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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Data is from peer reviewed journal

Data source

Reference
Reference Type:
publication
Title:
EFFECTS OF D&C YELLOW NO. 11 INGESTION ON F344/N RATS AND B6C3F1 MICE
Author:
W. C. Eastin , M. R. Elwell , S. Grumbein, J.-H. Yuan
Year:
1996
Bibliographic source:
Journal of Toxicology and Environmental Health vol 4. Issue 2 1996.

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: Chronic repeated dose toxicity
Principles of method if other than guideline:
Chronic repeated dose toxicity study of D & C yellow no.11 orally in mice.
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
other: Solid
Details on test material:
- Name of test material (as cited in study report): D & C yellow no.11 (2-(2-quinolyl)-1,3-indanedione)
- Molecular formula (if other than submission substance): C18H11NO2
- Molecular weight (if other than submission substance): 273.29 g/mole
- Substance type: Organic
- Physical state: solid
- Purity: 99%
- Impurities (identity and concentrations): 1 %

Test animals

Species:
mouse
Strain:
B6C3F1
Sex:
male/female
Details on test animals and environmental conditions:
Source: Taconic Farms
- Age at study initiation: Four week old
- Weight at study initiation: 19.1–20.0 g male, 16.7–17.6 g female
- Fasting period before study: No data
- Housing: mice were individually caged
- Diet: NIH 07 diet ad libitum
- Water : ad libitum
Acclimation period :Quarantined 13–15 days before the studies began

ENVIRONMENTAL CONDITIONS
- Temperature -70-76°F (21-24°C )
- Humidity (%):44–56%
- Air changes (per hr) - more than 10 room air changes per hour.
Photoperiod (hrs dark / hrs light): 12h/d

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: NIH 07 diet
Details on oral exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): Daily

VEHICLE
- Justification for use and choice of vehicle (if other than water): NIH 07 diet
- Concentration in vehicle: 0, 500, 1700, 5000, 17,000, and 50,000 ppm
- Amount of vehicle (if gavage): No data available
- Lot/batch no. (if required): No data available
- Purity: No data available
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
13 Weeks
Duration of treatment / exposure:
Daily
Frequency of treatment:
0, 500, 1700, 5000, 17,000, and 50,000 ppm (0, 83, 283, 833, 2833 and 8333 mg/kg/day)
No. of animals per sex per dose:
Total : 120
0 ppm: 10 male, 10 female
500 ppm: 10 male, 10 female
1700 ppm: 10 male, 10 female
5000 ppm: 10 male, 10 female
17000 ppm: 10 male, 10 female
50000 ppm: 10 male, 10 female
Control animals:
yes, concurrent vehicle
Details on study design:
No data available

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Twice a day
- Cage side observations checked in table [No.?] were included: Morbidity and mortality were examined.

DETAILED CLINICAL OBSERVATIONS: No data available
- Time schedule: No data available
BODY WEIGHT: Yes
Time schedule-Once per week

FOOD CONSUMPTION AND COMPOUND
INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data available

- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data available

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No
data available
OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: Yes No data available
- Time schedule for collection of blood: After 13 week exposure No data available
- Anaesthetic used for blood collection: Yes -Bio-Tal barbiturate No data available
- Animals fasted: No data No data available
- How many animals: 10 animals No data available
- Parameters checked were examined-Yes No data available

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: On termination of study.
- Animals fasted: No data available
- How many animals: All 60 animals were examined.
- Parameters checked in table [No.?] were examined: Serum activities of sorbitol dehydrogenase (SDH), alanine aminotransferase (ALAT), glutamic dehydrogenase (GDH), and ornithine carbamoyltransferase
(OCT) were examined.

URINALYSIS: No

CLINICAL CHEMISTRY: Yes
Time schedule for collection of blood: After 13 week exposure

NEUROBEHAVIOURAL EXAMINATION: No data

OTHER:
Organ weight: Yes,
Brain, heart, kidney, liver, lung, right testis and thymus weighted.
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
34 and 36 organs and tissues were observed for gross lesions.

