Methyl O-(4-amino-3,5-dichloro-6-fluoropyridin-2-yloxy)acetate

Carcinogenicity

Description of key information

In a 2-year chronic toxicity/carcinogenicity study in Wistar rats, at dietary dosages between 20 and 320 mg/kg/day, the NOEL was 80 mg/kg/day with 320 mg/kg/day causing an increased incidence of moderate or severe nephrosis in males. There was no evidence of carcinogenicity.
In Fischer 344 rats, 2-year daily dietary exposure using doses of 0, 100, 500 or 1000 mg Fluroxypyr/kg bw/day, caused excessive renal toxicity with increased mortality at 1000 mg/kg bw/day. Whereas renal failure was evident in males from the beginning of treatment, in females renal toxicity occurred only during the second year of treatment. Gross pathology and histopathological examination of the rats at termination revealed renal toxicity at 500 mg/kg bw/day in males and at 1000 mg/kg bw/day in females. However, there were no indications of Fluroxypyr possessing tumorigenic properties. The NOEL for chronic toxicity was 100 mg Fluroxypyr/kg bw/day in males and 500 mg Fluroxypyr/kg bw/day in females, whereas the NOAEL for carcinogenic effects was 1000 mg/kg bw/day.
In two 18-month toxicity and/or carcinogenicity studies in CD-1 mice, at dietary dosages between 20 and 1000 mg/kg/day, the NOAEL was 320 mg/kg/day with 1000 mg/kg/day causing reduced body weight of males and kidney lesions in females. Based on increased histopathological changes in the kidneys in the second study, the NOEL was 100 mg/kg bw/day. There was no evidence of carcinogenicity.

Justification for classification or non-classification

Fluroxypyr was neither carcinogenic in the mouse (CD-1 mouse) nor the rat (Wistar rat, Fischer 344 rat) following continous dietary exposure of up to 1000 mg/kg/day for 18 to 24 months.

Additional information

The long-term toxicity and carcinogenic potential of Fluroxypyr acid have been assessed in rats and mice.

 

The study results are summarised in the following table.

 

Table 1: Summary of long-term toxicity and carcinogenicity studies

Type of study / Species	Dose levels* [mg/kg bw/day]	NOEL (NOAEL)	Targets / Main effects	Reference
2-year, oral diet Rat, Wistar	0, 20, 80, 320*	80 (320)**	Kidney	Til et al., 1985, 1987
2-year, oral diet Rat, Fischer 344	0, 100, 500, 1000*	100 (1000)**	Mortality­due to renal toxicity Kidney	Quast & Mc Guirck 1995
78-week, oral diet Mouse, CD-1	0,20, 80, 320*	(320)	No effects	Perry et al., 1983
78-week, oral diet Mouse, CD-1	0, 100, 300, 1000*	100	Kidney, bodyweight¯	Cosse et al., 1993

* = Fluroxypyr acid;      ¯   = decreased   ­   = increased; ** = NOAEL for carcinogenicity

Two long-term toxicity and carcinogenicity studies with Fluroxypyr have been performed in rats.

 

The first combined chronic toxicity and carcinogenicity study (Til et al., 1985, 1987) was performed between 1982 and 1984 according to GLP standards and in compliance with EC Directive 87/302/EEC in Wistar rats. Groups of 70 male and 70 female rats received diets providing 0, 20, 80 or 320 mg/kg/day Fluroxypyr acid (>98.1% pure). The chronic toxicity element of the study comprised twenty rats/sex/group of which ten rats/sex/group were killed in Week 54 and the remainder were killed in Week 95. Fifty rats/sex/group were used in the assessment of carcinogenicity, which was completed after 105 weeks of treatment. In the carcinogenicity study, survival after 105 weeks of treatment was 70, 66, 72 and 74% in males and 78, 82, 70 and 76% in females in the control through high dosage groups, respectively.

From Week 54, water consumption at 320 mg/kg/day was consistently increased, most notably for females. Occasional intergroup differences were also reported in urine volume and density but only decreased urine density for high dosage females at Week 27 was probably attributable to treatment. High dosage females also had a slight but consistent reduction of plasma urea concentration from Week 27. As for previous studies, there was an elevation of plasma enzyme activity (i.e., ALP in males at 320 mg/kg/day) but differences from controls were only slight and not statistically significant. One other finding considered possibly related to treatment was a slight increase in mild bile duct sclerosis in males at 320 mg/kg/day after 54 weeks' treatment.

