Registration Dossier

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

The substance was assessed in a combined repeated gavage dose toxicity study with the reproduction/developmental toxicity screening test (according to OECD guideline 422 and under GLP) in rats (Rohm and Haas, 2002).

The substance was administered daily to rats by gavage at doses of 0, 100, 300 or 1000 mg/kg bw/day. Exposure of parental animals (12/sex/dose) began when the animals were approximately eleven weeks of age. Parental animals were mated after two weeks of exposure. Treatment continued throughout gestation, lactation, and until terminal necropsy.

Body weight, feed consumption, and clinical signs were monitored in parental animals throughout treatment. Animals were examined weekly using Detailed Clinical Observations (DCO). During Week 5 (males) and Week 7 (females), animals were assessed using a Functional Observational Battery (FOB) and monitored for motor activity (MA). Parental animals were euthanized and necropsied after weaning of their litters. Blood samples were collected for hematology and clinical chemistry analysis from all adult rats at terminal necropsy. Selected organs were weighed, and tissues were collected for histopathologic evaluation. Histopathologic evaluation was performed on five randomly selected animals/sex in the control and high dose group, and in a female (Group 3, 300 mg/kg bw/day) euthanized for humane reasons during the course of the study.

On Postnatal Day 0 (PND0), all offspring were examined externally, and their status (e.g., alive, dead, stillborn, or uncertain), sex, and weight were determined. On PND4, pups were again counted, sexed, weighed, and examined for gross abnormalities prior to being euthanized. Pups were discarded without further evaluation.

There were no treatment-related deaths or clinical signs of systemic toxicity in females during premating, females during gestation, females and pups during lactation, or in males throughout the study at any dose level. There were no treatment-related effects on body weight or feed consumption in females during the premating, gestation or lactation periods or in males throughout the study.

There were no treatment-related effects on any endpoint of mating or fertility at any dose.

There were no treatment-related effects on gestation index, gestation length, or number of pups per litter. There were no treatment-related deaths during delivery, and there were no litters entirely stillborn. There were no treatment-related effects on the mean number of implantation sites or post-implantation loss at any dose level. There were no treatment-related effects on offspring viability or the ratio of male to female pups.

There were no treatment-related effects on offspring body weight at any dose. There were no external abnormalities noted at any dose level. No treatment-related effects were seen in the Detailed Clinical Observations or Functional Observational Battery parameters. There were no treatment-related effects noted in motor activity in either sex at doses up to and including 1000 mg/kg bw/day. There were no treatment-related changes in any hematology or clinical chemistry parameters in either sex at any dose level.

No treatment-related changes in organ weights were noted in either sex at any dose level.

No treatment-related gross or microscopic pathological findings were observed in either sex at any dose level.

The substance, when administered to rats daily via gavage for approximately 8 weeks at doses of 0, 100, 300, or 1000 mg/kg bw/day, had a NOAEL for parental animal toxicity of 1000 mg/kg bw/day. The reproductive and developmental NOAEL was 1000 mg/kg bw/day.

Short description of key information:
In a combined repeated gavage dose toxicity study with the reproduction/developmental toxicity screening test via gavage in rats a NOAEL of 1000 mg/kg bw/day for parental toxicity was observed. The reproductive and developmental NOAEL was 1000 mg /kg bw/day. No adverse effects were observed at the dose levels tested.

In a combined repeated gavage dose toxicity study with the reproduction/developmental toxicity screening test via gavage in rats a NOAEL of 1000 mg/kg bw/day for parental toxicity was observed. The reproductive and developmental NOAEL was 1000 mg /kg bw/day. No adverse effects were observed at the dose levels tested.