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

Carcinogenicity

Description of key information

in an initial carcinogenicity study in rats, there was a treatment-relatedincrease in thyroid follicular cell adenomas (benign tumors) in female rats at a dosage of 25mg/kg/day that was considered secondary to enhancement ofthyroid hormone clearance. Therewas no increase in tumor incidence in mice up to 25mg/kg/day.Epithelial hyperplasia of the forestomach was observed in both studies.Simvastatin caused an increasedincidence in hepatocellular adenomas and carcinomas, pulmonary adenomas and harderian glandadenomas(NOAEL = 25 mg/kg/day). In rats, an increased incidence of hepatocellularneoplasms was observed (NOAEL = 25 mg/kg/day)

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

26th June 1989 to 2nd July 1991

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

CRL:CD (SD) BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories Inc., Wilmington, MA
- Age at study initiation: 29 days
- Weight at study initiation: 58 - 102g
- Housing: one animal per cage in suspended steel cages, environmentally controlled clean air rooms
- Diet: Purina certified rodent chow ad libitum
- Water: Tap water ad libitum

ENVIRONMENTAL CONDITIONS
- Photoperiod: 12hrs dark / 12hrs light)

Route of administration:

oral: gavage

Vehicle:

other: Methylcellulose 0.5%

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: The test item was suspended in 0.5% aqueous methylcellulose and appropriate dilutions made with methylcellulose for the remaining dose groups

VEHICLE
- Concentration in vehicle: 50, 100, 250 and 500 mg/kg/day
- Amount of vehicle (if gavage): 5ml/kg dose volume

Duration of treatment / exposure:

106 weeks

Frequency of treatment:

Daily

Post exposure period:

None

Dose / conc.:

500 mg/kg bw/day (nominal)

Dose / conc.:

250 mg/kg bw/day (nominal)

Dose / conc.:

100 mg/kg bw/day (nominal)

Dose / conc.:

50 mg/kg bw/day (nominal)

No. of animals per sex per dose:

50

Control animals:

yes, concurrent no treatment

Details on study design:

Treatment groups consisted of approximately 50 rats/sex/group and included 2 control groups which received the vehicle and 4 drug treated groups which received the test item at 50, 100, 250 and 500 mg/kg/day. Due to the severity of the top two doses, these groups were terminated and discarded without examination after 5 doses of 500 mg/kg/day and 21-22 doses of 250 mg/kg/day.

Positive control:

None

Observations and examinations performed and frequency:

CLINICAL OBSERVATIONS: Yes
- Time schedule: Daily during weeks 1-4 and weekly thereafter

PALPATATION FOR MASSES
- Time schedule: Weekly during weeks 1-60 and monthly thereafter

BODY WEIGHT: Yes
- Time schedule: Twice weekly during weeks 1-12 and weekly thereafter

FOOD CONSUMPTION
- Food consumption was measured weekly through week 60 on a 3 day intake period

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: Weeks 13, 26, 52, 77 and 104
- Dose groups that were examined: All control groups and 50 and 100 mg/kg day groups.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: Weekly up to Week 61 from all moribund animals
Then a revision was made whereby blood samples were taken at time of necroscopy (early sacrifice or terminal necroscopy) from only those animals that showed enlargement of spleen, lymph nodes and/or liver.

Sacrifice and pathology:

Complete necroscopies were carried out on all rats from the control groups and from the 50 and 100 mg/kg/day groups. This included microscopic examination of a detailed set of formalin-fixed, paraffin-embedded and hematoxylin-and-eosin stained slides.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

500 mg/kg/day dose groups.
Clinical signs observed in the first few days of dosing. Rats had morbidity, severe weight loss, decreased food consumption, decreased activity, pilo-erection, fecal/urine staining, hind limb weakness, sternal recumbency and alopecia.
250 mg/kg/day dose groups.
Clinical signs observed in the first few days of dosing. Rats had morbidity, weight loss and/or markedly decreased weight gain (50-80% below control in first 2 weeks), decreased activity, pilo-erection, hind limb weakness and alopecia.
The severity necessitated the termination of the 500 and 250 mg/kg/da dose groups after 5 days and 4 weeks respectively.

