Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

One publication is available which reports many information both for toxicity to reproduction and for carcinogenicity on rats.

No effects related to the tested substance were observed.

Link to relevant study records
Reference
Endpoint:
two-generation reproductive toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1988
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Version / remarks:
The reporduction toxicity was investigated during the OECD 453 study where treatment-related effects on fertility, gestation, parturition, lactation, pup survival through weaning or number of alive and still-born pups were checked.
Deviations:
not specified
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
other: Charles River CD
Sex:
male/female
Details on test animals and environmental conditions:
Charles River CD rats obtained from Charles River Breeding Laboratories, Wilmington, MA, were 63-70 days old at the initiation of the F 0 phase of the study. They were housed individually in stainless-steel cages except during the mating, lactation and post-weaning periods of the in utero phase. Each rat was identified with a metal ear tag. If this was lost the animal was re-tagged and/or toe- clipped. The rats were housed in an environmentally controlled room (20-21°C, 40-60% relative humi- dity) on a 12-hr light/dark cycle. Food was avail- able ad lib. Control animals received Purina Rodent Chow (Ralston Purina Co. Inc., St Louis, MO) and the treated animals received the appropriate dietary admixture.
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on exposure:
Fresh diets were prepared and presented weekly. The diets were blended in a twin-shell blender and assays were per- formed to determine the homogeneity and stability of the tested substance in the prepared diets prior to the start of the study. Dietary concentrations of the compound were determined weekly during the first 13 wk of the study, and then monthly thereafter. Analyses of the basic feed for heavy metals, chlorin- ated hydrocarbons and aflatoxin were conducted on all lots of feed used during the study. These analyses demonstrated that the basic feed contained accept- ably low levels of contaminants, that the diets were prepared properly, and that the dietary content of the test material was stable.
Details on mating procedure:
No data
Analytical verification of doses or concentrations:
not specified
Dose / conc.:
0.1 other: %
Remarks:
In the "in utero" phase / original study: 360 rats
Dose / conc.:
1 other: %
Remarks:
In the "in utero" phase / original study: 360 rats
Dose / conc.:
2 other: %
Remarks:
In the "in utero" phase / original study: 360 rats
Dose / conc.:
5 other: %
Remarks:
In the "in utero" / high dose study: 120 rats
Dose / conc.:
5 other: %
Remarks:
In the chronic phase
No. of animals per sex per dose:
In the "in utero" phase / original study: 360 rats (60/sex/group) at levels of 0.1, 1.0 or 2.0% in diet
In the "in utero" / high dose study: 120 rats (60/sex/group) received the compound at a level of 5.0%
In the chronic phase: 70/sex/group received the compound at a level of 5.0%
Control animals:
yes, plain diet
Details on study design:
Three control groups containing 360 rats (60/sex/group) received the basal diet only. Female rats were weighed on gestation days 0, 4, 14 and 21.
Parental animals: Observations and examinations:
Deaths, morbidity and gross signs of toxicity were recorded twice daily, with at least 5 hr between observations. Individual body weights for the F 0 rats were measured weekly for the first 14 wk, bi-weekly for the next 12 wk, and then every 4 wk thereafter. Detailed physical examinations for signs of toxicity and palpation for masses were conducted weekly. Ophthalmoscopic examinations were conducted on all rats once during the F 0 generation, and at in- itiation, and months 3, 6, 12, 18 and 24 of the chronic phase.
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, non-treatment-related
Description (incidence):
Two F0 female control rats died during the in utero phase of the original study, and one male and one female from the control and 5.0% group, respectively, died during the in utero phases of the high-dose study.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Slight decreases in body weight (4-5%) was noted in the F0 rats treated at a dietary level of 5.0%.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Slight increases in food consumption was noted in the F0 rats treated at a dietary level of 5.0%.
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:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Histopathological findings: neoplastic:
not specified
Other effects:
no effects observed
"In utero phase": The F0 animals received the tested substance in the diet for a minimum of 8 wk prior to the mating period. There were no compound-related effects on fertility, gestation, parturition, lactation, pup survival through weaning or number of live and still-born pups.
Dose descriptor:
NOAEL
Effect level:
5 other: %
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
Critical effects observed:
no
Lowest effective dose / conc.:
5 other: %
System:
other: -
Clinical signs:
not specified
Dermal irritation (if dermal study):
not specified
Mortality:
mortality observed, non-treatment-related
Description (incidence):
At the termination of the study 128 rats from the original study and 58 from the high-dose study were killed, whereas 472 rats from the original study and 182 rats from the high-dose study were killed in extremis, or died spontaneously or accidentally during the studies. There were no compound-related effects on the number of rats surviving.Increased mortality among the male rats of control group 1 and female rats of the 1.0% group resulted in the termination of the original study at wk 113 and 114 for males and females, respectively. The mortality among these two groups appeared to be random and not associated with the consumption of the tested substance.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Group mean body weights at termination were generally similar for control and treated rats in the original study except for males and females at the 1.0% dietary level in which decreases in group mean body weights were noted. The difference between the females treated at the 1.0% level and the controls was statistically significant (P <0.01). The rats (both male and female) from the high-dose study exhibited a statistically significant decrease in group mean body weights at termination.
Food consumption and compound intake (if feeding study):
effects observed, non-treatment-related
Description (incidence and severity):
Food consumption was similar for control and treated rats in the original study. Food consumption among the high-dose rats was generally higher than that of the controls although the increases were not statistically significant.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
effects observed, non-treatment-related
Description (incidence and severity):
Ophthalmoscopic examinations at most examination intervals revealed focal and diffuse retinopathy, conjunctivitis, uveitis, and cataracts in rats of all groups. None of these findings was compound related.
Haematological findings:
no effects observed
Description (incidence and severity):
Few of the haematological, clinical chemistry and urinalysis parameters differed significantly between the control and treated animals, and none of the differences appeared to be compound related.
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
effects observed, treatment-related
Description (incidence and severity):
Localized hair loss (due to friction against the cage) and nasal and ocular discharge occurred in low incidence throughout the study and were similarly distributed in control and treated rats. A yellow tint to the fur was noted in all treated animals and the faeces of the 1.0, 2.0 and 5.0% treated rats were yellow
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Description (incidence and severity):
In the ten rats of each sex from each group killed and necropsied after 1 yr on test in both studies, there were no compound-related gross or microscopic changes.
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
Histological evaluation revealed a variety of lesions, including neoplasms among the control and treated rats in the original and high-dose studies. These lesions were present in similar incidences in control and treated rats and appeared to be spon- taneous (Table 5). None of the lesions were determined to be related to the administration of the tested substance.
Other effects:
not specified
Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not specified
Dose descriptor:
NOAEL
Effect level:
5 other: %
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
Remarks on result:
other: 2641 mg/kg bw
Mortality / viability:
mortality observed, non-treatment-related
Description (incidence and severity):
There were no compound-related effects on pup survival.
Body weight and weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
The mean body weights of the pups in the 5.0% group at lactation day 21 were slightly lower than those of the controls, although the differences were not statistically significant. There were no compound-related effects on pup survival.
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
5 other: %
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality
Reproductive effects observed:
no
Lowest effective dose / conc.:
2 641 other: mg/kg bw Male
Treatment related:
yes
Reproductive effects observed:
no
Lowest effective dose / conc.:
3 348 other: mg/kg bw Female
Treatment related:
yes

