Ametryn

Endpoint summary

Description of key information

Wistar rats were administered Ametryn Technical (Ametryn) in the diet at concentrations of 0 (control), 75 ppm, 280 ppm, or 1000 ppm daily for 2 years in a key, GLP, combined chronic toxicity and carcinogenicity study conducted according to OECD Test Guideline 453. Based on a review of the key study data, the No Observed Effect Level (NOEL) was determined to be 75 ppm which is equivalent to 3.8, 5.0 and 4.4 mg/kg body weight/day for males, females and combined sex, respectively.  
Key studies also were reported for 28-day and 90-day oral studies and a 21-day dermal study.  A NOEL of 750 ppm (equivalent to 86.9, 101.7, and 94.3 mg/kg body weight/day of Ametryn for males, females, and combined, respectively) was established from a key 28-day dietary study conducted in rats.  The NOEL from a 90-day key dietary study in rats was determined to be 100 ppm (equivalent to 7.4 and 7.6 mg/kg body weight in males and females, respectively).  A 21-day key dermal study was conducted in New Zealand White rabbits.  The maximum tolerated dose (MTD) was determined to be 1000 mg/kg body weight/day and the NOEL was established at 100 mg/kg body weight/day.
Supportive studies included 28-day range-finding dietary studies in mice and dogs and subchronic 90-day studies in mice, rats (2 studies), and dogs.  A supportive 1-year study was conducted with Ametryn in Beagle dogs. Two supportive 2-year chronic toxicity studies were conducted in mice and a single supportive 2-year chronic toxicity study was conducted in rats.  
No inhalation repeat-dose toxicity studies have been conducted.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion

Dose descriptor:

NOAEL

4.4 mg/kg bw/day

Additional information

Wistar rats were administered Ametryn in the diet at concentrations of 0 (control), 75 ppm, 280 ppm, or 1000 ppm daily for 2 years in a key, GLP, combined chronic toxicity and carcinogenicity study (Krishnappa, 2002). This study was conducted according to OECD test guideline 453. Oral administration of Ametryn for 24 months at the dose of 75 ppm had no adverse effects on general health, growth, survival, and food consumption. There were no treatment related changes in hematology, clinical chemistry and urinalysis. No gross or histopathological changes were attributable to the test substance. Therefore this dose, which is equivalent to 3.8, 5.0, and 4.4 mg/kg body weight/day for males, females, and combined sex, respectively was considered the NOEL for chronic effects of Ametryn Technical in Wistar rats. 

In a 28-day key dietary study, rats were administered Ametryn at concentrations of 0, 750, 1500, 3000, or 6000 ppm in the diet (1999). This study was conducted GLP and according to OECD Test Guideline 407. There was no effect on the general health status, body weights, growth and organ weights (excepting for the reduced weights of thymus in males and heart in females). The NOEL was 750 ppm in feed which was equivalent to 86.9, 101.7, and 94.3 mg/kg body weight/day of Ametryn for males, females, and combined sex, respectively.

In a 90-day key dietary study, rats were administered Ametryn daily at concentrations of 0, 25, 100, 500, and 2000 ppm (males and females) (Bachmann, 1998).  This GLP study was conducted according to OECD Test Guideline 408, EU Method B.26, FIFRA 82-1, and MAFF (Japan). Treatment with Ametryn resulted in markedly depressed body weight development in high-dose animals (2000 ppm) followed by incomplete recovery. The changes to red and white blood cell parameters (at ≥500 ppm and 2000 ppm, respectively) and to clotting activity (≥500 ppm) at treatment end were completely reversible. Lower plasma levels of glucose and triglycerides and higher values for alkaline phosphatase activity reversed during the recovery period. The leukocyte count in urine samples was increased at treatment end, but was not increased after recovery. The changes to organ morphology were restricted to reversible hemosiderosis of the spleen in high-dose males. Based on body weight data, the authors reported that the MTD exceeded the high dose level of 2000 ppm. The authors reported that a NOEL for Ametryn is 100 ppm in males and females (corresponding to a mean daily intake of 7.4 and 7.6 mg/kg body weight in males and females, respectively).         

A key 21-day dermal repeat-dose study was conducted in New Zealand White rabbits. Ametryn was applied daily to an intact area of skin at concentrations of 0, 10, 100, or 1000 mg/kg for 6 hours.  There were no treatment-related deaths, dermal observations, changes in body weight, ophthalmoscopic changes, haematology, organ weights, gross pathology, or histopathology. Any changes noted in these parameters were not considered related to treatment. A transient reduction in mean food consumption was noted in high-dose males and females on Day 8 and was statistically significant only in males. Statistically significant increases in mean serum cholesterol and triglycerides were observed in high-dose males and females at the end of the study, however, were not considered toxicologically significant. A statistically significant increase in gamma glutamyl transpeptidase was noted in Group 3 and 4 males, but not females, on test Day 20. Since individual values for this parameter showed variations perdose that were similar to those on test day 20, the relationship of this change to treatment is unknown. The maximum tolerated dose (MTD) was determined to be 1000 mg/kg body weight/day and the NOEL was established at 100 mg/kg body weight/day.

Supportive 28-day range-finding dietary studies were conducted in mice (Krishnappa, 1999) and Beagle dogs (Prakash, 1998). Both studies conducted were GLP and according to OECD Test Guideline 407. Mice were administered Ametryn at concentrations of 0, 75, 225, 675, 2000 and  5000 ppm; while dogs were administered Ametryn at concentrations of 0, 100, 400, 1600, or 5000 ppm. The NOEL for mice was 225 ppm which was equivalent to 44.8, 51.8, and 48.3 mg/kg body weight/day for males, females, and combined sex, respectively. The NOEL for dogs was 400 ppm (which was equivalent to 7.81 mg/kg body weight/day in males and 6.64 mg/kg body weight/day in females).

