Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for aluminium tris(4-{[3-carboxy-5-oxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazol-4-yl]diazenyl}benzenesulfonate) (12225-21-7) .Male and female reproductive parameters were unaffected by test material administration. Hence, NOAEL was estimated to be 860mg/kg bw. When male and female wistar rats were exposed with aluminium tris(4-{[3-carboxy-5-oxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazol-4-yl]diazenyl}benzenesulfonate) (12225-21-7) orally.Thus, based on the predictions on aluminium tris(4-{[3-carboxy-5-oxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazol-4-yl]diazenyl}benzenesulfonate) (12225-21-7) and structurally similar read across substance Tartrazine(1934-21-0). It was considered that no adverse effects on reproductive parameter were observed. Thus, comparing this value with the criteria of CLP regulation aluminium tris(4-{[3-carboxy-5-oxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazol-4-yl]diazenyl}benzenesulfonate) (12225-21-7) cannot be classified as reproductive toxicant.

 

Link to relevant study records
Reference
Endpoint:
toxicity to reproduction
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
results derived from a valid (Q)SAR model and falling into its applicability domain, with limited documentation / justification
Justification for type of information:
Data is from OECD QSAR toolbox v3.3 and the QMRF report has been attached.
Qualifier:
according to
Guideline:
other: As mentioned below
Principles of method if other than guideline:
Prediction was done using OECD QSAR toolbox v3.3, 2017
GLP compliance:
not specified
Limit test:
no
Justification for study design:
No data available
Specific details on test material used for the study:
- Name of test material (IUPAC name): aluminum tris(4-{[3-carboxy-5-oxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazol-4-yl]diazenyl}benzenesulfonate)- Common name: FD&C Yellow No. 5 Aluminum Lake- Molecular formula: C48H33AlN12O27S6- Molecular weight: 495.4038g/mol-InChl:1S/C16H12N4O9S2.Al/c21-15-13(18-17-9-1-5-11(6-2-9)30(24,25)26)14(16(22)23)19-20(15)10-3-7-12(8-4-10)31(27,28)29;/h1-8,13H,(H,22,23)(H,24,25,26)(H,27,28,29);/b18-17+;- Substance type: Organic
Species:
rat
Strain:
Wistar
Details on species / strain selection:
No data available
Sex:
male/female
Details on test animals and environmental conditions:
No data available
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
No data available
Details on mating procedure:
No data available
Analytical verification of doses or concentrations:
not specified
Duration of treatment / exposure:
Male: 28 daysFemale: 49 days
Frequency of treatment:
Daily, females in labor were not treated.
Details on study schedule:
No data available
Dose / conc.:
860 mg/kg bw/day (nominal)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
No data available
Positive control:
No data available
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes - Time schedule: - Cage side observations checked in table [No.?] were included. DETAILED CLINICAL OBSERVATIONS: Yes - Time schedule: BODY WEIGHT: Yes / No / No data - Time schedule for examinations: FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study): yes - Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data - Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data - Time schedule for examinations: OTHER:
Oestrous cyclicity (parental animals):
No data available
Sperm parameters (parental animals):
Parameters examined in [all/P/F1/F2] male parental generations: [testis weight, epididymis weight, daily sperm production, sperm count in testes, sperm count in epididymides, enumeration of cauda epididymal sperm reserve, sperm motility, sperm morphology, other:]Sperm parameters were observed
Litter observations:
No data available
Postmortem examinations (parental animals):
No data available
Postmortem examinations (offspring):
No data available
Statistics:
No data available
Reproductive indices:
No data available
Offspring viability indices:
No data available
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
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:
not specified
Gross pathological findings:
no effects observed
Neuropathological findings:
not specified
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not specified
Other effects:
not specified
Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
not specified
Dose descriptor:
NOAEL
Effect level:
860 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
body weight and weight gain
food consumption and compound intake
gross pathology
histopathology: non-neoplastic
reproductive function (sperm measures)
Remarks on result:
other: No effects on reproductive function
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
not specified
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
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:
not specified
Sexual maturation:
not specified
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
no effects observed
Histopathological findings:
not examined
Other effects:
not specified
Behaviour (functional findings):
not specified
Developmental immunotoxicity:
not specified
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
860 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
viability
clinical signs
mortality
gross pathology
Remarks on result:
other: No developmental toxicity was observed
Critical effects observed:
not specified
System:
other: not specified
Organ:
not specified
Treatment related:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Reproductive effects observed:
not specified
Treatment related:
not specified
Relation to other toxic effects:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified

The prediction was based on dataset comprised from the following descriptors: NOAEL
Estimation method: Takes average value from the 5 nearest neighbours
Domain  logical expression:Result: In Domain

(((((((("a" or "b" or "c" )  and ("d" and ( not "e") )  )  and ("f" and ( not "g") )  )  and ("h" and ( not "i") )  )  and ("j" and ( not "k") )  )  and ("l" and ( not "m") )  )  and ("n" and ( not "o") )  )  and ("p" and "q" )  )

Domain logical expression index: "a"

