Registration Dossier

Administrative data

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

Data source

Reference
Reference Type:
publication
Title:
AY23 - CHRONIC TOXICITY/CARCINOGENICITY STUDIES OF FD & C YELLOW NO. 5 (TARTRAZINE) IN RATS
Author:
J. F. BORZELLECA and J. B. HALLAGAN
Year:
1988
Bibliographic source:
Fd Chem. Toxic. Vol. 26, No. 3, pp. 179-187, 1988

Materials and methods

Test guideline
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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
solid: particulate/powder
Details on test material:
No data

Test animals

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.

Administration / exposure

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
Doses / concentrationsopen allclose all
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.

Examinations

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.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

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

Details on results (P0)

"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.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
5 other: %
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality

Target system / organ toxicity (P0)

Critical effects observed:
no
Lowest effective dose / conc.:
5 other: %
System:
other: -

Results: P1 (second parental generation)

General toxicity (P1)

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 / performance (P1)

Reproductive function: oestrous cycle:
not specified
Reproductive function: sperm measures:
not specified
Reproductive performance:
not specified

Effect levels (P1)

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

Results: F1 generation

General toxicity (F1)

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.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
5 other: %
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
mortality

Overall reproductive toxicity

open allclose all
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

Any other information on results incl. tables

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.

Applicant's summary and conclusion

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.