Registration Dossier

Administrative data

Description of key information

NOAEL: (90 days, male/female rats, oral) = 240 mg/kg bw/day (actual dose received)(equivalent or similar to EU Method B.26 (2008); GLP complaint)

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
240 mg/kg bw/day
Study duration:
subchronic
Species:
rat

Mode of Action Analysis / Human Relevance Framework

Additional information

Repeated dose toxicity: oral

The test item was administered daily by oral gavage to SPF-bred Wistar rats of both sexes at dose levels of 80, 240 and 800 mg/kg body weight/day for a period of at least 91 days.

 

The changes in clinical biochemistry parameters mainly observed in animals treated with 800 mg/kg bw/day and to a much lesser extent in animals treated with 240 mg/kg bw/day reflect the main target organs kidney and liver. Increased urinary volume in males treated with 800 mg/kg bw/day and increased urinary protein in males and females treated with 800 mg/kg bw/day observed in the urinalysis examinations are also indicative of altered kidney function. After the 4-week recovery period, no differences in clinical laboratory parameters were observed between the corn oil-treated and the vehicle-treated animals and those treated with 800 mg/kg bw/day, thus indicating that the treatment-related changes were still reversible after 91 days of treatment. Considering that all clinical laboratory values, except for triglyceride levels in females treated with 800 mg/kg bw/day and phospholipids and globulin levels in males treated with 800 mg/kg bw/day, were within the range of historical control data, and that all changes observed were reversible within the 4 week recovery period, the few changes in clinical laboratory values observed in females treated with 240 mg/kg bw/day are considered to be still adaptive rather than adverse.

 

The primary target organ for the test item is considered to be the kidney. All these degenerative/regenerative and inflammatory changes correlated with increased absolute and relative organ weights of main study males treated with 80, 240 and 800 mg/kg bw/day as well as increased kidney/body weight ratio in recovery males treated with 800 mg/kg/day. The histopathologic changes in the kidney were consistent with possible irritant effect of the test item and/or its metabolites excreted in the urine. A minor incidence of centrilobular hepatocellular hypertrophy at minimal severity without any further indicator for liver injury in male animals treated with 240 and 800 mg/kg bw/day correlated with accentuated lobular pattern and increased absolute and relative liver weights. Minimal hepatocellular hypertrophy was also recorded in few females treated with 800 mg/kg bw/day. Due to the absence of any further lesion, this finding is deemed to be by metabolic adaption. The stomach may also be regarded as primary target organ. The lesions observed in the stomach represented a localized stomach reaction to a repeatedly gavaged slightly irritant test item. The cause of regurgitation (the latter is best demonstrated by nasal cavity/nasopharynx lesions) is unclear.

 

In conclusion, based on the histopathological findings observed in kidneys, stomach, and liver, as well as findings related to accidental aspiration/regurgitation of the vehicle/test item, the histopathological NOEL for females could be established at 80 mg/kg bw/day. However, a histopathological NOEL for males could not be established.

 

The only test item-related findings recorded in males of the low dose group (treated with 80 mg/kg bw/day) were hyaline droplets, tubular basophilia, casts and tubular dilation. These findings are common findings in untreated control animals. Based on these considerations, a NOAEL for effects relevant to human risk assessment may be established at 240 mg/kg/day for females under the conditions of this study. This conclusion is supported by the observations in males because besides the signs of α2u-globulin nephropathy, that was considered not relevant for humans, no additional adverse effects occurred at 240 mg/kg bw/day.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
See Discussion section

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver; digestive: stomach

Justification for classification or non-classification

Repeated dose toxicity, oral

Specific target organ toxicant (STOT)- repeated exposure: oral

No classification and labelling of the test substance according to regulation (EC) 1272/2008 as specific target organ toxicant (STOT) – repeated exposure, oral is necessary, since the guidance value for a Category 1 classification of C<10 mg test substance/kg bw/day (based on sub-chronic toxicity study), and the guidance value for a Category 2 classification of 10<C<100 mg test substance/kg bw/day (based on sub-chronic toxicity study) are not met.

No effects relevant for human risk assessment were observed at and below a dose level of 240 mg/kg bw/d in male and female rats in 13 -week oral toxicity study, and the NOAEL was determined to be 240 mg/kg bw/day.