Registration Dossier

Administrative data

Description of key information

No NOAEL is available however, the target organ has been identified (liver) and as quinoline produces early onset hepatocarcinogenesis, a NOAEL should be hardly obtained in repeated studies (no threshold).

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
repeated dose toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
no data
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Only few parameters were checked in this study which was focussed on carcinogenicity in the liver and no NOAEL is obtained. Only males are included in the study.
Reason / purpose:
reference to same study
Qualifier:
no guideline followed
Principles of method if other than guideline:
The principles are similar to the OECD guideline however fewer parameters were evaluated, and no attempt was made to find a NOAEL.
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Clea Japan Inc
- Age at study initiation: no data
- Weight at study initiation: 160-185 g
- Fasting period before study: no data
- Housing: Individually in screen-bottomed cages
- Diet: semisynthetic basal diet composed of 75% polished rice powder, 10% casein, 4% salt mixture, 10% corn oil, and 1% vitamin mixture.
- Water: no data
- Acclimation period: no data


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24°
- Humidity (%): no data
- Air changes (per hr): air-conditioned room no further data
- Photoperiod (hrs dark / hrs light): no data


IN-LIFE DATES: no data
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): once a week
- Mixing appropriate amounts with (Type of food): see above
- Storage temperature of food: stoarge in a dark cold room


VEHICLE
none
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
40 weeks
Frequency of treatment:
daily
Remarks:
Doses / Concentrations:
0.05; 0.1 and 0.25%
Basis:
nominal in diet
No. of animals per sex per dose:
20 males per group
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: no data
- Rationale for animal assignment (if not random): no data
- Rationale for selecting satellite groups: none
- Post-exposure recovery period in satellite groups: none
- Section schedule rationale (if not random): no data
Positive control:
none
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: no data, at least at the beginning and at the end of the study

FOOD CONSUMPTION AND COMPOUND INTAKE: no data

FOOD EFFICIENCY: no data

OPHTHALMOSCOPIC EXAMINATION: No data

HAEMATOLOGY: Yes
- Time schedule for collection of blood: at the end of the study
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: 6 of the low dose and of the control groups
- Parameters that were examined: Erythrocyte and leukocyte counts, the hematocrit, and the contents of hemoglobin

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at the end of the study
- Animals fasted: No data
- How many animals: 6 of the low dose and of the control groups
- Parameters that were examined: SGOT, SGPT, alkaline phosphatase, cholinesterase, cholesterol, total protein, and blood urea nitrogen

URINALYSIS: No data

NEUROBEHAVIOURAL EXAMINATION: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
not specified
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not specified
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
effects observed, treatment-related
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
Rats treated with a high concentration of quinoline gained their weight slowly. Some animals treated with 0.25% quinoline died of massive intra-abdominal hemorrhage due to rupture of vascular tumors in the liver.
In general, groups treated with quinoline showed increased liver weight. (See table 1 of the ESR 7.7 Hirao 1976)
Changes in the erythrocyte and leukocyte counts, the hematocrit, and the hemoglobin content are summarized in Table 3 of the ESR 7.7 Hirao 1976. These changes in the cell counts and hemoglobin level were not significant.
The levels of SGOT and alkaline phosphatase increased slightly in rats treated with 0.05% quinoline, but the levels of SGPT, cholinesterase, total protein, and blood urea nitrogen did not change markedly.
In the nonneoplastic region of the liver, there appeared a slight to moderate degree of oval cell infiltration and proliferation of the bile ducts and also fatty degeneration of liver parenchymal cells. Occasionally, small foci were seen showing dilated sinusoidal spaces and proliferated endothelial cells with a multilayered arrangement. No cholangiofibrosis, fibrosis, or cirrhotic changes were seen in any groups.
Dose descriptor:
NOAEL
Effect level:
0.05 other: %
Sex:
male
Basis for effect level:
other: Based on the increase of the liver weight and slight increase of SGOT and alkaline phosphatase at this level.
Remarks on result:
not determinable
Remarks:
no NOAEL identified
Critical effects observed:
not specified
Conclusions:
Effects on the liver are seen at the lowest concentration tested in this study so no NOAEL is obtained.
Executive summary:

A carcinogenicity study on the liver was performed with quinoline administrated to male rats in feed for 40 weeks at doses 0.05; 0.1 and 0.25%.

Some general toxicity endpoints were included in this study (clinical signs, haematology and serum chemistry). No NOAEL is obtained in this study due to increase of the liver weight and slight increase of the SGOT and alkaline phosphatase in the serum at the lowest dose.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
20 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
See the discussion below

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

No valid repeated toxicity study is available with quinoline. All the studies were done in the frame of a hepatocarcinogenicity or a mutagenicity study, so no exhaustive assessment of the general toxicity of quinoline is available. However, the data recovered from these studies show that the liver is the target organ and no effect was seen in other organs. The males seem to be more susceptible to quinoline than females in rat and mouse, and also in a lesser extent in hamsters. In conditions causing hepatocarcinogenesis in rat and mouse, Guinea pigs did not show adverse effects in the liver. 2 studies were performed with several doses, a NOAEL at 50 mg/kg/d was obtained for 28 -d exposure in male rats, however the observations were very limited. No NOAEL for toxicity is obtained in other studies. A LOAEL at 0.05% in diet is available, corresponding to 20 mg/kg/d (according to chapter R8 of the guidance on information requirements and chemical safety assessment), it comes from a 40 -w study on male rats. As quinoline produces early onset hepatocarcinogenesis, a NOAEL should be hardly obtained in repeated studies (no threshold).

Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
See the discussion below

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

No appropriate data is available to set up a classification.