Histopathological examination of tissues from the carcinogenicity study revealed a statistically significant increase in the number of male rats with moderate or severe nephrosis (group incidence was 19/48 controls versus 31/49 animals at 320 mg/kg/day). There were no other non-neoplastic histopathological findings and no evidence to suggest that Fluroxypyr could induce hyper- or preneoplastic lesions or possessed tumourigenic properties.

 

In conclusion, Fluroxypyr was not carcinogenic in the Wistar rat following continuous dietary exposure of up to 320 mg/kg/day for two years. The high dosage was minimally toxic to the principal target organ, the kidney and, based on the results of a subsequent study in Wistar rats , must also have been at least half of the maximum tolerable dosage for a study of this duration. The NOEL for toxicity was 80 mg/kg/day for both males and females, based on renal effects at 320 mg/kg/day.

 

A second study was performed in Fischer 344 rats (Quast & Mc Guirck, 1995 ) according to OECD guideline 453 and EEC Directive 88/302/EEC, as well as according to GLP. Sixty rats per sex per group received diets providing 0, 100, 500 or 1000 mg Fluroxypyr/kg bw/day.

Due to excessive renal toxicity mortality of high dose males was increased during the first 13 weeks. For reasons of animal welfare the remaining males of the high-dose group were sacrificed on day 118. In high-dose females (at 1000 mg/kg bw/day) increased mortality due to renal failure was observed during the second year of treatment. Based on necropsy results the renal toxicity was considered treatment-related. Decreased body weights were also noted in high-dose animals.

General condition, behaviour, body weight and survival were not adversely affected in the lower dose groups.

Gross pathology and histopathological examination of the rats at termination revealed renal toxicity at 500 mg/kg bw/day in males and at 1000 mg/kg bw/day in females. However, there were no indications of Fluroxypyr possessing tumorigenic properties.

The NOEL for chronic toxicity was 100 mg Fluroxypyr/kg bw/day in males and 500 mg Fluroxypyr/kg bw/day in females, whereas the NOAEL for carcinogenic effects was 1000 mg/kg bw/day.

 

 

A combined toxicity and carcinogenicity study in mice (Perry et al., 1983) was conducted between 1983 and 1984, according to GLP standards. No test guidelines are cited but the design is compliant with EC Directive 87/302/EEC. Groups of 60 male and 60 female CD-1 mice received diets providing 0, 20, 80 or 320 mg/kg/day Fluroxypyr acid (99.4% pure).

There were no treatment-related effects noted in any dose group. In the carcinogenicity study, survival after 78 weeks of treatment was 88, 68, 86 and 78% in males and 80, 74, 74 and 82% in females in the control through high dosage groups, respectively.

In conclusion, Fluroxypyr was not carcinogenic in the CD-1 mouse following continuous dietary exposure of up to 320 mg/kg/day for 18 months. The NOAEL for toxicity was also 320 mg/kg/day, the highest dosage tested.

 

A second mouse carcinogenicity study (Cosse et al., 1993) was conducted to assess the effect of a limit dosage of Fluroxypyr acid in the CD-1 strain. This study was performed between 1990 and 1991, according to GLP standards and OECD 451 and 87/302/EEC test guidelines. Groups of 60 male and 60 female CD-1 mice received diets providing 0, 100, 300 or 1000 mg/kg/day Fluroxypyr acid (98.9% pure) for 18-months.

Toxicity was evident at the high-dose of 1000 mg/kg bw/day. Survival after 78 weeks of treatment was 52, 42, 38 and 43% in males and 62, 70, 77 and 57% in females in the control through high dosage groups, respectively. Survival in males was below the guidance level of 50 % at 18 months but this level was exceeded only in the last few weeks of the study and assessment of carcinogenicity was not compromised. Male body weight gain indicated a slight reduction from the start of treatment at the high dosage. The target organ was the kidney, with statistically identified increased incidences of renal papillary necrosis and severe chronic regenerative nephrosis in female at 1000 mg/kg/day. At 300 mg/kg bw/day there were also an increased incidence of histopathological renal changes, but without reaching statistical significance. There was no evidence of a tumourigenic or carcinogenic effect.

In conclusion, Fluroxypyr was not carcinogenic in the CD-1 mouse at the EC/OECD limit dosage of 1000 mg/kg/day, a dosage that was also toxic to males and females. The NOEL for toxicity in males and females was 100 mg/kg/day, based on renal effects at 300 mg/kg/day.