A 2-generation chronic toxicity/carcinogenicity study was conducted with different concentrations of Acid Yellow 23. Male and female rats were fed a basal diet (control group) or basal diet blended

with commercial Acid Yellow 23 (0.1, 1.0, 2.0, 5.0 %) for approx. 2 months prior to mating. No treatment-related effects on fertility, gestation, parturition, lactation, pup survival through weaning or number of alive and still-born pups were observed. Slight decreases in body weight (4-5 %), and slight increases in food consumption were noted at the 5.0 % dose group.

The NOAEL for reproductive and teratogenic toxicity of Acid Yellow 23 was 5 % in the diet.

Conclusions:
Not toxic for reproduction.
NOAEL = 2641 mg/kg bw (male)
NOAEL = 3348 mg/kg bw (female)
Executive summary:

Lifetime exposure of rats to the tested substance as a dietary admixture at levels up to 5.0% did not demonstrate toxic effects.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
2 641 mg/kg bw/day
Study duration:
chronic
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

REPRODUCTIVE TOXICITY: one publication is available which reports many information both for toxicity to reproduction and for carcinogenicity on rats.

1) In a lifetime toxicity/carcinogenicity study, groups of rats (60/sex/group) were administered 0, 0, 0.1, 1.0 or 2.0% FD&C Yellow No. 5 in the diet daily for approximately 2 months prior to mating. In the high-dose study, 60/sex/group received 0 or 5% FD&C Yellow 5 for approximately 2 months prior to mating. The 3 controls groups received the basal diet only. A maximum of 2 rats/sex/litter were randomly selected for the chronic phase of the study. There were 70/sex/group at the initiation of the chronic phase and these offspring were exposed to the same dietary levels as their parents for 113 weeks. During the in utero phase, there were no treatment-related effects on fertility, gestation, parturition, lactation, pup survival through weaning or number of live and still-born pups.