Organs and tissues were preserved in 10% buffered formalin and routinely processed for preparation of histologic sections for microscopic examination.

HISTOPATHOLOGY: Yes
All histologic sections were examined from the high-dose and control mice.
Other examinations:
Brain, heart, kidney, lung, right testis, and thymus, were examined.
Statistics:
Statistical analysis were performed by Jonckheere’s test was used to evaluate the significance of dose-response trends for data on organ weight to body weight ratios, serum enzyme activities.
If the analysis indicated a significant trend, the nonparametric multiple comparison procedure of Shirley test was used to assess the significance of pairwise comparisons between dosed and control groups; otherwise, Dunn’s test was used for pairwise comparisons.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
Mortality: No effect were observed on survival of treated mice as compared to control. Clinical signs: Yellow colored fur was observed in treated female mice.
Mortality:
no mortality observed
Description (incidence):
Mortality: No effect were observed on survival of treated mice as compared to control. Clinical signs: Yellow colored fur was observed in treated female mice.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weight and weight gain: In male mean body weight were decreased as compared to control. In all treated females, slightly increased weight gain was observed as compared to control.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
Food consumption was similar in all groups.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
effects observed, treatment-related
Description (incidence and severity):
Compound intake: Estimated daily compound intake was 9.9 g /k g.
Ophthalmological findings:
not specified
Haematological findings:
not specified
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
Description (incidence and severity):
Kidney weights were slightly increased for all groups of treated females and Relative kidney weights were increased in males that 5000 ppm or more.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Carcasses were yellow in most male and female mice receiving 5,000 ppm or more. Pigment was noted in the large and small intestines of males and females receiving 500 ppm or greater.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
not specified
Details on results:
Clinical chemistry:
In male, alanine aminotransferase(ALAT) were significantly increased in 50000 ppm & in female at all dose groups as compared to control.
In female, ornithine carbamoyltransferase (SDH) at 1700 & 50000 ppm dose and glutamic dehydrogenase (OCT) at 17000 and 50000 ppm dose were increased but the values were not dose related & differences were not biologically significant.

Histopathology:
Mild to moderate yellow-brown pigmentation that increased with increasing dose was found in periportal hepatocytes , Kupffer cells , and the biliary epithelium of all treated animals .
Hepatocellular degeneration of minimal severity was observed in 50,000 ppm dose group mice.

Effect levels

open allclose all
Dose descriptor:
NOEL
Effect level:
83 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: No effect were observed on survival, clinical chemistry, organ weights and histopathology
Dose descriptor:
LOEL
Effect level:
8 333 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Effect on body weight, clinical chemistry, organ weight, gross pathology and histopathology

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The No Observed effect level (NOEL) for male was considered to be 500 ppm (83 mg/kg/day) and Low Observed effect level (LOEL) for female was considered to be 50,000 ppm (8333 mg/kg/day) when B6C3F1 male and female mice were treated with D &C Yellowno.11.
Executive summary:

In a Chronic repeated dose toxicity study, B6C3F1male and female mice were exposed to D & C yellow no.11 in theconcentration of 0, 500, 1700, 5000, 17000 and 50000 ppm (0, 83, 283, 833, 2833 and 8333 mg/kg/day)orally. No effect was observed on survival of treated mice. In male, decreased in body weight, increase in aminotransferase (ALAT) and relative kidney weights were observed and in female Yellow colored fur, slightly increased weight gain, changes in ornithine carbamoyltransferase (SDH), glutamic dehydrogenase (OCT) and aminotransferase (ALAT) level and slightly increased kidney weight were observed in treated mice. In addition, yellow Carcasses, Pigment in large and small intestines in 5,000 ppm or more dose group and Mild to moderate yellow-brown pigmentation in periportal hepatocytes , Kupffer cells and biliary epithelium, and minimal severity of hepatocellular degeneration observed in 50,000 ppm dose group mice. Therefore, NOEL for male was considered to be 500 ppm (83 mg/kg/day) and LOEL for female was considered to be 50,000 ppm (8333 mg/kg/day) when B6C3F1male and female mice were treated with D &C Yellowno.11.