Referential boundary: The target chemical should be classified as SN1 OR SN1 >> Nitrenium Ion formation OR SN1 >> Nitrenium Ion formation >> Aromatic azo OR SN1 >> Nitrenium Ion formation >> Unsaturated heterocyclic azo by DNA binding by OECD ONLY

Domain logical expression index: "b"

Referential boundary: The target chemical should be classified as Schiff base formation OR Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives OR Schiff base formation >> Pyrazolones and Pyrazolidinones derivatives >> Pyrazolones and Pyrazolidinones  by Protein binding by OASIS v1.3 ONLY

Domain logical expression index: "c"

Referential boundary: The target chemical should be classified as Acylation OR Acylation >> Direct Acylation Involving a Leaving group OR Acylation >> Direct Acylation Involving a Leaving group >> Acetates OR SN2 OR SN2 >> SN2 reaction at sp3 carbon atom OR SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl diazo by Protein binding by OECD

Domain logical expression index: "d"

Referential boundary: The target chemical should be classified as No alert found by DNA binding by OASIS v.1.3

Domain logical expression index: "e"

Referential boundary: The target chemical should be classified as AN2 OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds OR AN2 >> Michael-type addition on alpha, beta-unsaturated carbonyl compounds >> Four- and Five-Membered Lactones OR AN2 >> Shiff base formation after aldehyde release OR AN2 >> Shiff base formation after aldehyde release >> Specific Acetate Esters OR Non-covalent interaction OR Non-covalent interaction >> DNA intercalation OR Non-covalent interaction >> DNA intercalation >> DNA Intercalators with Carboxamide Side Chain OR Non-specific OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    OR Non-specific >> Incorporation into DNA/RNA, due to structural analogy with  nucleoside bases    >> Specific Imine and Thione Derivatives OR Radical OR Radical >> Generation of reactive oxygen species OR Radical >> Generation of reactive oxygen species >> Thiols OR Radical >> Generation of ROS by glutathione depletion (indirect) OR Radical >> Generation of ROS by glutathione depletion (indirect) >> Haloalkanes Containing Heteroatom OR Radical >> Radical mechanism via ROS formation (indirect) OR Radical >> Radical mechanism via ROS formation (indirect) >> Nitroarenes with Other Active Groups OR Radical >> Radical mechanism via ROS formation (indirect) >> Specific Imine and Thione Derivatives OR SN1 OR SN1 >> Alkylation after metabolically formed carbenium ion species OR SN1 >> Alkylation after metabolically formed carbenium ion species >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN1 >> Nucleophilic attack after carbenium ion formation OR SN1 >> Nucleophilic attack after carbenium ion formation >> Specific Acetate Esters OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation OR SN1 >> Nucleophilic attack after diazonium or carbenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation OR SN1 >> Nucleophilic attack after reduction and nitrenium ion formation >> Nitroarenes with Other Active Groups OR SN1 >> Nucleophilic substitution on diazonium ions OR SN1 >> Nucleophilic substitution on diazonium ions >> Specific Imine and Thione Derivatives OR SN2 OR SN2 >> Acylation OR SN2 >> Acylation >> Specific Acetate Esters OR SN2 >> Alkylation, direct acting epoxides and related OR SN2 >> Alkylation, direct acting epoxides and related >> Epoxides and Aziridines OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation OR SN2 >> Alkylation, direct acting epoxides and related after P450-mediated metabolic activation >> Polycyclic Aromatic Hydrocarbon Derivatives OR SN2 >> Alkylation, ring opening SN2 reaction OR SN2 >> Alkylation, ring opening SN2 reaction >> Four- and Five-Membered Lactones OR SN2 >> Direct acting epoxides formed after metabolic activation OR SN2 >> Direct acting epoxides formed after metabolic activation >> Quinoline Derivatives OR SN2 >> DNA alkylation OR SN2 >> DNA alkylation >> Alkylphosphates, Alkylthiophosphates and Alkylphosphonates OR SN2 >> Nucleophilic substitution at sp3 Carbon atom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Haloalkanes Containing Heteroatom OR SN2 >> Nucleophilic substitution at sp3 Carbon atom >> Specific Acetate Esters OR SN2 >> SN2 at an activated carbon atom OR SN2 >> SN2 at an activated carbon atom >> Quinoline Derivatives OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 OR SN2 >> SN2 attack on activated carbon Csp3 or Csp2 >> Nitroarenes with Other Active Groups by DNA binding by OASIS v.1.3

Domain logical expression index: "f"

Referential boundary: The target chemical should be classified as Acylation AND Acylation >> Direct Acylation Involving a Leaving group AND Acylation >> Direct Acylation Involving a Leaving group >> Acetates AND SN2 AND SN2 >> SN2 reaction at sp3 carbon atom AND SN2 >> SN2 reaction at sp3 carbon atom >> Alkyl diazo by Protein binding by OECD

Domain logical expression index: "g"