2) In utero phase of repeated oral toxicity test: During the in utero phase, there were no treatment-related effects on fertility, gestation,

parturition, lactation, pup survival through weaning or number of live and still-born pups. Slight decreases in body weight (4-5%) and slight increases in food consumption were noted in the F0 rats treated at dietary level of 5.0%. Two F0 female controls rats died during the in utero phase of the original study and one male and one female from the control and 5.0% group, respectively, died during the in utero phases of the high-dose study. There were no treatment related effects on pup survival.

Effects on developmental toxicity

Description of key information

Two publications are available which reports many information for developmental toxicity.

No effects related to the tested substance were observed.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1990
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
not specified
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Osborne-Mendel
Remarks:
FDA strain
Details on test animals and environmental conditions:
Male and female Osborne- Mendel (FDA strain) rats were obtained from the FDA rat breeding colony. At the start of the study, female rats were 13-21 wk old and weighed 210-270 g. This strain of rats was selected because of the availability of historical data. The general appearance and well-being of the rats were monitored daily. Food (Purina Laboratory Chow, Ralston Purina Company, St Louis, MO, USA) and distilled water were available ad lib.The rats were weighed daily and food consumption was measured weekly. Water intake was not measured. All rats were identified by numbered metal ear tags and were housed in stainless-steel hanging cages. The foetuses were grouped by litter for identification. Hygrothermographs monitored temperature (20.5-25°C) and humidity (30-50%).An automatic light provided a 12-hr light/dark cycle (8.00 am-8.00 pm).
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
Fresh solutions were prepared daily and administered by gavage in a volume of 1 ml/100 g body weight at approximately the same time each day. Controls received an equivalent amount of distilled water.
Analytical verification of doses or concentrations:
not specified
Details on mating procedure:
On mating days, two females were randomly mated with one male at approximately 4.30 pm. The following morning, the presence of sperm in the vaginal smear was con- sidered to be evidence of copulation and the sperm- positive females were considered to be at day 0 of gestation. Then 40-41 of the females presumed to be pregnant were placed in each dosage group by random number: 0 (distilled water only), 60, 100, 200, 400, 600 or 1000 mg/kg body weight/day. Each rat was treated daily from day 0 to day 19 to simulate human consumption that occurs throughout gestation. On day 20 of gestation, starting at 1.00 pm, the females were examined for gross abnormalities for the last time before being killed by CO2 asphyxiation.
Frequency of treatment:
daily
Duration of test:
20 days
Dose / conc.:
0 mg/kg bw/day (nominal)
Remarks:
negative control
Dose / conc.:
60 mg/kg bw/day (nominal)
Dose / conc.:
100 mg/kg bw/day (nominal)
Dose / conc.:
200 mg/kg bw/day (nominal)
Dose / conc.:
400 mg/kg bw/day (nominal)
Dose / conc.:
600 mg/kg bw/day (nominal)
Dose / conc.:
1 000 mg/kg bw/day (nominal)
No. of animals per sex per dose:
not specified
Control animals:
yes, concurrent vehicle
Details on study design:
Caesarean sections were performed, corpora lutea were counted and the uteri were opened and exam- ined in situ. The uterine positions of all implantation sites were noted and their condition (early or late resorptions, alive or dead foetuses) was determined. Each live foetus was promptly weighed, sexed and examined for gross external malformations, and the crown-rump length was measured. Any foetus that weighed less then 70% of the average weight of the concurrent male or female controls was considered to be a runt (Leuschner and Czok, 1973). Approximately half of the foetuses were examined for skeletal variations after being fixed in alcohol, cleared and stained with Alizarin Red S by a modifi- cation of Dawson's method (Dawson, 1926). The remaining foetuses were fixed in Bouin's solution and sectioned according to the method of Wilson (Wilson, 1973; Wilson and Warkany, 1965) in order to detect internal visceral variations. Each sperm-positive female was given a random test number, which was carried over as a litter number after the female was killed. To preclude the possibility of bias, evaluations of the dams and foetuses during caesarean sections and during skeletal or visceral analysis were done without the evaluators knowing the dose group to which the animal belonged.
Maternal examinations:
No unusual behaviour or remarkable external maternal findings were noted.
Statistics:
All analyses for statistical significance were performed by the Division of Mathematics at the FDA. Data on maternal initial body weight and maternal food consumption were analysed by straight analysis of variance (ANOVA) and a two-tailed t-test, and by regression analysis. Data on litters having one or more, or two or more, resorptions were analysed by Fisher's exact test.
Clinical signs:
not specified
Dermal irritation (if dermal study):
not examined
Mortality:
mortality observed, non-treatment-related
Description (incidence):
