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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
data from handbook or collection of data
Justification for type of information:
Data is from peer reviewed publication

Data source

Reference
Reference Type:
publication
Title:
Repeated dose oral toxicity study of the test chemical
Author:
Burnett et al
Year:
1986
Bibliographic source:
Food and chemical toxicology

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: Refer below principle
Principles of method if other than guideline:
Combined repeated dose repro-devp. Screen was performed to determine the toxic nature of test chemical upon repeated exposure by oral route
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material : D & C Yellow No. 8, sodium fluorescein
- Molecular formula : C20H10Na2O5
- Molecular weight : 376.274 g/mol
- Substance type: Organic
- Physical state: No data
- Imprities: 13%

Test animals

Species:
rat
Strain:
other: Charles River CD Sprague-Dawley
Details on species / strain selection:
No data
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source:
Female rats: Charles River Breeding Laboratories, Portage, Michigan.
Male rats: Langshaw Farms, Augusta, Michigan
- Age at study initiation: 18 weeks
- Weight at study initiation: No data
- Fasting period before study: No data
- Housing: The animals were housed in wire bottomed cages
- Diet (e.g. ad libitum): Purina Certified Rodent Chow No. 5002 ad libitum
- Water (e.g. ad libitum): Water ad libitum
- Acclimation period: 4 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.2 ± -15.5 ˚C
- Humidity (%): 50 ± 15%
- Air changes (per hr): No data
- Photoperiod (hrs dark / hrs light): 12 hrs light/dark cycle

IN-LIFE DATES: From: To: No data

Administration / exposure

Route of administration:
oral: gavage
Details on route of administration:
No data
Vehicle:
water
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS: The test chemical was mixed with water as vehicle at dose levels of 0, 100, 500 or 1500 mg/kg body weight and prepared daily

DIET PREPARATION
- Rate of preparation of diet (frequency): No data
- Mixing appropriate amounts with (Type of food): No data
- Storage temperature of food: No data

VEHICLE
- Justification for use and choice of vehicle (if other than water): No data
- Concentration in vehicle: 0, 100, 500 or 1500 mg/kg bw
- Amount of vehicle (if gavage): 10 mL/Kg
- Lot/batch no. (if required): No data
- Purity: No data
Analytical verification of doses or concentrations:
not specified
Details on analytical verification of doses or concentrations:
No data
Duration of treatment / exposure:
14 days
Frequency of treatment:
Daily from 6-15 days of gestation
Doses / concentrations
Remarks:
0, 100, 500 or 1500 mg/kg bw
No. of animals per sex per dose:
Total: 100 females
0 mg/Kg bw: 25 females
100 mg/Kg bw: 25 females
500 mg/Kg bw: 25 females
1500 mg/Kg bw: 25 females
Control animals:
yes, concurrent vehicle
Details on study design:
No data
Positive control:
No data

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: During the study period
- Cage side observations checked in table [No.?] were included. Mortality

DETAILED CLINICAL OBSERVATIONS: No data
- Time schedule: No data

BODY WEIGHT: Yes
- Time schedule for examinations: body weights were recorded on days 6, 9, 12 and 16 of gestation

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No data
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No data

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

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data
- Time schedule for examinations: No data

OPHTHALMOSCOPIC EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data

HAEMATOLOGY: No data
- Time schedule for collection of blood: No data
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

CLINICAL CHEMISTRY: No data
- Time schedule for collection of blood: No data
- Animals fasted: No data
- How many animals: No data
- Parameters checked in table [No.?] were examined. No data

URINALYSIS: Yes
- Time schedule for collection of urine: No data
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked in table [No.?] were examined. No data

NEUROBEHAVIOURAL EXAMINATION: No data
- Time schedule for examinations: No data
- Dose groups that were examined: No data
- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data

OTHER: No data
Sacrifice and pathology:
GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: No data
Other examinations:
No data
Statistics:
No data

Results and discussion

Results of examinations

Clinical signs:
not specified
Description (incidence and severity):
No data
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Survival was 100% in the controls and the groups receiving 100 and 500 mg/kg of dye. Six rats in the high-dose group (1500 mg/kg) died during the dosing period.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
There were slight reductions in body-weight gains in 1500 mg/Kg bw group, compared with controls, throughout the dosing period
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 specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
Orange discoloration of the urine was noted in all treated rats during the treatment period.
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
At autopsy, green discoloration of the amniotic fluid was noted in 1, 10 and 16 rats in the 100, 500 and 1500 mg/kg/day groups, respectively, and the small intestines were green in colour in many rats in the 500 mg/Kg group.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified

Effect levels

Dose descriptor:
NOAEL
Effect level:
1 500 mg/kg bw (total dose)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: No significant effects were noted at the mentioned dose level

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Table: Mean maternal body weights for rats given D & C Yellow No. 8 by gavage on days 6-19 of gestation

Days of gestation

Mean Maternal Body Weight (g)

0

100

500

1500

0

246 ± 145

249 ± I3.7

249 ± 14.7

241 ± 12.4

6

272 ± 16.8

271 ± 14.4

276 ± 14.5

263 ± 12.2

9

279 ± 18,1

278 ± 15.9

283 ± 16.7

269 ± 16.5

12

294 ± 20.1

292 ± 17.5

296 ± 16.1

282 ± 16.9

16

321 ± 23.4

320 ± 18.9

323 ± 2(}.4

300 ± 30.7

20

379 ± 30.0

378 ± 21.2

374 ± 32.2

359 ± 33.3

 

Table 2. Mean maternal body-weight changes in rats given D & C Yellow No. 8 by gavage on days 6-19 of gestation

Days of gestation

Mean Maternal Body Weight (g)

0

100

500

1500

0-6

26

22

27

22

6-9

7

7

7

6

9-12

15

14

13

13

12-16

27

28

27

18

16-20

58

58

51

59

6-20

107

107

98

96

0-20

133

129

125

118

Applicant's summary and conclusion

Conclusions:
The No Observed adverse effect level (NOAEL) for test chemical is considered to be 1500 mg/kg bw
Executive summary:

Combined repeated dose repro-devp. Screen was performed to determine the toxic nature of test chemical upon repeated exposure by oral route.An aqueous solution of the dye was administered by garage to groups of 25 Charles River Sprague-Dawley rats at doses of 100, 500 and 1500 mg/kg on days 6- 19 of gestation. A control group received water on a comparable basis. Individual doses were determined on the basis of body weights recorded on days 6, 9, 12 and 16 of gestation.Survival was 100% in the controls and the groups receiving 100 and 500 mg/kg of dye. Six rats in the high-dose group (1500 mg/kg) died during the dosing period. There were slight reductions in body-weight gains in 1500 mg/Kg bw group, compared with controls, throughout the dosing period.Orange discoloration of the urine was noted in all treated rats during the treatment period.At autopsy, green discoloration of the amniotic fluid was noted in 1, 10 and 16 rats in the 100, 500 and 1500 mg/kg/day groups, respectively, and the small intestines were green in colour in many rats in the 500 mg/Kg group. Based on the above observations made, the No Observed adverse effect level (NOAEL) for test chemical is considered to be 1500 mg/kg bw