Bis(pentane-2,4-dionato-O,O')magnesium

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

28 days

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2021

Report date:

2021

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

Deviations:

no

GLP compliance:

no

Remarks:

The study was conducted in compliance with Good Laboratory Practice (GLP) of Certification and Accreditation Administration of the People’s Republic of China (CNCA) (revised edition in 2013).

Test material

Test material information

Constituent 1

Reference substance name:

Bis(pentane-2,4-dionato-O,O')magnesium

EC Number:

237-857-7

EC Name:

Bis(pentane-2,4-dionato-O,O')magnesium

Cas Number:

14024-56-7

Molecular formula:

C10H14MgO4

IUPAC Name:

magnesium;4-oxopent-2-en-2-olate

Test material form:

solid: particulate/powder

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Duration of treatment / exposure:

28 days

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

600 mg/kg bw (total dose)

Remarks:

High dose

Doses / concentrations 2

Dose / conc.:

300 mg/kg bw (total dose)

Remarks:

Middle dose

Doses / concentrations 3

Dose / conc.:

120 mg/kg bw (total dose)

Remarks:

Low dose

Doses / concentrations 4

Dose / conc.:

30 mg/kg bw (total dose)

Remarks:

Low dose

Doses / concentrations 5

Dose / conc.:

0 mg/kg bw (total dose)

Remarks:

Control group

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

There was no death or near death in the whole experiment, no obvious toxic reaction was observed in each dose group of male and female animals. On day 17 and 24 of the administration period, the average body weight of female and male rats in high dose group were lower than the control, showed extremely significant or significant differences. On day 3 of the administration period, weight gain of male and female rats in high dose group were inhibited. On day 17 of the administration period, weight gain of male rats in high dose group were inhibited. On day 3 of the administration period, the average food intake of female and male rats in the high dose group were lower than the control, showed extremely significant or significant differences.
No toxicological changes were found in blood routine, hemagglutination, blood biochemistry and urine routine examination. The blood routine examination showed that reticulocyte (RET) of female and male rats in high dose group were higher than the control at the end of administration period, showed extremely significant or significant differences. There was no statistically significant change in hemagglutination test. The blood biochemistry examination showed that aspartate aminotransferase (AST) of male rats in high dose group were lower than the control at the end of the administration period, showed significant difference. Total bilirubin (TBIL) of male rats in high dose group were higher than the control at the end of the administration period, showed extremely significant difference. Aspartate aminotransferase (AST) and cholinesterase (CHE) of female rats in high dose group were lower than the control at the end of the administration period, showed significant difference. The urine routine examination showed urine ketones (KET) of male rats in high dose group were lower than the control at the end of the administration period, showed significant difference.
The gross anatomical results showed that, one female rat (2109) had large heart and heart yellow-white color change in very low dose group; One female rat (2300) had large uterus in middle dose group, and other animals were not abnormal.
The results of organ weight showed that absolute weight and testis of male rats in high dose group were lower than the control at the end of the administration period, showed extremely significant or significant statistical difference. Liver to body weight ratio, brain to body weight ratio and adrenal gland to body weight ratio of male rats in high dose group were higher than the control at the end of the administration period, showed extremely significant or significant statistical difference. Testis to brain ratio of male rats in high dose group were lower than the control at the end of the administration period, showed significant statistical difference. Kidney to body weight ratio of female rats in high dose group were higher than the control at the end of the administration period, showed significant statistical difference.
Histopathological examination showed that the incidence of splenic vacuolar degeneration and the decrease of splenic red pulp cells in female middle and high dose groups were very significantly (or significantly) higher than those in the control group. It was considered that this test had the effect of inducing splenic vacuolar degeneration and the decrease in the number of splenic red pulp cells in the middle and high dose groups of females under the experimental conditions. There were only two cases of splenic vacuolar degeneration in the female low-dose group, and there was no significant difference. However, since these two lesions were the results of the role of the test chemical, it was considered that under the experimental conditions, the test chemical also had the effect of reducing the number of splenic red pulp in the female low dose group, and no such lesion was found in the spleen of male experimental animals.

Mortality:

no mortality observed

Description (incidence):

There was no death or near death in the whole experiment, no obvious toxic reaction was observed in each dose group of male and female animals.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

On day 17 and 24 of the administration period, the average body weight of female and male rats in high dose group were lower than the control, showed extremely significant or significant differences. On day 3 of the administration period, weight gain of male and female rats in high dose group were inhibited. On day 17 of the administration period, weight gain of male rats in high dose group were inhibited. On day 3 of the administration period, the average food intake of female and male rats in the high dose group were lower than the control, showed extremely significant or significant differences.

Description (incidence and severity):

The urine routine examination showed urine ketones (KET) of male rats in high dose group were lower than the control at the end of the administration period, showed significant difference.

Description (incidence and severity):

The results of organ weight showed that absolute weight and testis of male rats in high dose group were lower than the control at the end of the administration period, showed extremely significant or significant statistical difference. Liver to body weight ratio, brain to body weight ratio and adrenal gland to body weight ratio of male rats in high dose group were higher than the control at the end of the administration period, showed extremely significant or significant statistical difference. Testis to brain ratio of male rats in high dose group were lower than the control at the end of the administration period, showed significant statistical difference. Kidney to body weight ratio of female rats in high dose group were higher than the control at the end of the administration period, showed significant statistical difference.

Description (incidence and severity):

Histopathological examination showed that the incidence of splenic vacuolar degeneration and the decrease of splenic red pulp cells in female middle and high dose groups were very significantly (or significantly) higher than those in the control group. It was considered that this test had the effect of inducing splenic vacuolar degeneration and the decrease in the number of splenic red pulp cells in the middle and high dose groups of females under the experimental conditions. There were only two cases of splenic vacuolar degeneration in the female low-dose group, and there was no significant difference. However, since these two lesions were the results of the role of the test chemical, it was considered that under the experimental conditions, the test chemical also had the effect of reducing the number of splenic red pulp in the female low dose group, and no such lesion was found in the spleen of male experimental animals.

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

30 mg/kg bw/day (nominal)

Sex:

female

Basis for effect level:

histopathology: non-neoplastic

Remarks on result:

other: splenic vacuolar degeneration and the decrease in the number of splenic red pulp cells in the middle and high dose groups of females under the experimental conditions

2

Dose descriptor:

NOAEL

Effect level:

300 mg/kg bw/day (nominal)

Sex:

male

Basis for effect level:

body weight and weight gain

Target system / organ toxicity

Critical effects observed:

no

Applicant's summary and conclusion

Conclusions:

According to the results of this experiment, it was concluded that repeated oral administration of N56 for 28 days had toxic effects on SD rats at the dose of 600 mg/kg, suspected to have an impact on the spleen of female rats. At the end of the 14d recovery period, no significant delayed toxicity effect was observed. According to the results of average weight change, the NOAEL in male rats was 300 mg/kg ; According to the results of pathological examination, the NOAEL in female rats was 30 mg/kg.