One female in the group given 60mg/kg body weight/day died at day 13 of gestation of gavage difficulties unrelated to dosage.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Initial body weight at day 0 and maternal body-weight gain during gestation did not vary significantly between treated and control groups
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Throughout gestation, the mean daily food consumption of the rats given 1000mg/kg body weight/day was significantly greater than that of the controls. Overall mean daily food consumption by the rats treated with 6-600mg/kg body weight/day was not significantly different from that of the controls, although consumption in some individual weeks was significantly higher than that of the controls.
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not specified
Haematological findings:
not specified
Clinical biochemistry findings:
not specified
Urinalysis findings:
not specified
Behaviour (functional findings):
not specified
Immunological findings:
not specified
Organ weight findings including organ / body weight ratios:
not specified
Gross pathological findings:
not specified
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
not specified
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Number of abortions:
no effects observed
Description (incidence and severity):
The pregnancy rate was high in all groups, ranging from 87.5 to 95.0%.
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Implantation efficiency was similar in all groups.
Total litter losses by resorption:
not specified
Early or late resorptions:
not specified
Dead fetuses:
not specified
Changes in pregnancy duration:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): not specified
Changes in number of pregnant:
not specified
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
mortality
Abnormalities:
no effects observed
Localisation:
other: -
Fetal body weight changes:
not specified
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): not specified
Reduction in number of live offspring:
not specified
Changes in sex ratio:
not specified
Changes in litter size and weights:
not specified
Changes in postnatal survival:
not specified
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
Examination of offspring for external variations yielded one foetus with a string tail in the control group and three hydrocephalic pups in a single litter in the 200 mg/kg body weight/day group. The three hydrocephalic foetuses have been added to and analysed with the visceral variations. Foetuses with haemorrhages were observed in all treated and control groups. These external haemorrhages, not shown in the table, were seen on all parts of foetuses and their incidence was not correlated with dosage.In the control group, two litters, each with one foetus, were affected. In the 1000mg/kg body weight/day group, four foetuses from three litters were affected. In the remaining five treated groups, the number of litters affected ranged from one to seven without relation to dosage.
Skeletal malformations:
no effects observed
Description (incidence and severity):
No dose-related increase in sternebral variations occurred among the foetuses with reduced ossification, bipartite, missing or malaligned sternebrae. No dose-related increase occurred among the foetuses with skeletal variations.The incidences of foetuses with skeletal variations and of litters containing those foetuses were similar in all groups
Visceral malformations:
not specified
Other effects:
not specified
Details on embryotoxic / teratogenic effects:
No teratogenic effects were observed.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: general consideration about exminations
Abnormalities:
effects observed, non-treatment-related
Localisation:
other: brain
Description (incidence and severity):
see details in the related field
Developmental effects observed:
no
Lowest effective dose / conc.:
1 000 mg/kg bw/day (nominal)
Treatment related:
yes
Conclusions:
Not teratogenic
NOAEL = 1000 mg/kg bw
Executive summary:

The tested substance appears to be neither developmentally toxic nor teratogenic.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
chronic
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

DEVELOPMENTAL TOXICITY: two tests are available.

In the first study, Tartrazine was given to Osborne-Mendel rats (no detail on number) by gavage at doselevels of 0, 60, 100, 200, 400, 600, or 1000 mg/kg bw/day on days 0-19 of gestation.

No dose-related effects were observed on the number and type of implantations, fetal viability or external fetal development. Fetal skeletal and visceral development was not different from controls.

In the second study, Tartrazine was given to Osborne-Mendel rats in the drinking water at levels of 0.05, 0.1, 0.2, 0.4, or 0.7 % (based on typical fluid consumption equivalent to 0, 67, 132, 292, 568, and 1064 mg/kg bw/day, respectively) throughout gestation.

No dose-related changes were seen in maternal clinical findings, number and type of implantations, fetal viability or fetal size (weight and length).
No dose-related fetal terato or visceral and skeletal aberrations were noted.

Toxicity to reproduction: other studies

Additional information

Based on the results of the available tests, Acid Yellow 23 did not show any adverse effects both for reproduction and for development.

Justification for classification or non-classification

No classification for toxicity to reproduction is warranted under Regulation CE 1272/2008.