Referential boundary: The target chemical should be classified as Acylation >> Direct Acylation Involving a Leaving group >> Anhydrides OR Acylation >> Direct Acylation Involving a Leaving group >> Azlactone OR Acylation >> Isocyanates and Related Chemicals OR Acylation >> Isocyanates and Related Chemicals >> Isocyanates OR Michael addition OR Michael addition >> Acid imides OR Michael addition >> Acid imides >> Acid imides-MA OR No alert found OR SN2 >> SN2 reaction at sp3 carbon atom >> Allyl acetates and related chemicals OR SN2 >> SN2 reaction at sp3 carbon atom >> alpha-Halobenzyls (and related cyano, sulfate and sulphonate subs. chem.) by Protein binding by OECD

Domain logical expression index: "h"

Referential boundary: The target chemical should be classified as No alert found by rtER Expert System ver.1 - USEPA

Domain logical expression index: "i"

Referential boundary: The target chemical should be classified as Salicylates by rtER Expert System ver.1 - USEPA

Domain logical expression index: "j"

Referential boundary: The target chemical should be classified as Not categorized by Repeated dose (HESS)

Domain logical expression index: "k"

Referential boundary: The target chemical should be classified as Amineptine (Hepatotoxicity) Alert by Repeated dose (HESS)

Domain logical expression index: "l"

Referential boundary: The target chemical should be classified as Imine form - 1,3-H shift by Tautomers unstable

Domain logical expression index: "m"

Referential boundary: The target chemical should be classified as Conjugated ketoamine(scy) - 1,5-H shift OR Enol form by Tautomers unstable

Domain logical expression index: "n"

Referential boundary: The target chemical should be classified as Inclusion rules not met by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "o"

Referential boundary: The target chemical should be classified as Esters of organic sulfonic or sulfuric esters OR Ketones OR Phenols by Skin irritation/corrosion Inclusion rules by BfR

Domain logical expression index: "p"

Parametric boundary:The target chemical should have a value of log Kow which is >= -1.09

Domain logical expression index: "q"

Parametric boundary:The target chemical should have a value of log Kow which is <= 11.3

Conclusions:
In reproductive toxicity study, NOAEL was estimated to be 860mg/kg bw. When male and female wistar rats were exposed with aluminium tris(4-{[3-carboxy-5-oxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazol-4-yl]diazenyl}benzenesulfonate) (12225-21-7) orally.
Executive summary:

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for aluminium tris(4-{[3-carboxy-5-oxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazol-4-yl]diazenyl}benzenesulfonate) (12225-21-7) .Male and female reproductive parameters were unaffected by test material administration. Hence, NOAEL was estimated to be 860mg/kg bw. When male and femalewistarrats were exposed with aluminium tris(4-{[3-carboxy-5-oxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazol-4-yl]diazenyl}benzenesulfonate) (12225-21-7) orally.

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
860 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Data is Klimicsh 2 and from QSAR Toolbox 3.3. (2017)
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

In different studies, aluminium tris(4-{[3-carboxy-5-oxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazol-4-yl]diazenyl}benzenesulfonate) (12225-21-7) has been investigated for reproductive toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for aluminium tris(4-{[3-carboxy-5-oxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazol-4-yl]diazenyl}benzenesulfonate) (12225-21-7).The predicted data using the OECD QSAR toolbox has also been compared with the experimental studies performed on structurally similar read across substance Tartrazine(1934-21-0).

In a prediction done by SSS (2017) using the OECD QSAR toolbox with log kow as the primary descriptor, the reproductive toxicity was estimated for aluminium tris(4-{[3-carboxy-5-oxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazol-4-yl]diazenyl}benzenesulfonate) (12225-21-7) .Male and female reproductive parameters were unaffected by test material administration. Hence, NOAEL was estimated to be 860mg/kg bw. When male and female wistar rats were exposed with aluminium tris(4-{[3-carboxy-5-oxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazol-4-yl]diazenyl}benzenesulfonate) (12225-21-7) orally.

It is supported by experimental study conducted by Toyohito Tanaka, Osamu Takahashi, Shinshi Oishi, Akio Ogata (Reproductive Toxicology 26 ,156–163,2008)on structurally similar read across substance Tartrazine(1934-21-0) .A three generation reproductive toxicity study was conducted for Tartrazine(1934-21-0) in(Crlj: CD1 male and female mice. The design of the study was based on the guidelines issued by ICH[12]and OECD[13]adapted for mice The test material was given to male and female mice in the diet at levels of 0 (control), 0.05%, 0.15%, and 0.45%(0, 71.3, 214.9 and 642.8 mg/kg/day)from 5 weeks of age of the F0 generation to 9weeks of age of the F2 generation. 10 males and 10 females in each dose group. Clinical sign, body weight, food consumption, chemical intake, reproductive and neurobehavioral parameters were measured. The litter size or sex ratio at birth, litter weight and viability index of offspring were also observed. No. of females examined, No. of pregnant females, No. of litters No. of offspring, Average litter size, Average litter weight, Total sex ratio (male/female) and Average sex ratio (male %) were also observed. Exploratory behaviour of mice was measured in an animal movement analysing system ANIMATE AT- at 8 weeks of in the F0.

