17-hydroxy-6-methylenepregn-4-ene-3,20-dione 17-acetate

Endpoint summary

Description of key information

Subacute oral toxicity (4 weeks, rat) - NOAEL: 650mg/kg/day [Draft report, Seibert 1997]

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

other information

Study period:

September to October 1996

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: guideline study with restriction (actual ingested doses differ from intended dose levels)

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Species:

rat

Strain:

other: Han: WIST (SPF)

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

other: 1 % Klucel LF, 0.9 % NaCl solution, 0.085 % Myrj 53 per 100 ml bidest. water

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analysis of content was performed in one sam pie of each concentration once at the beginning and at the end of the treatment period. The results showed that the actual concentrations of the first preparation were within the acceptable range of 91 to 94% of the nominal concentrations. However, the content of the last preparation revealed only an actual content of 66% of nominal concentration for the low and mid concentration and a conte nt of 84% at the high concentration level. These results indicate that the animals might have received doses over the treatment period which were about 35% below the intended dose levels, assuming that the results of the last preparation represent the greatest deviation from the intended content.

Duration of treatment / exposure:

ca. 4 weeks (29 applications)

Frequency of treatment:

once daily

Remarks:

Doses / Concentrations:
ca. 25, 130, 650 mg/kg bw
Basis:
other: actual ingested on the basis of the results of content analysis

Remarks:

Doses / Concentrations:
40, 200, 1000 mg kg bw
Basis:
other: nominal values

No. of animals per sex per dose:

6

Control animals:

yes, concurrent vehicle

Statistics:

For statistical evaluation the Dunnett-test was used.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

no effects observed

Water consumption and compound intake (if drinking water study):

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

no effects observed

Behaviour (functional findings):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

no effects observed

Dose descriptor:

NOAEL

Effect level:

650 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Dose descriptor:

NOEL

Effect level:

130 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

other: increase in serum glucose levels

Dose descriptor:

NOEL

Effect level:

25 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: decrease in body weight gain; increase in serum glucose level

Critical effects observed:

not specified

The only compound-related effects which were observed during this study were an increase in serum glucose levels in male animals from the mid-dose level onwards and in female animals at the high-dose level as weil as a slight decrease in body weight gain in males from the middose level onwards. The difference in mean body weights of male animals from the high-dose group in comparison to the controls was less than 7% on the last day of weighing (day 27). Furthermore, the reduced body weight gain was not associated with a reduced food-intake. Neither the effect on glucose levels nor the slight decrease in body weight development have to be judged as an overt sign of toxicity of the test compound, due to their slight extent and the absence of any other compound-related pathological condition. In conclusion, the low dose of ca. 25 mg /kg/day was identified as no-effect-dose in male rats and 130 mg/kg/day as no-effect-dose in female rats in the present study. The highdose level of 650 mg/kg/day was characterized as no-observable-adverse-effect dose in male and female rats.

Executive summary:

Three groups of 6 male and 6 female rats each received daily intragastric administrations of nominal doses of 40, 200 and 1000 mg /kg, respectively, as microcrystalline suspensions at an application volume of 10 ml/kg over aperiod of ca. 4 weeks (29 applications). A control group of 6 male and 6 female rats were treated with the vehicle under the same conditions. The formulations were prepared freshly on each day of the study. The results of the formulation analyses which were performed with the first and last preparation indicated, however, that only the first formulation was prepared adequately with a conte nt of ~ 91 % of nominal concentration while the content of the last preparation lay about 35% below the intended concentration. Therefore, only approximate dose ranges can be stated for the three compound-treated animal groups. The lower limits of the actual dose ranges per group were based here on the assumption that the analysis results of the last preparation indicate the"worst case" of underdosing wh ich might have occurred throughout the study.

The effects of the test substance were evaluated using clinical, biochemical and hematological parameters as weil as bone marrow examination, urinalysis, coagulation studies, necropsy findings, organ weight analysis and microscopic examinations.

The intragastric treatment of rats with the test substance over ca. 4 weeks up to a dose of ca. 650 mg/kg/day produced a slight reduction of body weight gain and an increase in serum glucose levels, but did not lead to overt signs of toxicity. Furthermore, the low dose level of ca. 25 mg kg/day was identified as no-observableeffect-dose in male rats and 130 mg/kg/day as no-observable-effect-dose in female rats in the present study.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

650 mg/kg bw/day

Study duration:

subacute

Species:

rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Three groups of 6 male and 6 female rats each received daily intragastric administrations of nominal doses of 40, 200 and 1000 mg /kg, respectively, as microcrystalline suspensions at an application volume of 10 ml/kg over aperiod of ca. 4 weeks (29 applications). A control group of 6 male and 6 female rats were treated with the vehicle under the same conditions. The formulations were prepared freshly on each day of the study. The results of the formulation analyses which were performed with the first and last preparation indicated, however, that only the first formulation was prepared adequately with a conte nt of ~ 91 % of nominal concentration while the content of the last preparation lay about 35% below the intended concentration. Therefore, only approximate dose ranges can be stated for the three compound-treated animal groups. The lower limits of the actual dose ranges per group were based here on the assumption that the analysis results of the last preparation indicate the"worst case" of underdosing wh ich might have occurred throughout the study.

The effects of the test substance were evaluated using clinical, biochemical and hematological parameters as weil as bone marrow examination, urinalysis, coagulation studies, necropsy findings, organ weight analysis and microscopic examinations.

The intragastric treatment of rats with the test substance over ca. 4 weeks up to a dose of ca. 650 mg/kg/day produced a slight reduction of body weight gain and an increase in serum glucose levels, but did not lead to overt signs of toxicity. Furthermore, the low dose level of ca. 25 mg kg/day was identified as no-observableeffect-dose in male rats and 130 mg/kg/day as no-observable-effect-dose in female rats in the present study.

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Only one study available

Justification for classification or non-classification

Based on the study results a classification according to Directive 67/548/EEC or Regulation (EC) No. 1272/2008 (CLP) is not required.