse effects were observed at the dose level of 1000 ppm in either sex. Therefore, this dose level, corresponding to 58 mg/kg bw/day for males and to 70 mg/kg bw/day for females, was determined to be the NOAEL.

Prior to the evaluation of the subchronic toxicity of the test substance in dogs, a dose-range finding study was performed (Eigenberg, 2005). The purpose of this 28-day feeding study in dogs was to determine the toxicity profile and palatability of the test substance for dose selection in the subchronic study. The dogs were fed a diet with doses of 3200, 10000, and 30000 ppm of the test substance. Microscopic lesions in the kidney of males and females in the 30000 ppm dose group and in males in the 10000 ppm dose group were observed.

Based on the outcome of the previous study, in the subchronic toxicity study (OECD 409), 4 dogs/sex were fed a diet containing 2500, 7500, and 15000 ppm of the test substance (corresponding to 75, 221, and 416 mg/kg bw/day for males and 79, 221, 341 mg/kg bw /day for females) over a period of 90 to 92 days (Eigenberg, 2005).

One female animal of the high-dose group was sacrificed in-extremis due to clinical signs of impending deaths. The death was considered to be compound-related due to kidney calculi and abscessation. Body weight loss was observed in females of the high-dose group and reduced food consumption in both sexes. Treatment-related urinalysis findings were elevated urine volume in males, a decrease in urine specific gravity in males and females and a decreased pH in females. At histopathology, calculi in the renal pelvis, ureter and/or urinary bladder were seen in most animals of the high-dose group. Correlated microscopic changes of the urinary tract were inflammatory changes, renal pelvis epithelium hyperplasia and necrosis as well as associated changes in the ureters and urinary bladder of males and females. At 7500 ppm, the only treatment-related effect was a decrease in urine specific gravity in females. As there were no microscopic pathology observations to correlate, the NOAEL was considered to be 7500 ppm (corresponding to 221 mg/kg bw/day for both sexes) and the LOAEL was 15000 ppm, corresponding to 416 and 341 mg/kg bw/day for males and females, respectively.

In addition, there is a subchronic toxicity study in mice available according to OECD 408 (Kennel, 2003). The animals received doses of 500, 2000 and 7000 ppm of the test substance in their feed for a period of 91 to 93 days The doses corresponded to 79, 321 and 1110 mg/kg bw/day for males and 95, 398 and 1297 mg/kg bw/day for females (10 animals/sex/group). In this study no effects were observed at the dose level of 500 and 2000 ppm for females and males, respectively. Lymphocytolysis in the thymus of females given 7000 ppm was observed. Therefore, the dose of 1297 mg/kg bw/day in females was considered as LOAEL in this study. Consequently, the NOAEL was set at 398 for females and at 1110 mg/kg bw/day for males.

 

Two chronic studies are available addressing toxicity after repeated exposure, the first one a chronic toxicity study according to OECD 452, and the second one a combined chronic toxicity and carcinogenicity study accordingto OECD 453.

In the OECD 452 study, dogs (4/sex/dose) received doses of 1000, 2500 and 8000 ppm in their feed for a period of 370 to 372 days, corresponding to 29, 66 and 226 mg/kg bw/day for males and 28, 67, and 242 mg/kg bw/day for females (Eigenberg, 2007). No treatment-related effects were observed up to 2500 ppm. Therefore, this dose level was determined to be the NOAEL, corresponding to 66 and 67 mg/kg bw/day for males and females, respectively. At the high-dose level of 8000 ppm, macroscopic and microscopic findings in the kidney and the urinary bladder were observed in both sexes. Like in the previous 90-day dog and the 90-day rat studies, the effects (haemorrhages, inflammation and hyperplasia) were consistent with the formation of stones in the urinary tract. Therefore 8000 ppm, corresponding to 226 and 242 mg/kg bw/day for males and females, respectively, was determined as LOAEL.

The combined chronic toxicity and carcinogenicity study in rats was conducted in accordance with OECD 453 (Langrand-Lerche, 2006). The animals were exposed to dose levels of 200, 1000, 4000 and 8000 ppm (corresponding to 9, 45, 181, 364 mg/kg bw/day for males and to 13, 62, 249, 491 mg/kg bw/day for females) for a 12-month period to investigate chronic toxicity (70 animals/sex/dose; 10 animals/sex/dose only for the 200 ppm dose group).

There were no treatment-related effects on food consumption, ophthalmological examination, neurotoxicity assessment, hematology and clinical chemistry evaluation at any dose level in either sex observed. At 8000 and 4000 ppm, there were no treatment-related effects on mortality observed during the 12- month chronic toxicity period. Treatment-related clinical signs consisted of soiled anogenital region. Mean cumulative body weight gain was reduced during the first week of treatment in males (8000 and 4000 ppm) and females (8000 ppm) when compared to controls. Thereafter, mean body weight and body weight gain parameters were comparable to controls in both sexes throughout the study. Urinalysis revealed the presence of sulfonamide-like crystals throughout the study in both sexes, the effect being more pronounced in females than in males. In addition, a tendency towards slightly lower urinary protein levels was noted throughout the study in both sexes. This change was considered not to be adverse in view of its low magnitude. At the 12-month interim sacrifice, there were no treatment-related effects on organ weights and macroscopic observations. Treatment-related non-neoplastic findings were seen microscopically in the kidney and the urinary bladder only at 8000 ppm. In addition, a treatment-induced nephropathy was observed in a prematurely sacrificed female, which was considered to be the cause of death. At 1000 ppm, the only treatment-related changes observed at this dose level were a slightly increased incidence of soiled anogenital region at the physical examination in males and a tendency towards lower urinary protein levels at urinalysis in males. These minor changes in the absence of corresponding histopathological findings were considered not to be adverse.

At 200 ppm, no treatment-related changes were observed in either sex.

Taking these effects into consideration, the NOAEL over a 12-month period of dietary administration is 4000 ppm in both sexes (equivalent to 181 and 249 mg/kg bw/day in males and females, respectively). The LOAEL was set at 8000 ppm (equivalent to 364 and 491 mg/kg bw/day in males and females, respectively) due to urinalysis and histopathological findings.


Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: kidneys

Justification for classification or non-classification

The available data on repeated dose toxicity of the test substance 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.