 In parents, movement activity of exploratory behaviour at 8 weeks of age, no variables of measurement showed a significant adverse effect of tartrazine in male and female mice of treated group compare to control. No significant change was observed in the male and female mice during the preconception or mating periods in all treated group compare to control. Even the average body weight of dams showed no significant adverse effect during the gestation or lactation period in treated group compare to control. No significant change was observed in the food consumption of male and female mice during the preconception, mating periods, gestation and lactation period in all treated group compare 0, 0.05%, 0.15%, and 0.45%to control. No significant change was observed in the chemical intake of male and female mice during the preconception, mating periods, gestation and lactation period in all treated group compare 0, 0.05%, 0.15%, and 0.45%to control. Abortion was observed in four dams, one dam each in the 0.05% dose group and 0.15 %dose groups and two dams in the 0.45% dose groups .One dam in the 0.45% dose group killed it’s all offspring during the first week of lactation. One dam in the control (0%) group had not nursed its offspring during the first week of lactation.

 In the F1 generation, In the,0.05%dosed group, the average body weight of male and female offspring was increased significantly throughout the lactation period .In the0.15%dosed group, the average body weight of male offspring was increased significantly at PND 7.In the0.45%dosed group, the average body weight of male offspring was increased significantly at PND 21.No significant change was observed in the male and female mice during the preconception or mating periods in all treated group compare to control in F1 generation.

The average body weight of dams showed no significant adverse effect during the gestation or lactation period in all treated group0, 0.05%, 0.15%, and 0.45% compare to control. No significant change was observed in the food consumption of F1male and female mice during the preconception, mating periods, gestation and lactation period in all treated group compare 0, 0.05%, 0.15%, and 0.45%to control. The development of swimming direction at postnatal day (PND) 7 was accelerated significantly in male offspring in a dose-related manner. Surface righting at PND 7 was affected significantly in female offspring in dose-related manner. Several variables in exploratory behaviour showed significant tendencies to be affected in the treatment groups in male offspring at 3 weeks of age.

 In the F2 generation, In the 0.05% dosed group, the average body weight of female offspring was affected significantly at birth and was increased significantly at PNDs 14 and 21, and that of male offspring was increased significantly at PNDs 7, 14 and 21. In 0.15% dosed group, the average body weight of male offspring was increased significantly throughout the lactation period, and that of female offspring was increased significantly at PNDs 7, 14 and 21. There was no sex-related difference in average body weight during the lactation period. No significant change was observed in the food consumption of F2male and female mice during the preconception, mating periods, gestation and lactation period in all treated group compare 0, 0.05%, 0.15%, and 0.45%to control. No significant change was observed in the chemical intake of F2male and female mice during the preconception, mating periods, gestation and lactation period in all treated group 0,0.05%, 0.15%, and 0.45%compareto control. The development of swimming direction at PND 7was accelerated significantly in the 0.45%dosed group in male offspring. Time taken of olfactory orientation at PND 14 was accelerated significantly in male offspring in a dose-related manner. Several variables in exploratory behaviour showed significant tendencies to be affected in the treatment groups in male offspring at 3 weeks of age, and in males at 8 weeks of age. The dose levels of tartrazine in the present study produced a few adverse effects on neurobehavioral parameters throughout generations in mice .But no adverse effect were observed on reproductive parameter in all generations of (Crlj: CD1 male and female mice in all treated group 0,0.05%, 0.15%, and 0.45% compare to control. Therefore NOAEL was considered to be 642.8 mg/kg/day (0.45%) for Tartrazine(1934-21-0) in both P and F1 generation (Crlj: CD1 male and female mice for reproductive toxicity effect.

It is further supported by experimental study conducted by N. Mehedi, S. Ainad-Tabet, N. Mokrane, S. Addou, C. Zaoui, O. Kheroua and D. Saidi (American Journal of Pharmacology and Toxicology 4 (4): 130-135)on structurally similar read across substance Tartrazine(1934-21-0). A sub chronic study was conducted for Tartrazine(1934-21-0) in male swiss albino mice for 13 weeks. They were administrated Tartrazine at the concentration of0, 0.1%, 1% and 2.5% (173.9 ±0.25, 1767.8±0.32and 5541.4±0.47 mg/kg/day ) by oral drinking water. Groups of Tartrazine treated mice, six males per dose group, were mated 1:1 with untreated females for 1 week. Females were then separated and allowed to gestate to term. For females that failed to deliver a litter, this was considered as a sign of male infertility whereas litter delivery indicated male fertility. Food and water consumption, body weight, reproductive function, Reproductive performance, organ weight and histopathology were observed.

