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

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Justification for type of information:

Intertnal method in accordance with SOPs.

Qualifier:

according to guideline

Guideline:

other: Internal method in accordance with standard operating procedures.

GLP compliance:

yes

Limit test:

no

Specific details on test material used for the study:

Composition:
98.4% L-654,969

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

15 females and 15 males

Route of administration:

oral: gavage

Vehicle:

water

Details on oral exposure:

dosed twice daily for 91 days males and 92 days females.

Duration of treatment / exposure:

Test duration: 90 days

Frequency of treatment:

Dosing regime: 7 days/week

Dose / conc.:

0 mg/kg bw/day (nominal)

Remarks:

control

Dose / conc.:

2 mg/kg bw/day (nominal)

Dose / conc.:

10 mg/kg bw/day (nominal)

Dose / conc.:

20 mg/kg bw/day (nominal)

No. of animals per sex per dose:

Male: 15 animals at 0 mg/kg bw/day
Male: 15 animals at 2 mg/kg bw/day
Male: 15 animals at 10 mg/kg bw/day
Male: 15 animals at 20 mg/kg bw/day
Female: 15 animals at 0 mg/kg bw/day
Female: 15 animals at 2 mg/kg bw/day
Female: 15 animals at 10 mg/kg bw/day
Female: 15 animals at 20 mg/kg bw/day

Control animals:

yes, concurrent vehicle

Clinical signs:

not examined

Mortality:

mortality observed, non-treatment-related

Description (incidence):

No drug-related mortality was observed. A moribund rat in the low dose group was sacrificed in Week 1. Gross examination revealed that the cause of death was due to an intubation accident.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

The was no difference in the bodyweight gain of control and treated female rats. There was a decrease in bodyweight gain of high dose males (8%, p=0.018) and a slight, but not statistically significant decrease (4%, p=0.57) in bodyweight gain of middle dose males as compared to controls.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

There was no difference in the food consumption between control and treated rats.

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

no effects observed

Description (incidence and severity):

There were no treatment-related differences in haematology in control and treated rats.

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

There were no treatment-related differences in serum biochemistry in control and treated rats.

Urinalysis findings:

no effects observed

Description (incidence and severity):

There were no treatment-related differences in urinalysis in control and treated rats.

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

In addition, increased liver weights were seen (absolute and relative to brain and bodyweight) in the middle and high dosage group females; no similar changes were observed in males. Histologically, the only liver changes apparent were cellular atypia and bile duct proliferation in 2 females in the high dose group. No other animals in this study showed similar changes.

There was a non-significant but dose-related trend towards increased thyroid weights in females in all 3 treatment groups and in males in the middle and high dose groups.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

At necropsy, grossly thickened non-glandular mucosa was observed in the stomachs of rats in all treated groups.
Microscopically, this appeared as very slight to moderate hyperkeratosis and acanthosis with submucosal oedema and cellular infiltration present.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Key result

Dose descriptor:

NOEL

Effect level:

< 2 mg/kg bw/day (nominal)

Based on:

not specified

Sex:

male/female

Basis for effect level:

body weight and weight gain

gross pathology

organ weights and organ / body weight ratios

Remarks on result:

other: due to the increased incidence of changes in the stomachs of all treated rats, a NOEL could not be specifically established; NOEL therefore defined above as < the lowest dose given.

Critical effects observed:

not specified

Conclusions:

No no-effect level was established. The changes observed in the nonglandular mucosa of rats are similar to those observed in studies with structurally-related compounds.
Although the pathogenesis of the changes is not clearly understood, it appears to be related to the inhibition of HMG-CoA reductase caused by the substance. No similar gastric epithelium is found, nor in the dog oesophagus, where similar squamous epithelium is found. Since the effect appears to be specific to the rat, it is not considered to be relevant to human exposure.
The notifier thus considers, despite the fact that no "no-effect level" has been established, that the substance should be classifed as STOR RE 1 and labelled with H372. The Irish CA considers that the substance should be classified as "Toxic".
This 90-day study has been compared with Annex V and also the OECD 90-day Guideline No. 408.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

LOAEL

2 mg/kg bw/day

Study duration:

subchronic

Experimental exposure time per week (hours/week):

13

Species:

rat

Quality of whole database:

1

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 - local effects

Endpoint conclusion

Endpoint conclusion:

no study available