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Administrative data

Description of key information

Six repeat dose oral studies are available:
Stott WT, Yano BL, Beyer JE, Kropscott BE, Eddy SL (1991): 2 year Combined Chronic Toxicity/Carcinogenicity Study in rats: NOAEL: 500 mg/kg bw/day (actual ingested) (male) and 1000 mg/kg bw/day (actual ingested) (female)
Zempel JA, Grandjean M & Szabo JR (1988): 90-Day Oral Toxicity Study in rats: NOAEL: 250 mg/kg bw/day (actual ingested) (male) and 1000 mg/kg bw/day (actual ingested) (female)
Yano BL, Firchau HM, Quast JF & Stott WT (1988): 2 and 4 week oral study in rats: NOAEL: 1000 mg/kg bw/day (actual ingested) (male)
Bond DM, Yano BL, Cosse PF, Hopkins PJ & Kropscott BE (1987): 90-Day Oral Toxicity in mice: NOEL: 1000 mg/kg bw/day (actual ingested) (male/female)
Cosse PF, Yano BL, Stott WT (1989): 90-Day Oral Toxicity in Beagle dogs: no NOAEL identified: (male), NOAEL: 500 mg/kg bw/day (actual ingested) (female)
Yano BL, Cosse PF & Corley RA (1991): Chronic Toxicity (approx. 1 year) in Beagle dogs: NOAEL: 100 mg/kg bw/day (actual ingested)
One repeat dose dermal study is available:
Stebbins KE, Zielke GJ, Hanley TR (1990): Repeated Dose Dermal Toxicity - 21 Days in rabbits: NOEL: > 1000 mg/kg bw/day (male/female)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
chronic
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rabbit

Additional information

Exposure via the oral route was considered to best represent the hazards posed by the substance in terms of repeated dose toxicity.

The key oral study selected is a chronic study conducted on rats. This was selected as key on the basis that it was a reliable study conducted to an OECD test method, was conducted on a typical species used to address this endpoint and was perfomed for the longest duration compared to any of the other available studies.

Within this chronic study, the only significant treatment-related changes observed upon gross and histological examination of tissues were in the kidneys of high dose group male rats following 12 or 24 months dosing. A few of these animals were observed at necropsy to have a roughened surface in the papillary region of the kidneys and/or dilated renal pelves with or without calculi. Histologic examination of this tissue revealed atrophy of the renal papilla(e), hyperplasia of the epithelium overlying the papilla(e) and/or mineralization of the pelvic epithelium. Examination of tissues at necropsy also revealed that the ceca of a number of male and female rats ingesting 500 or 1000 mg/kg/day Flumetsulam were visibly enlarged and were heavier than those of control rats. However, these latter changes were unassociated with any histopathological change in cecal tissues and were attributed to a physiological adaptation to increased levels of ingesta present in this tissue.

Sub-acute and sub-chronic oral studies were also performed on rats. The results of these studies supported the outcome of the chronic key study.

A sub-chronic study performed on mice showed no adverse toxcological effects of any significance at the highest dose of 1000 mg/kg bw/day.

The other 2 supporting oral sub-chronic studies were perfomed on Beagle dogs. The one year study gave an NOAEL of 100 mg/kg bw/day, which is lower the the NOAEL from the key study. Due to the fact that Beagle dogs are not a typical species used for classification of a substance under CLP, this was not selected as the key study, despite the lower NOAEL. However, the effects demonstrated in this study should not be ignored when assessing the risk of the chemical.

Male and female dogs given 500 mg/kg/day had lower body weights and feed consumption. Significant inflammatory and atrophic changes occurred in the kidneys of two females given 500 mg/kg/day and were secondary to kidney calculi. One male given 500 mg/kg/day also had a very slight renal tubular atrophy.

The dermal study available for this endpoint was considered reliable enough to be a key study for the dermal route. The study was sub-acute and showed no toxcological effects of any significance at the highest dose of 1000 mg/kg bw/day.


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

Repeated dose toxicity: dermal - systemic effects (target organ) other: all gross lesions and masses

Justification for classification or non-classification

With reference to the information available on this substance, no classification for repeat dose toxicity is required in accordance with Directive 67/548/EEC or Regulation (EC) No. 1272/2008.