Body weight gain was significantly increased in 1767.8mg/kg/day dose group (p<0.05). This increased body weight gain is not evidence related dose. Significant decrease in the food consumption was observed at all dose level 0.1%, 1% and 2.5% in treated group compare to control. Significant increase in the water consumption was observed at all dose level 0, 0.1%, 1% and 2.5% in treated group compare to control. Total number of spermatids count was reduced significantly in the mice administered 5541.4 mg/kg /day dose group (p<0.01). Sperm concentration in epididymides was reduced in all treated groups (173.9, 1767.8, and 5541.4mg/kg/day) but sperm epididymis reserves were reduced significantly only in mice treated in 5541.4mg/kg/day dose group (p<0.01).The percentage motility was reduced in1767.8, and 5541.4mg/kg/day dose groups (p<0.01).The percentage morphologically normal spermatozoa were significantly affected in 5541.4mg/kg/day dose group(p<0.01).  Male mating index was decreased in the 2.5% treated groups compared to the control values. There was significant decrease in the litter sizes and weight at treated dose group173.9, 1767.8, and 5541.4mg/kg/day comparison to litters sired from control males. Therefore NOAEL was considered to be173.9±0.25 mg/kg/day(0.1%) as tartrazine has toxic effects on the testis and the epididymides of Swiss Albino mice when it is administered at high doses equivalent to 5541.4 mg /kg/ day and it also affects testis structure and sperm motility at middle doses equivalent to 1767.8 mg/ kg/ day. There were no significant effect were observed at the dose level of 173.9mg/kg/day.

 Another experimental study conducted by T. F. X. COLLJNS, T. N. BLACK, L. H. BROWN and P. BULHACK (Food Chem Toxic, Vol. 28, No. 12, pp. 821-827, 1990)on structurally similar read across substance Tartrazine(1934-21-0). Reproductive toxicity study was observed for Tartrazine (1934-21-0) in female Osborne-Mendel rats, when they were exposed at the concentration of0, 60,100, 200, 400, 600 or 1000mg/kg body weight/day on days 0-19 of gestation by oral gavage.259 female rats were used in the study.  All the animals were observed for Clinical sign and weight daily. Food consumption was observed weekly. Water intake was not measured. The foetuses were grouped by litter for identification. 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 than 70% of the average weight of the concurrent male or female controls was considered tobe a runt. External visceral and sternebral variations were also observed. On day 20 of gestation, the females were examined for gross abnormalities for the last time before being killed by CO2 asphyxiation. Caesarean sections were performed, corpora lutea were counted and the uteri were opened and examined in situ. The uterine positions of all implantation sites were noted and their condition (early or late resorptions, alive or dead foetuses) was determined. Approximately half of the foetuses were examined for skeletal variations after being fixed in alcohol, cleared and stained with Alizarin Red S by a modification of Dawson's method. The remaining foetuses were fixed in Bouin's solution and sectioned according to the method of Wilson in order to detect internal visceral variations. Specific sternebral variation were observed in all fetuses like Incomplete , Bipartite, Missing and Malaligned. Specific soft tissue variation like Hydroureter, Enlarged renal pclvis,Ectopic kidney ,Haemorrhages , Hydrocephalus ,Ectopic/incomplete descended testes ,Ectopic ovary ,Microphthalmia ,Anophthalmia ,Oedema and Defective heart valve were observed .Skeletal variation like 15 rib,l4th rib l3th rib ,l2th rib, Ribs, fused Ribs, wavy ribs, Centra. red. on. Centra, misshapen , Centra, bipartite ,Centra, missing Centra, fused wI dorsal arches ,Vertebrae. missing Caudal oss ibcation ,Dorsal arches, red Dorsal arches, fused Interparietal, red. oss. , Pariewl, red ,Frontal, red oss. ,Nasal red. oss. Supraoccipital, red. Oss, Supraoccipitaf. bipartite Hyoid. Red oss.Squuamosa, red. Zygomatic, red. ms. ,Pubis, red oss. Metacarpals, red. Scapula. red oss. ,Scapula, curved ,Clavicle, misshapen Maxillary, red. oss. ere observed .

 

No significant change were observed in body weight at all treated group60, 100, 200, 400 and 600 mg/kg/day compare to control. Except at dose group 1000 mg/kg/day, where body weight increased compare to control. Initial body weight at day 0 and maternal body-weight gain during gestation did not vary significantly between treated and control groups. No significant change were observed in food consumption at all treated group60, 100, 200, 400 and 600 mg/kg/day compare to control. Except at dose group 1000 mg/kg/day, where food consumption increased compare to control. No significant changes were observed in% pregnant rats and %implantation efficiency in all treated group60, 100, 200, 400, 600 and 1000 mg/kg /day compare to control. No significant change were observed in number of implants and number of resorption sites all treated group60, 100, 200, 400, 600 and 1000 mg/kg /day compare to control.

No significant change was observed in the viability for male and female foetuses in all treated group compare to control. No significant changes were observed in the crown rump length of male and female foetuses in all treated group compare to control. No significant changes were observed in the body weight of male and female foetuses in all treated group compare to control. No significant change were observed in Specific sternebral variation all treated group60, 100, 200, 400, 600 and 1000 mg/kg /day compare to control. No significant change was observed in Specific Skeletal variation in all treated group60, 100, 200, 400, 600 and 1000 mg/kg /day compare to control. No significant change were observed in Specific soft tissue variation like Hydroureter, Enlarged renal pclvis, Ectopic kidney ,Haemorrhages , Hydrocephalus ,Ectopic/incomplete descended testes ,Ectopic ovary ,Microphthalmia ,Anophthalmia ,Oedema and Defective heart valve all treated group60, 100, 200, 400, 600 and 1000 mg/kg /day compare to control. Therefore NOAEL was considered to be 1000 mg/kg/day as no significant maternal toxicity was observed at all dose level. No significant change were observed in the clinical sign, body weight, food consumption, reproductive performance (% pregnant rats and %implantation efficiency )and gross pathology of female Osborne-Mendel rats when treated with for Tartrazine (1934-21-0)on days 0-19 of gestation by oral gavage.

