Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Two Repeat Dose studies, a 28-Day Oral and a 90-Day Oral,  have been conducted on IOA.
28-Day Oral NOAEL: 1000 mg/kg
90-Day Oral NOAEL: 600 mg/kg

Key value for chemical safety assessment

Additional information

Two Repeat Dose studies, a 28-Day Oral and a 90-Day Oral, have been conducted on IOA.


28-Day Oral NOAEL: 1000 mg/kg


90-Day Oral NOAEL: 600 mg/kg



28-Day Oral Study:

The repeated-dose oral toxicity potential of MTDID 7819 (clear colorless liquid, lot 4/2009) was evaluated in male and female Wistar rats. METHODS: This study was performed in compliance with OECD GLP (1997). The study design was based on the following guidelines: EC No. 440/2008 B.7 (2008), OECD 407 (2008) and OPPTS 870.3050 EPA 712-C-00-366 (2000). MTDID 7819 was prepared in corn oil (vehicle) within 6 hours prior to dosing. Rats (5/sex/group) received 0 (vehicle), 30, 300 or 1000 mg/kg-day MTDID 7819 via oral gavage for 28 days. Parameters evaluated: clinical observations (daily), functional observations (week 4), body weight (weekly), food consumption (weekly), clinical pathology (termination), macroscopic examination (termination), organ weights and microscopic examination of specific tissues. RESULTS: No toxicologically-relevant changes were noted for clinical observations, functional observations, body weights, food consumption or hematology. Adaptive liver changes included increased liver weights (300 mg/kg-day males and 1000 mg/kg-day males and females); centrilobular hepatocellular hypertrophy (1000 mg/kg-day males); total bilirubin, cholesterol, potassium, and/or inorganic phosphate concentrations (1000 mg/kg-day males and females); and cholesterol changes in 300 mg/kg-day females. Although these changes were adaptive, the report authors considered the magnitude of the liver weight increase in the 1000 mg/kg-day-treated animals (i.e. >20%) to be adverse. Adaptive thyroid changes included increased thyroid weights (1000 mg/kg-day males and females); and increased incidence and severity of thyroid follicular epithelium hypertrophy/hyperplasia (1000 mg/kg-day males). Hyperplasia was noted in the forestomach of 300 mg/kg-day-treated females and males and females at 1000 mg/kg-day. The hyperplasia was considered an adaptive response to local irritation in the forestomach and is a common adaptive phenomenon in rat studies. Hyaline droplet formation was noted in the kidneys of the 300 and 1000 mg/kg-day-treated male rats. This result is attributed to the male rat-specific alpha-2u-globulin protein and is not considered relevant for female rats or higher species, including humans. Nephroblastoma correlated with nodules and higher kidney weight in one 1000 mg/kg-day-treated male rat which was considered spontaneous and not related to the test article.


CONCLUSION: Based on the results of this study, the authors proposed a rat NOAEL of 30 mg/kg-day. The findings at 300 mg/kg-day were considered rat-specific and of no relevance to humans.  Results seen at 1000 mg/kg are either adaptive changes or not related to the test article. The main effect seen at 1000 mg/kg is increased liver weight. In the absence of clinical or histological findings, this effect is not classified as adverse. Based on these results, 1000 mg/kg-day is considered to be the dose descriptor for human risk assessment calculations.


90-Day Study

The toxicity potential of the test article was evaluated in a 90-day repeat dose study in male and female Crl:WI(Han) rats. The study was conducted under GLP conditions. The test method was based on OECD 408 (1998). The test material was diluted in corn oil (vehicle) to the appropriate dose concentrations. Male and Female rats (10/sex/group) received 0 (vehicle), 40, 150, or 600 mg/kg/day of the test article via oral gavage for 90 days. Clinical observations (daily), body weight (weekly), food consumption (weekly), functional tests (week 12), ophthalmoscopic examination (pretest and week 13), haematology (prior to necropsy), clinical chemistry (prior to necropsy), urinalysis (at end of treatment), gross pathology (at necropsy), histopathology (at necropsy) and immunohistochemistry (at necropsy) were each examined. No abnormal clinical signs or mortality were observed during the study. Functional observations, ophthalmoscopic examination, body weights and body weight gain, food consumption, haematology and clinical chemistry were all normal and no toxicologically relevant changes were noted. Upon urinalysis lower pH in males and females in the 600 mg/kg group was noted. In addition, a higher concentration of ketones was noted in 600 mg/kg group females.  Upon gross necropsy, higher liver weight and liver to body weight ratio was noted in males and females at 600 mg/kg (mean liver to body weight ratio 18% higher than control rats). Higher kidney weight was noted in males at 40, 150, and 600 mg/kg and females at 600 mg/kg, and higher kidney to body weight ratio in males and females at 150 and 600 (mean kidney to body weight ratio 10, 16, and 30% higher (males) or 6, 11, and 20% higher (females) than control means at 40, 150, and 600 mg/kg respectively). Accentuated lobular pattern of the liver was noted in 4/10 males at 40 mg/kg and 3/10 males and 1/10 females at 600 mg/kg. Enlarged liver was noted in 1/10 males at 150 mg/kg and 4/10 males at 600 mg/kg. Enlarged kidneys were noted in 6/10 males at 600 mg/kg. Upon histopathological examination of the kidneys, cortical hyaline droplets were increased in incidence and severity in all treated groups of males increasing from minimal in 3 control (group 1) males to slight to severe in all ten high dose (group 4) males. Immunohistochemical staining confirmed that these hyaline droplets represented alpha 2 globulin in high dose (group 4) males. Associated with the above findings were granular casts recorded at minimal or moderate degree in two middle dose (group 3) males and at minimal to moderate degree in 6 high dose (group 4) males. Minor degrees (minimal or slight) of corticomedullary tubular basophilia were increased in all treated groups of males. Upon histopathological examination of the liver, diffuse midzonal/centrilobular hypertrophy at a minimal degree was seen in 2 middle dose (group 3) and at minimal or slight degree in 8 high dose (group 4) males.(minimal also in one high dose (group 4) female). Upon histopatholigical examination of the thyroid glands, diffuse follicular hypertrophy/hyperplasia was recorded at minimal degree in 2 control (group 1), 1 low dose (group 2), 3 middle dose (group 3), and at minimal or slight degree in 5 high dose (group 4) males. Based on the presence of granular casts in the kidneys of males at 150 and 600 mg/kg, combined with the higher kidney weights in males and females at 600 mg/kg and in males at 150 mg/kg, a No Observed Adverse Effect Level (NOAEL) for the test article of 40 mg/kg (males) or 150 mg/kg (females) was established. Kidney damage in males was found to have been caused by an increase in alpha 2 globulin which ultimately lead to proximal cortical tubule cell injury, the formation of granular casts, and an increased cell turnover as manifest by an increased incidence/severity of tubular basophilia in males at 40, 150, and 600 mg/kg. This triad of lesions has been referred to as male rat nephropathy syndrome. As alpha 2 globulin is not present in female rats nor in higher mammals, including humans, nephropathy syndrome is considered to be of no risk to humans.


Kidney effects were seen in both studies but histopathology and immunohistochemical staining have shown that these effects are due to male rat nephropathy syndrome and are not relevant to human risk assessment. Because the only adverse effect is caused by the male rat nephropathy syndrome, the NOAEL for purposes of human risk assessment is set at 600 mg/kg.

Justification for classification or non-classification

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