Ammonium 7-(2,6-dimethyl-8-(2,2-dimethylbutyryloxy)-1,2,6,7,8,8a-hexahydro-1-naphthyl)-3,5-dihydroxyheptanoate

Endpoint summary

Key value for chemical safety assessment

Genetic toxicity in vitro

Description of key information

The substance was negative with metabolic activation and negative without metabolic activation in a In Vitro Ames study

Link to relevant study records

Reference

Endpoint:

in vitro gene mutation study in bacteria

Type of information:

experimental study

Adequacy of study:

key study

Study period:

This test represents the results of two independent studies. 20th June 1985 to 24th June 1985 24th May 1989 to 1st June 1989

Reliability:

1 (reliable without restriction)

Qualifier:

according to guideline

Guideline:

other: Internal method in accordance with standard operating procedures (see comments).

GLP compliance:

yes

Type of assay:

bacterial reverse mutation assay

Species / strain / cell type:

S. typhimurium TA 1535, TA 1537, TA 98, TA 100 and E. coli WP2

Details on mammalian cell type (if applicable):

Salmonella typhimurium TA1535, TA97a, TA98 and TA100 E.Coli: WP2, EP2 urvA,
WP2 urvA pKm101

Metabolic activation:

with and without

Metabolic activation system:

S9

Test concentrations with justification for top dose:

Concentration range in the main test (with metabolic activation): 30 ... 3000 μg/plate
Concentration range in the main test (without metabolic activation): 30 ... 3000 μg/plate

Vehicle / solvent:

Solvent: Ethanol

Negative solvent / vehicle controls:

yes

Remarks:

DMSO

Positive controls:

yes

Positive control substance:

other: Hydrazine sulfate

Negative solvent / vehicle controls:

yes

Remarks:

DMSO

Positive controls:

yes

Positive control substance:

other: 2-aminoanthracene

Details on test system and experimental conditions:

Concentration of the test substance resulting in precipitation: 3000 μg/plate

Key result

Species / strain:

other: Salmonella typhimurium TA1535, TA97a, TA98 and TA100 E.Coli: WP2, EP2 urvA, WP2 urvA pKm101

Metabolic activation:

with

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

cytotoxicity

Positive controls validity:

valid

Key result

Species / strain:

other: Salmonella typhimurium TA1535, TA97a, TA98 and TA100 E.Coli: WP2, EP2 urvA, WP2 urvA pKm101

Metabolic activation:

without

Genotoxicity:

negative

Cytotoxicity / choice of top concentrations:

cytotoxicity

Positive controls validity:

valid

Additional information on results:

Observations:
No evidence of mutagenic potential of L-654,969 was observed either in the presence or absence of metabolic activation.

Remarks on result:

other: Test system: main test (migrated)

Conclusions:

Interpretation of results (migrated information):
negative with metabolic activation
negative without metabolic activation

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)

Genetic toxicity in vivo

Description of key information

There was no evidence for induction of chromosome aberrations in MK-0733 under the conditions of a In Vivo ChromAb test

Link to relevant study records

Reference

Endpoint:

in vivo mammalian somatic cell study: cytogenicity / bone marrow chromosome aberration

Type of information:

experimental study

Adequacy of study:

key study

Study period:

6th January 1986 to 27th June 1986

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

according to guideline

Guideline:

other: Internal method in accordance with standard operating procedures

GLP compliance:

yes

Type of assay:

mammalian bone marrow chromosome aberration test

Species:

mouse

Strain:

CD-1

Sex:

male

Details on test animals or test system and environmental conditions:

Mice were sourced from Charles River Breeding Farms, weight range 14 - 27.1 The mice were housed 4-12 per cage. Each animal was identified by a metal ear tag.
Food: Purina Certified Rodent Chow
Water: ad libitum

Route of administration:

oral: gavage

Vehicle:

Aqueous Methylcellulose

Duration of treatment / exposure:

6, 24 and 48 hours

Frequency of treatment:

once

Dose / conc.:

5 000 mg/kg bw/day

Dose / conc.:

1 667 mg/kg bw/day

Dose / conc.:

500 mg/kg bw/day

No. of animals per sex per dose:

10

Control animals:

yes

Positive control(s):

Mitomycin C

Tissues and cell types examined:

Bone marrow cells

Details of tissue and slide preparation:

Bone marrow was harvested in pre-warmed Hank's Balanced Salt Solution. Bone marrow cells were treated with a hypotonic solution of potassium chloride in water and is fixed in freshly prepared absolute methanol : glacial acetic acid (3:1).
Fixed cells were dropped onto clean wet slides and allowed to dry. All slides were stained with Giemsa and coverslips applied.

Evaluation criteria:

For each mouse the following quantities were calculated:
% mitotic cells
Total aberrant cells
% aberrant cells
Total aberrants
frequency of aberrant/cell

Statistics:

Adjusted trend P-value

Sex:

male

Genotoxicity:

negative

Toxicity:

no effects

Vehicle controls validity:

valid

Negative controls validity:

valid

Positive controls validity:

valid

Conclusions:

There was no evidence for induction of chromosome aberrations in MK-0733 under the conditions of this test

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (negative)