Also supported by experimental study conducted by T. F. X. COLLJNS, T. N. BLACK, L. H. BROWN and P. BULHACK (Food Chem Toxic, Vol. 30, No. 4, pp. 263-268, 1992) on structurally similar read across substance Tartrazine(1934-21-0). Reproductive toxicity study was observed for Tartrazine(1934-21-0) in female Osborne-Mendel rats, when they were exposed at the concentration of0.05, 0.1, 0.2, 0.4 or 0.7% (67.4, 131.8, 292.4, 567.9 and 1064.3mg/kg/day) on days 0-19 of gestation. They were administered test material by using distilled water as vehicle. Distilled water served as the control. On mating days ,two females were randomly placed in cage with one male at approx. 16.30hr. The following morning, the presence of sperm in the vaginal smear was considered to be evidence of copulation and the sperm positive females were considered to be at day 0 of gestation. Morbidity and mortality were observed daily. Clinical sign and abnormality in behaviour was also observed daily. The rats were weighed and fluid consumption was measured daily. Food consumption was measured weekly. On day 20 of gestation, the females were examined for gross abnormalities for the last time before being killed by CO2 asphyxiation. Caesarean sections were performed and the uterus of each female was opened and examined in situ for the presence and position of resorption sites and fetuses (dead or alive), number of corpora lutea and number of implantation sites. Viability of fetuses, each live fetus was promptly weighed, sexed and examined for gross external malformations, and the crown-rump length was measured. Any fetus that weighed less than 70% of the average weight of the concurrent male or female controls was considered to be a runt. Approximately half of the fetuses were examined for skeletal variations after being fixed in alcohol, cleared and stained with Alizarin Red S by a modification of Dawson's method. The remaining fetuses were fixed in Bouin's solution, serially sectioned according to the method of Wilson and examined for internal visceral variations. Approximately half of the fetuses were examined for skeletal variations after being fixed in alcohol, cleared and stained with Alizarin Red S by a modification of Dawson's method. The remaining fetuses were fixed in Bouin's solution, serially sectioned according to the method of Wilson and examined for internal visceral variations.

 No significant change was observed in behaviour and clinical sign. No mortality was observed .Except one female in the control group of unknown causes during the study. No significant change were observed in body weight of initial maternal body weight at day 0 and weight gain during days 0-20 in all treated group0.05, 0.1, 0.2, 0.4 or 0.7% compare to control. No significant changes were observed in food consumption at all treated group0.05, 0.1, 0.2, 0.4 or 0.7% compare to control. A significant increase in the fluid consumption was observed in all treated group0.05, 0.1, 0.2, 0.4 or 0.7% compare to control. Especially in dose group 0.7% significant increase in the fluid consumption was observed. A significant increase in pregnancy rate was observed in all group compare to control. No significant change were observed in %implantation efficiency in all treated group0.05, 0.1, 0.2, 0.4 or 0.7% compare to control.

Reproductive findings at the time of caesarean sections were unremarkable. Nine litters were totally resorbed, but the resorptions were not related to dosage (0.05%, 1 litter; 0.1%, 3 litters; 0.4%, 2 litters; 0.7%, 3 litters). No significant change was observed in number of implants and number of resorption sites all treated group 0.05, 0.1, 0.2, 0.4 or 0.7% compare to control.

No significant change were observed in the viability for male and female foetuses in all treated group compare to control .Also No significant change were observed in thecrown rump length of male and female foetuses in all treated group compare to control. The body weight of male and female foetuses in all treated group no significant changes were observed compare to control. No significant change were observed in Specific sternebral variation all treated0.05, 0.1, 0.2, 0.4 or 0.7% compare to control and No significant change were observed in Specific Skeletal variation in all treated0.1, 0.2, or 0.7% compare to control. Except in dose level0.05 and 0.4%, this was considered random because they are not dose related. No significant change were observed in the specific soft tissue variation like Hydro-ureter, Enlarged renal pelvis, Haemorrhage, internal Microcephalus ,Hydrocephalus ,Eetopic tongue ,Diaphragmatic hernia ,Polydactyly Adrenal black in all treated group0.05, 0.1, 0.2, 0.4 or 0.7% compare to control .Therefore NOAEL was considered to be 1064.3 mg/kg/day as no dose-related changes were seen in maternal clinical findings, implantations, foetal viability or foetal size (weight and length). Neither visceral development nor skeletal development (sternebral and other skeletal bones) was affected by the Tartrazine. The small numbers of statistically significant increases in skeletal variations in the 0.05 and 0.4% levels are considered random because they are not dose related.When pregnant Osborne-Mendel rats were treated with Tartrazine (1934-21-0) throughout gestation by orally.

