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Diss Factsheets

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 from WHO Food Additive Series

Data source

Reference
Reference Type:
publication
Title:
Toxicological Evaluation Of Certain Food Additives and Contaminants
Author:
WHO Expert Committee on Food Additives
Year:
1969
Bibliographic source:
INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY, WORLD HEALTH ORGANIZATION,Series No. 46A WHO/FOOD ADD/70.36

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: Repeated dose carcinogenicity
Principles of method if other than guideline:
Repeated dose carcinogenicity study of FD&C Green No. 3 orally in mice
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Dihydrogen (ethyl)[4-[4-[ethyl(3-sulphonatobenzyl)amino](4-hydroxy-2-sulphonatobenzhydrylidene]cyclohexa-2,5-dien-1-ylidene](3-sulphonatobenzyl)ammonium, disodium salt
EC Number:
219-091-5
EC Name:
Dihydrogen (ethyl)[4-[4-[ethyl(3-sulphonatobenzyl)amino](4-hydroxy-2-sulphonatobenzhydrylidene]cyclohexa-2,5-dien-1-ylidene](3-sulphonatobenzyl)ammonium, disodium salt
Cas Number:
2353-45-9
Molecular formula:
C37H36N2O10S3.2Na
IUPAC Name:
disodium 2-({4-[ethyl(3-sulfonatobenzyl)amino]phenyl}{4-[ethyl(3-sulfonatobenzyl)iminio]cyclohexa-2,5-dien-1-ylidene}methyl)-5-hydroxybenzenesulfonate
Details on test material:
- Name of test material (as cited in study report): FD&C Green No. 3 - Molecular formula (if other than submission substance): C37H34N2Na2O10S3 - Molecular weight (if other than submission substance): 808.84 g/mole - Substance type: Organic - Physical state: solid

Test animals

Species:
mouse
Strain:
other: Charles-River CD-1
Sex:
male/female
Details on test animals or test system and environmental conditions:
- Age at study initiation: 43 days study

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: diet
Details on oral exposure:
mice were fed diets containing 0, 0.5, 1.5, or 5.0% Fast Green FCF
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
24 months
Frequency of treatment:
Daily
Doses / concentrations
Remarks:
Doses / Concentrations:0, 0.5, 1.5 and 5.0 % (714.3, 2143 and 7142.85 mg/kg/day respectively)Basis:nominal in diet
No. of animals per sex per dose:
Total : 3000 %: 60 male, 60 female 0.5 % 30 male, 30 female 1.5 % : 30 male, 30 female 5.01 % : 30 male, 30 female
Control animals:
yes, concurrent vehicle

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes - Time schedule: No data available- Cage side observations checked in table [No.?] were included: Mortality and morbidity was observedDETAILED CLINICAL OBSERVATIONS: No data available - Time schedule: No data availableBODY WEIGHT: Yes - Time schedule for examinations: No data available FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): No data available- 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: No data available FOOD EFFICIENCY: No data available- 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 availableWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data available - Time schedule for examinations: No data available OPHTHALMOSCOPIC EXAMINATION: No data available - Time schedule for examinations: No data available- Dose groups that were examined: No data available HAEMATOLOGY: Yes - Time schedule for collection of blood: At 3, 6, 12, 18 months and on completion of study.- Anaesthetic used for blood collection: No data available - Animals fasted: No data available - How many animals: 10 animals from each group at 3, 6, 12, 18 months and all on completion of study. - Parameters checked in table [No.?] were examined: Haemoglobin, haematocrit, and erythrocyte counts were examined. CLINICAL CHEMISTRY: No data available- Time schedule for collection of blood:- Animals fasted: No data available- How many animals: No data available- Parameters checked in table [No.?] were examined: No data available URINALYSIS: No data available- Time schedule for collection of urine: No data available- Metabolism cages used for collection of urine: No data available - Animals fasted: No data available- Parameters checked in table [No.?] were examined: No data available NEUROBEHAVIOURAL EXAMINATION: No data available - Time schedule for examinations: No data available- Dose groups that were examined: No data available- Battery of functions tested: sensory activity / grip strength / motor activity / other: No data availableOTHER: No data available
Sacrifice and pathology:
GROSS PATHOLOGY: Yes Gross changes/tissue masses were examined for all animals in treated dose groups. HISTOPATHOLOGY: Yes Tissues were examined histologically from all control and 5% dose groups as well as all animals dying or killed in extremis from these groups Organ examined:Adrenals, aorta, bone and marrow (femur), brain (3 sections), eyes (with optic nerve), gall bladder, gastrointestinal tract (oesophagus, stomach,duodenum, ileum, caecum, colon), heart, kidneys, liver, lung, lymph nodes (mesenteric and mediastinal), mammary gland, nerve (sciatic), ovaries, pancreas, pituitary, prostate, salivary gland, seminal vesicles, skeletal muscle, skin, spinal cord, spleen, testes with epididymides, thymus, thyroid/parathyroid, trachea, urinary bladder, uterus and gross lesions/tissue masses were examined.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No mertality were observed in treated male and female mice as compare to control.
Mortality:
no mortality observed
Description (incidence):
No mertality were observed in treated male and female mice as compare to control.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
When treated with 5 % in male mice mean body weight was significantly decreased at weeks 52 and 78 as compare to control. In female mice mean body weight was consistently decreased as compare to control.
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:
effects observed, treatment-related
Description (incidence and severity):
When treated with 5% in male mice slight reductions in haemoglobin, haematocrit, and erythrocyte counts were observed at 18 months but no other consistent or dose-related haematological changes were observed.
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
-Clinical signs and mortalityMortality : No mertality were observed in treated male and female mice as compare to control.Clinical sign: No data available -Body weight and weight gain: When treated with 5 % in male mice mean body weight was significantly decreased at weeks 52 and 78 as compare to control.In female mice mean body weight was consistently decreased as compare to control.-Haematology:When treated with 5% in male mice slight reductions in haemoglobin, haematocrit, and erythrocyte counts were observed at 18 months but no other consistent or dose-related haematological changes were observed.-Histopathology: Histological examination did not reveal any treatment-related lesions and the incidence, origins and histology of benign and malignant neoplasms did not differ significantly between controls and treated animals.

Effect levels

Dose descriptor:
NOAEL
Effect level:
7 142.85 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effect on survival, body weight, hematology, gross pathology and histopathology

Target system / organ toxicity

Critical effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
NOAEL for repeated dose toxicity study was considered to be 5% (7142.85 mg/kg/day) in male and female mice when exposed to FD&C Green No. 3 by oral route for 24 months. 
Executive summary:

A Chronic study was conducted to evaluate the toxic effects of repeated administration of FD&C Green No. 3 to male and female mice by feed. FD&C Green No. 3 was administered to mice in diet at dosages of 0, 0.5, 1.5 and 5.0 % (714.3, 2143 and 7142.85 mg/kg/day) for 24 months. No mortalities occurred that could be directly attributed to treatment. Change was observed in body weight of male and female mice at 5 % but no other consistent differences in body weight were noted. Similarly, no changes were observed in hematology of female mice, in male mice change was observed in haemoglobin, haematocrit, and erythrocyte counts at 18 months but no other consistent or dose-related haematological changes were observed. In addition, no change were observed in histopathology of treated male and female mice when compare with control. Therefore, NOAEL for repeated dose toxicity study was considered to be 5% (7142.85 mg/kg/day) in male and female mice when exposed toFD&C Green No. 3by oral route for 24 months.