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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
publication
Title:
Reproductive and neurobehavioral effects of Sunset Yellow FCF administered to mice in the diet
Author:
TOYOHITO TANAKA
Year:
1996
Bibliographic source:
Toxicology and industrial health,Vol 12,No.1,page no.69-79.1996

Materials and methods

Principles of method if other than guideline:
The reproductive effects of Sunset Yellow FCF on male and female Charles River CD rats by oral (Diet) route at different dose levels was examined.
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
Disodium 6-hydroxy-5-[(4-sulphonatophenyl)azo]naphthalene-2-sulphonate
EC Number:
220-491-7
EC Name:
Disodium 6-hydroxy-5-[(4-sulphonatophenyl)azo]naphthalene-2-sulphonate
Cas Number:
2783-94-0
Molecular formula:
C16H12N2O7S2.2Na
IUPAC Name:
disodium 6-hydroxy-5-[(4-sulfonatophenyl)diazenyl]naphthalene-2-sulfonate
Details on test material:
- Name of test material (as cited in study report):Sunset Yellow FCF or FD&C Yellow No. 6.
- Molecular formula (if other than submission substance):C16H12N2O7S2.2Na
- Molecular weight (if other than submission substance): 452.4 g/mole
- Substance type: organic
- Physical state: Solid

Test animals

Species:
mouse
Strain:
other: Crj: CD-1
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan Inc., Kanagawa, Japan
- Age at study initiation: four weeks of age
- Weight at study initiation: Not available
- Fasting period before study: Not available
- Housing: housed individually in polycarbonate solid-floored cages with wood flakes
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C):24 +/-1 deg c
- Humidity (%):55+/-5 deg c
- Air changes (per hr): Not available
- Photoperiod (hrs dark / hrs light): 12-h light/dark cycle

Administration / exposure

Route of administration:
oral: feed
Type of inhalation exposure (if applicable):
not specified
Vehicle:
other: basal diet(Nihon Clea, CE-2)
Details on exposure:
DIET PREPARATION
- Mixing appropriate amounts with (Type of food):Nihon Clea, CE-2
Details on mating procedure:
- M/F ratio per cage: 1:1
- Length of cohabitation: 5 days
- Proof of pregnancy: [vaginal plug / sperm in vaginal smear] referred to as [day 0 / day 1] of pregnancy: no data
- Further mating after two unsuccessful attempts: [no / yes (explain)] Not available
- After successful mating each pregnant female was caged (how): individually
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
17 weeks
Frequency of treatment:
Daily
Details on study schedule:
At nine weeks of age, each female was paired with one male from the same treatment group for a period of five days. The males were removed from the females after five days, and the females were allowed to carry their litters to term, and deliver and rear all of their offspring.
In the F 1 generation, litter size, litter weight, and sex ratio (male/female) were measured on postnatal day (PND) 0 (at birth). The offspring were weighed individually on PNDs 0, 4, 7,14, and 21 during the lactation period. The offspring were weaned when they were four weeks old, and one male and one female were selected randomly to continue treatment from each litter. The animals were weighed individually at four, five, six, seven, eight, and nine weeks of age after weaning.
Doses / concentrations
Remarks:
Doses / Concentrations:
0,300,600,1200 mg/kg bw
Basis:

No. of animals per sex per dose:
0mg/kg bw (Control):10 female and 10 male mice
300 mg/kg bw (low dose group):10 female and 10 male mice
600 mg/kg bw (mid dose group):10 female and 10 male mice
1200 mg/kg bw (high dose group):10 female and 10 male mice
Control animals:
yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:
DETAILED CLINICAL OBSERVATIONS: Yes
BODY WEIGHT: Yes
- Time schedule for examinations: weighed individually on experimental days 0, 2, 4, 7, 14, 21, 28, and 30 during the preconception period.
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: Yes
OTHER:
Movement activity of exploratory behavior: Yes
Oestrous cyclicity (parental animals):
No data
Sperm parameters (parental animals):
No data
Litter observations:
STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: [yes/no]: no data
PARAMETERS EXAMINED
The following parameters were examined in [F1 / F2 / F3] offspring: F2 generation
Litter size, litter weight, and sex ratio were examined.
GROSS EXAMINATION OF DEAD PUPS: yes
Statistics:
Food intake, litter size, litter weight, and body weight were assessed with the Bonferroni’ss multiple comparison test after the analysis of variance (ANOVA) or the Kruskal-Wallis test.
Sex ratio, survival, and behavioral developmental data were assessed with the Chi-square test (mxn) of frequency analysis. Movement activity data were assessed with the Mann-Whitney U-test of nonparametric method (Martin and Bateson, 1990). Multiple water T-maze performance data were assessed with the Sign-Wilcoxon test for trials and assessed with the Wilcoxon test within each treatment group.
Offspring viability indices:
Yes

