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Administrative data

Description of key information

Three repeat dose oral toxicity studies have been conducted:
5 Day Repeat Dose with 7 Day Recovery: NOAEL 28 mg/kg/day
28 Day Repeat Dose: NOAEL Male: 10 mg/kg/day, NOAEL Female: 100 mg/kg/day
90 Day Repeat Dose: NOAEL Male: 10 mg/kg/day, NOAEL Female: 100 mg/kg/day

Key value for chemical safety assessment

Additional information

The potential oral toxicity of ADONA (lot 140499-8/25, purity 30.3%), was evaluated when administered via daily oral gavage for 5 days followed by a 7-day recovery period. All materials were tested as liquids. The study design was based on a modified OECD guideline 401 and Redbook 2000, Toxicological principles for the safety assessment of food ingredients, IV.B.1 (2003). The test material was administered as received. A control group (6 rats/sex) was administered sterile water at 5 mL/kg for 5 days. A recovery control group (6 rats/sex) was administered a similar dose of sterile water and observed for 7 days after the last dose. All rats were euthanatized and a necropsy was performed at the end of their respective observation periods. Parameters evaluated: clinical signs, body weights, body weight changes, food consumption, clinical pathology (hematology, clinical chemistry, and urinalysis), toxicokinetics, gross necropsy, organ weights, and histopathology. The test article was administered to rats (3/sex/group) at actual doses of 28, 104, or 298 mg/kg/day for 5 days (expected dose was 29, 91 and 288 mg/kg/day). Recovery groups (3 rats/sex/group) were administered similar doses and observed for 7 days after the last dose. All surviving animals were euthanatized and a necropsy was performed at the end of their respective observation periods. All female rats (6/6) in the 298 mg/kg/day test article group died by Day 5. The 298 mg/kg/day test article females had decreased activity; all other test article treated rats were normal. The 298 mg/kg/day test article males had slightly lower body weights and body weight gains at the end of the dosing period and males and females in this group had reduced food consumption during the dosing period relative to controls. Mean absolute liver weights increased by 47% in 288 mg/kg/day treated males relative to control animals. There were no other toxicologically meaningful differences in hematology, clinical chemistry, urinalysis, or absolute or relative organ weights in the test article treated animals relative to controls. The 104 and 298 mg/kg/day test article treated groups had treatment related microscopic changes in the kidneys typified by focal/multifocal degenerative tubular changes with dilation of cortical tubules and flattening of tubular cells at the end of the dosing period. Microscopic evaluation of the surviving recovery animals was normal. Based on the histopathological evaluation of the kidneys, the NOAEL was interpreted to be 28 mg/kg/day.

The potential toxicity of ADONA (liquid, supplied at 29.9 ± 0.1% in water, lot 140499-19/10) was evaluated in male and female Wistar rats when administered by daily oral gavage for 28 days following OECD Guideline No. 407. The test material was diluted in Milli-U water to the appropriate concentrations and stock solution strength and specific gravity were included in calculations. The test article was administered by oral gavage to 5 animals/sex/group at 0 (Milli-U water), 10, 30 and 100 mg/kg daily for 28 days. The following parameters were evaluated: clinical signs daily; functional observation tests in week 4; body weight and food consumption weekly; clinical pathology and macroscopy at termination; organ weights and histopathology on a selection of tissues. There were no test material related findings for any dose group in clinical appearance, functional observations, body weight and food consumption. The following changes in serum levels were noted in males treated at 100 mg/kg: increased alkaline phosphatase, increased glucose (also in males at 30 mg/kg), increased urea, increased inorganic phosphate, increased potassium (also in males at 30 mg/kg), decreased hemoglobin, and decreased hematocrit. Findings in females were limited to increased creatinine and decreased calcium in the 100 mg/kg dose group. Liver weight was increased in males at 30 and 100 mg/kg which was supported by an increased incidence and severity of hepatocellular hypertrophy/hyperplasia. Increased incidence and severity of thyroid follicular hypertrophy up to 100 mg/kg in males was considered an adaptive change to the increases in liver. The increase in liver weight was considered adverse. In conclusion, the No Observed Adverse Effect Level (NOAEL) for the test article in this study was 10 mg/kg for males and 100 mg/kg for females.

The toxicity potential of ADONA (liquid, lot 140449-19/10, supplied at 30.3% in water) was evaluated in a 90-day repeated dose study in male and female Sprague Dawley rats. This study was based on the following guidelines: EC Directive 67/548/EEC Repeated Dose (90 Days) Toxicity (oral), 2001; OECD 408, 1998; OPPTS 870.3100 EPA 712-C-98-199, 1998; and the Japanese Chemical Substances Control Law 1987, Notification of Nov. 21, 2003 by MHLW (No. 1121002), METI (No. 2), and ME (No. 031121002). The test material was diluted in Elix water (vehicle) to the appropriate concentrations; corrections were made for the purity and specific gravity of the test substance. Male rats (10/group) received 0 (vehicle), 1, 3, or 10 mg/kg/day of the test article via oral gavage for 90 days. Female rats (10/group) received 0 (vehicle), 10, 30, or 100 mg/kg/day of the test article via oral gavage for 90 days. Satellite groups of males or females (10/group) received the same dose levels, as appropriate by sex, and were used for toxicokinetic blood sampling. Parameters Evaluated: clinical observations (daily), body weight (weekly), food consumption (weekly), ophthalmoscopy (pretest and week 13), clinical pathology (termination), urinalysis (overnight prior to termination), toxicokinetic blood sampling (weeks 1, 4, and 13), macroscopy at termination, organ weights, and histopathology on select tissues. No treatment-related changes were noted in clinical observations, body weight, food consumption, opthalmoscopy, macroscopic examination, or organ weights. Slight changes in red blood cell parameters occurred in males at 3 mg/kg/day (e.g. lower hematocrit) and at 10 mg/kg/day (e.g. lower red blood cell counts and hematocrit values) and in females at 100 mg/kg/day (e.g. higher mean corpuscular hemoglobin concentration). There was no morphological evidence of altered red blood cell turn over. Therefore, these changes in blood cell parameters were not considered an adverse effect on red blood cell life span. In most males at 10 mg/kg/day a minimal or slight centrilobular hepatocytic hypertrophy was observed together with slightly higher aspartate aminotransferase. These changes are considered adaptive responses to exposure to xenobiotics. Slightly higher prothrombin time was noted in males at 10 mg/kg/day; this finding was not an adverse effect on clotting potential. Females at 100 mg/kg/day had lower calcium excretion and concentration in the urine. No other urinary changes were noted and there were no morphological indications of renal toxicity. This change was not toxicologically relevant. Based on the results of this study, the No Observed Adverse Effect Level (NOAEL) for the test article was 10 mg/kg/day (males) or 100 mg/kg/day (females) which was the highest dose evaluated in either sex.

Justification for classification or non-classification

ADONA does not meet the DSD or CLP criteria for classification as a target organ toxicant after repeated exposure.