Also, supportive subchronic 90-day studies were conducted with Ametryn in Swiss albino mice (Kumar, 1999), rats (Dickhaus, 1984; Krishnappa, 1998), and dogs (Prakash, 1999). 

In a subchronic oral dietary 90-day study, Swiss-albino mice were administered Ametryn daily at concentrations of 0, 150, 600, or 2400 ppm (Kumar, 1999). This GLP study was conducted according to OECD Test Guideline 408. There was no effect on general health status, growth, hematological and clinical chemistry parameters, organ weights, and histopathological changes in the low-dose (150 ppm) group. Adverse effects were reported in mid-dose (600 ppm) and high-dose (2400 ppm) groups. The NOEL was considered to be 150 ppm (equivalent to 26.9, 32.6, and 29.8 mg/kg body weight/day for males, females and combined sex, respectively.

In a subchronic oral dietary 90-day study, Wistar rats were administered Ametryn daily at concentrations of 250, 750, or 2250 ppm (Krishnappa, 1998). This GLP study was conducted according to OECD Test Guideline 408 and Commission Directive 87/302/EEC (No. L133/8). There were no adverse effects on the general health, growth, hematological and clinical parameters in the low-dose (250 ppm) group. Adverse effects were reported in mid-dose (750 ppm) and high-dose (2250 ppm) groups. Therefore, the NOAEL was considered to be 250 ppm equivalent to 20.1, 23.6, and 21.8 mg/kg body weight/day for males, females, and combined sex, respectively.

In a subchronic oral dietary 90-day study, Wistar rats were administered Ametryn daily at concentrations of 250, 1000, or 4000 ppm (Dickhaus, 1984). This non-GLP study was equivalent to OECD Test Guideline 408. Administration of Ametryn in the diet for 90 days resulted in decreased feed consumption and weight gains and increased alkaline phosphatase levels and liver weights in the high-dose group (4000 ppm), increased liver weights in the mid-dose group (1000 ppm), and no significant effects at the low-dose level (250 ppm), which was selected as the NOEL. The authors reported that this dose level corresponds to 20 mg/kg body weight/day.

In a subchronic oral dietary 90-day study, Beagle dogs were administered Ametryn daily at concentrations of 300, 900, or 2470 ppm (Prakash, 1999). This study was GLP and conducted according to OECD Test Guideline 409. The evaluated NOEL of Ametryn in Beagle dogs was 300 ppm in food which was equivalent to 6.4 mg/kg body weight/day in males and 7.4 mg/kg body weight/day in females.

A 1-year chronic study was conducted with Ametryn in Beagle dogs (O'Connor, McCormick, and Green, 1987). This GLP study was conducted according to EPA OPP 83-1 and equivalent to OECD Test Guideline 452. Animals were administered Ametryn in the diet for 5, 9, or 52 consecutive weeks at concentrations of 0, 20, 200, 2000, 2500 to 4500, or 3000 to 8000 ppm for groups 1, 2, 3, 4, 5, and 6, respectively. Dietary concentrations for groups 5 and 6 were reduced during the study due to effects on body weight and feed consumption. The primary treatment findings were considered to be effects on feed consumption, liver enzymes, and liver morphology. The maximum tolerated dose of Ametryn in the dog was between 2000 and 4000 ppm and the NOEL was considered to be 200 ppm. 

The authors considered the maximum tolerated dose of Ametryn in the dog to be between 2000 and 4000 ppm and the authors reported the no-observed-effect level (NOEL) to be 200 ppm in this study.   

Two supportive 2-year chronic toxicity studies were conducted in mice (Burdock, 1981; Kumar, 2002) and a single supportive combined 2-year chronic toxicity and oncogenicity study was conducted in rats (Hazelette and Green, 1987). 

In a non-GLP carcinogenicity study, CD-1 mice were administered Ametryn daily in the diet at concentrations of 10, 1000, or 2000 ppm for 102 consecutive weeks (Burdock, 1981). This study was equivalent to OECD Test Guideline 451. There were no indications of a compound effect with regard to mortality, clinical signs, body weights, food consumption, incidences of suspect neoplasms, gross pathology, and histopathology. The authors did not report a NOEL for this study.

In a chronic repeat-dose toxicity study, Swiss-Albino mice were administered Ametryn in the diet daily at concentrations of 0, 30, 100, 400, and 1600 ppm (males and females) for 18 months (Kumar, 2002). This GLP study was equivalent to OECD Test Guideline 453. The NOEL established for this study was 100 ppm for male and females as it had no effects on general health, growth, food consumption, pre-terminal deaths and life expectancy, differential leukocyte count values, and changes in organ weights. No gross or histopathological changes seen were attributable to the test substance.

In a combined chronic toxicity and oncogenicity study, Ametryn was administered in the diet to rats daily for 104 consecutive weeks at concentrations of 0, 50, 500, and 5000 ppm (Hazelette and Green, 1987). However, due to extreme reductions in body weight gain in both sexes, the highest dose was decreased to 4000 ppm during Week 21 and further reduced to 2000 ppm on Week 35. This GLP study was conducted according to OECD Test Guideline 453. Compound-related effects on survival, body weight, food and water consumption, erythroid parameters, and organ weights were observed primarily in the high-dose animals. It was concluded that the highest feeding level of 2000 ppm at least achieved or exceeded the MTD, and 50 ppm was the NOEL for this study.