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Dam having underdeveloped mammary glands
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The average body weight of male and female mice showed no significant adverse effects from the treatment during the preconception period, and the average body weight of dams showed no significant adverse effects during the gestation or lactation periods.
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
The average body weight of male and female mice showed no significant adverse effects from the treatment during the preconception period, and the average body weight of dams showed no significant adverse effects during the gestation or lactation periods.
Organ weight findings including organ / body weight ratios:
not specified
Histopathological findings: non-neoplastic:
not specified
Other effects:
no effects observed
Description (incidence and severity):
Test substance intake: There was no significant adverse effect of Sunset Yellow FCF on the average food intake during any period

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
no effects observed

Details on results (P0)

OTHER FINDINGS (PARENTAL ANIMALS):
No significant adverse effect on movement activity of exploratory behavior in either sex at eight weeks of age.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no observed adverse effect

Results: F1 generation

General toxicity (F1)

Clinical signs:
not specified
Mortality / viability:
mortality observed, treatment-related
Description (incidence and severity):
The survival indices at PND 0 showed viability indices at birth. The survivals were significantly reduced in the middle-dose group (600 mg/kg bw/day) of each sex.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No significant adverse effect was observed in litter weight
Sexual maturation:
no effects observed
Description (incidence and severity):
No significant adverse effect was observed in sex ratio at birth
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Histopathological findings:
not specified

Details on results (F1)

OTHER FINDINGS (OFFSPRING)
No significant adverse effect was observed in litter size

Results: F2 generation

Effect levels (F2)

open allclose all
Dose descriptor:
LOAEL
Generation:
F2
Effect level:
600 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: Effects: Dam having underdeveloped mammary glands.The survival indices at PND 0 showed viability indices at birth. The survivals were significantly reduced in the middle-dose group (600 mg/kg bw/day) of each sex.
Dose descriptor:
NOAEL
Generation:
F2
Effect level:
300 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

Conclusions:
The NOAEL for maternal toxicity study was considered to be 300 mg/kg bw/day whereas LOAEL was considered to be 600 mg/kg bw/day in Crj: CD-1 strain mouse when Sunset Yellow FCF was administered orally by diet.
Executive summary:

Sunset Yellow FCF was administered in the diet to 60 mice (10/sex/group) at dietary levels of 300, 600, and 1200 mg/kg bw/day the control groups (20 mice, 10/sex) were given basal diets (Nihon Clea, CE-2) to investigate for possible reproductive effect. Individual food intake of mice was measured during five divided periods - preconception (from five weeks of age to mating), mating (5 days), gestation (14 days), lactation (from birth to weaning), and F 1 generation (four to nine weeks of age).

During experiment adverse effects observed as dam having underdeveloped mammary glands. The survival indices at PND 0 showed viability indices at birth. The survivals were significantly reduced in the middle-dose group (600 mg/kg bw/day) of each sex.

And on other side the average body weight of male and female mice showed no significant adverse effects from the treatment during the preconception period, and the average body weight of dams showed no significant adverse effects during the gestation or lactation periods. No effects on food consumption, No significant adverse effect on movement activity of exploratory behavior in either sex at eight weeks of age.

Therefore, NOAEL for maternal toxicity study was considered to be 300 mg/kg bw/day whereas LOAEL was considered to be 600 mg/kg bw/day in Crj: CD-1 strain mouse when Sunset Yellow FCF was administered orally by diet.