50 and 100 mg/kg/day dose groups.
Excessive pre and/or post dose salivation

Mortality:

mortality observed, treatment-related

Description (incidence):

500 mg/kg/day dose groups.
8 rats in first five days of dosing. (4/sex)

250 mg/kg/day dose groups.
2 rats dead in the first 12 days of dosing. (Day 9 and 12)
8 rats sacrificed in moribund condition in the first 3 weeks of dosing. (6 female, 2 male)

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

500 mg/kg/day dose groups.
Average weight loss - 12.4g in females and 11.8g in males after 3 days of treatment.

250 mg/kg/day dose groups.
Average weight loss - 3.8g in females and 4g in males.
After 2 weeks of treatment weight gain began to improve and by week 3 the body weight of females began to approximate those of the control animals, while that of males remained 34% below the controls.

50 and 100 mg/kg/day dose groups.
A statistically significant decreasing trend in body weight gain was determined for females at both doses and for males at 100 mg/kg/day

Ophthalmological findings:

effects observed, treatment-related

Description (incidence and severity):

100 mg/kg/day dose groups.
Increase in lenticular opacities after 103 weeks - 25.4% versus 14.8% in controls
posterior polar cataracts (PPC) - 2 animals
posterior subcapsular cataracts (PSC) - 7 animals
complete cataracts (CC) - 7 animals

50 mg/kg/day dose groups.
Similar to control at 103 weeks - however, the incidence of complete cataracts was 4/100 compared to 1/200 in controls

Histopathological findings: neoplastic:

effects observed, treatment-related

Description (incidence and severity):

100 mg/kg/day dose groups.
Hepatocellular adenoma females x 13, males x 12
Hepatocellular carcinoma females x 11, males x 12

50 mg/kg/day dose groups.
Hepatocellular adenoma females x 13, males x 6
Hepatocellular carcinoma females x 5, males x 4

Thyroid Gland
apparent increased incidence but not statistically significant

Other effects:

effects observed, treatment-related

Description (incidence and severity):

Hepatic and gastric changes:
Centrilobular, acidophilic and hypertrophy, focal cystic degeneration, eosinophilic and basophilic, focal cellular alteration of the liver, acanthosis, hyperkeratosis, cellular infiltration, and edema of the forestomach.

Key result

Dose descriptor:

NOEL

Effect level:

25 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical signs

histopathology: neoplastic

mortality

ophthalmological examination

Conclusions:

At doses of 200 and 500 mg/kg/day, MK-0733 produced severe toxicity in rats necessitating early termination of these two treatment groups within the first 4 weeks of study initiation. Treatment related findings included loss of weight and/or marked depression in body weight gain accompanied by marked decrements in food intake, decreased activity, hind limb weakness/paralysis, morbidity and death.

In the 50 and 100 mg/kg/day treatment groups, MK-0733 was well tolerated. Treatment related changes included slight statistically significant decrements in body weight gain in females at both doses and in males at 100 mg/kg/day. In addition, an increased incidence of lenticular opacities occurred in both the 50 and 100 mg/kg/day dose animals after 103 weeks. An increased incidence of hepatocellular neoplasms was observed in both the 50 and 100 mg/kg/day dose groups.

In an initial carcinogenicity study in rats, there was a treatment-relatedincrease in thyroid follicular cell adenomas (benign tumors) in female rats at a dosage of 25mg/kg/day that was considered secondary to enhancement ofthyroid hormone clearance. Therewas no increase in tumor incidence in mice up to 25mg/kg/day.Epithelial hyperplasia of the forestomach was observed in both studies.Simvastatin caused an increasedincidence in hepatocellular adenomas and carcinomas, pulmonary adenomas and harderian glandadenomas(NOAEL = 25 mg/kg/day). In rats, an increased incidence of hepatocellularneoplasms was observed (NOAEL = 25 mg/kg/day). Therefore, the NOEL for carcinogenesis remains at 25 mg/kg/day (as established in this previous study). In addition, an increase in the incidence of thyroid hyperplastic lesions was also observed. The hyperplastic response induced by MK-0733 in the rat thyroid is a species specific response, directly related to the liver enlargement caused by MK-0733 in rats and has no implications for man.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

25 mg/kg bw/day

Study duration:

chronic

Species:

rat

Quality of whole database:

1

Organ:

liver

lungs

stomach

thyroid gland

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available