Thus, based on the above studies and predictions on aluminium tris(4-{[3-carboxy-5-oxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazol-4-yl]diazenyl}benzenesulfonate) (12225-21-7) and structurally similar read across substance Tartrazine(1934-21-0). It was considered that no adverse effects on reproductive parameter were observed. Thus, comparing this value with the criteria of CLP regulation aluminium tris(4-{[3-carboxy-5-oxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazol-4-yl]diazenyl}benzenesulfonate) (12225-21-7) cannot be classified as reproductive toxicant.

 

Effects on developmental toxicity

Description of key information

The substance aluminium tris(4-{[3-carboxy-5-oxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazol-4-yl]diazenyl}benzenesulfonate) (12225-21-7) is expected to show the similar toxicological effect based on the effects observed in structurally similar read across substance Tartrazine(1934-21-0). Since no effective dose value (NOAEL) is reported to be 1000 mg/kg orally. Also there are no known evidence of adverse effect on development in human of CAS: 12225-21-7. Thus, comparing this value with the criteria of CLP regulation aluminium tris(4-{[3-carboxy-5-oxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazol-4-yl]diazenyl}benzenesulfonate) (12225-21-7) can be "Not classified" for developmental toxicity.

 

.

Link to relevant study records
Reference
Endpoint:
developmental toxicity
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 journal
Qualifier:
according to
Guideline:
other: OECD Guideline 426 (Developmental Neurotoxicity Study)
Principles of method if other than guideline:
Three-generation reproductive and neurobehavioral toxicity study of Tartrazine in male and female mice
GLP compliance:
not specified
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report):Tartrazine- Molecular formula:C16H12N4O9-S2.3Na- Molecular weight :534.36 g/mole- Substance type:Organic- Physical state:Liquid , dye- Analytical purity:85.0%- Impurities (identity and concentrations):No data available.
Species:
mouse
Strain:
Crj: CD(SD)
Details on test animals and environmental conditions:
Details on test animalTEST ANIMALS- Source: Charles River Japan Inc., Kanagawa, Japan- Age at study initiation: 5 weeks of age of the F0 generation to 9 weeks of age of the F2 generation.- Weight at study initiation: (P) Males: x-x g; Females: x-x g; (F1) Males: x-x g; Females: x-x g- Fasting period before study: No data available.- Housing: They were housed individually in polycarbonateSolid-floored cages with wood flakes.- Diet (e.g. ad libitum): Basal diets (Nihon Clea, CE-2) ad libitum.- Water (e.g. ad libitum): They were given water ad libitum.- Acclimation period: 1 weekENVIRONMENTAL CONDITIONS- Temperature (°C): 25±1 ◦C- Humidity (%):50±5%. - Air changes (per hr): No data available- Photoperiod (hrs dark / hrs light): 12 h light/12 h dark cycle
Route of administration:
oral: feed
Vehicle:
other: Basal diets (Nihon Clea, CE-2)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: DIET PREPARATION- Rate of preparation of diet (frequency): The experimental diets were prepared bimonthly (three times) in the laboratory.- Mixing appropriate amounts with (Type of food): After mixing tartrazine with the powdered diet (basal Diets, Nihon Clea, CE-2), pellets were formed and fed to mice. Tartrazine was stable in the pellets during the experimental period when previously measured byHPLC. The homogeneity of the test compound was ensured by the preparation procedures of the experimental diets in the laboratory when previously measured by HPLC. The concentration and homogeneity of the test compound in the diet was not tested during the experimental period. - Storage temperature of food: No data available.
Analytical verification of doses or concentrations:
not specified
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 available.- After ... days of unsuccessful pairing replacement of first male by another male with proven fertility.- No data available.- Further matings after two unsuccessful attempts: [no / yes (explain)]- No data available.- After successful mating each pregnant female was caged (how):No data available.- Any other deviations from standard protocolNo data available.
Duration of treatment / exposure:
199 days (approx 200)
Frequency of treatment:
Daily
Duration of test:
199 days (approx 200)
Remarks:
0, 0.05%, 0.15%, and 0.45% (0,71.3, 214.9 and 642.8 mg/kg/day)
No. of animals per sex per dose:
Total no. of animals-800 mg/kg bw/day -10 male and 10 female71.3 mg/kg bw/day -10 male and 10 female214.9 mg/kg bw/day -10 male and 10 female642.9 mg/kg/day -10 male and 10 female
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale:Micewere assigned to the groups by the stratified randomization method.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes - Time schedule: - Cage side observations checked in table [No.?] were included. DETAILED CLINICAL OBSERVATIONS: Yes / No / No data - Time schedule: BODY WEIGHT: Yes - Time schedule for examinations:he animals were 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): Yes :Food intake and chemical intake was also observed during the preconception period. - Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes / No / No data - Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes / No / No data WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No data - Time schedule for examinations: POST-MORTEM EXAMINATIONS: Yes / No / No data - Sacrifice on gestation day # - Organs examined: OTHER:
Ovaries and uterine content:
No data available.
Fetal examinations:
- External examinations: Yes: - Soft tissue examinations: No data - Skeletal examinations: No data - Head examinations: No dataLitter observation- For F1 generation offspring were weighed individually on PNDs 0, 4, 7, 14, and 21 during the lactation period. The survival indices were calculated as (live offspring at each period)/ (live and dead offspring at birth) ×100%. Negative geotaxis, Cliff avoidance, Swimming behavior and olfactory orientation were observed on PND 4-14 .Food intake and chemical intake was observed during Preconception, mating, gestation and Lactation.For F2 generation offspring were weighed individually on PNDs 0, 4, 7, 14, and 21 during the lactation period. The survival indices were calculated as (live offspring at each period)/ (live and dead offspring at birth) ×100%. The offspring were weaned when they were 4 weeks of age, and one male and one female were selected at random from each litter to continue treatment. The animals were weighed individually at 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, and 9 weeks of age after weaning.Animals at 7weeks of age in the F1 and F2 generation each performed 1 trial per day for 3 days in a Biel-type multiple-T water maze adapted for mice. Exploratory behavior of mice was measured in an animal movement analyzing system ANIMATE AT- at 8 weeks of in the F1 and F2.
Statistics:
Food intake, litter size, litter weight, and body weight were assessed with Bonferroni’s multiple comparison tests after the analysis of variance (ANOVA) or the Kruskal–Wallis test. Sex ratio, survival and behavioural developmental data were assessed with the X2-test or with Fisher’s exact test of frequency analysis. Movement activity data were assessed with the Steel–Dwass test of non-parametric methods. Multiple-T water maze performance data were assessed with the Sign–Wilcoxon test for trials and assessed with the Steel–Dwass test within each treatment group. Dose-response effects were assessed with the Jonckheere test for ordered alternatives or the cumulative -test (multi) for frequency data.
Indices:
Fertility index and viability index of offspring were opbserved.
Historical control data:
No data available.
Clinical signs:
no effects observed
Description (incidence and severity):
In movement activity of exploratory behavior at 8weeks of age, no variables of measurement showed a significant adverse effect of tartrazine in male and female mice of treated group compare to contol.
Dermal irritation (if dermal study):
not specified
Mortality:
not specified
Body weight and weight changes:
no effects observed
Description (incidence and severity):
The average body weight of dams showed no significant adverse effect during the gestation or lactation period in treated group compare to control
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No significant change was observed in the food consumption of male and female mice during the preconception ,mating periods, gestation and lactation period in all treated group compare 0, 0.05%, 0.15%, and 0.45% to control
Food efficiency:
not specified
Water consumption and compound intake (if drinking water study):
no effects observed
Description (incidence and severity):
No significant change was observed in the chemical intake of male and female mice during the preconception ,mating periods, gestation and lactation period in all treated group compare 0, 0.05%, 0.15%, and 0.45% to control.
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:
effects observed, treatment-related
Description (incidence and severity):
Abortion was observed in four dams, one dam each in the (0.05%) dosedand (0.15%)dosed groups and two dams in the (0.45%) dosed groups
Pre- and post-implantation loss:
not specified
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
Other effects:
not specified
Details on maternal toxic effects:
Maternal toxic effects:no effectsDetails on maternal toxic effects:Body weight -No significant change was observed in the male and female mice during the preconception or mating periods in F0 generation compare to control.Food consumption:No significant effect on food consumption were observed in treated mice in F0 generation as compared to control. Test substance intake- No significant change was observed in the chemical intake of male and female mice during the preconception ,mating periods, gestation and lactation period in F0 generation as compared to control.Reproductive performance- No significant adverse effect was observed on survival, litter size, litter weight, or sex ratio at birth were observed in F0 generation as compared to control.
Dose descriptor:
NOAEL
Effect level:
642.8 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Remarks on result:
other: No effects on developmental parameters
Abnormalities:
not specified
Fetal body weight changes:
no effects observed
Description (incidence and severity):
No significant change was observed in the male and female mice during the preconception or mating periods in all treated groupcompare to control in F1 generation.The average body weight of dams showed no significant adverse effect during the gestation or lactation period in all treated group 0, 0.05%, 0.15%, and 0.45% compare to control.There was no sex-related difference in average body weight during the lactation period.
Reduction in number of live offspring:
no effects observed
Description (incidence and severity):
No significant adverse effect was observed in Viability index in all treated group 0, 0.05%, 0.15%, and 0.45%compare to control during lactation period.
Changes in sex ratio:
no effects observed
Description (incidence and severity):
No significant adverse effect was observed in sex ratio at birth
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
No significant adverse effect was observed in litter size, litter weight at birth
Changes in postnatal survival:
not specified
External malformations:
not specified
Skeletal malformations:
not specified
Visceral malformations:
not specified
Other effects:
effects observed, treatment-related
Description (incidence and severity):
Significant change were observed in the neurobehaviur test ,Swimming direction at PND7 in F1 generation male at dose level 0.15%and surface righting at PND7 in female offspring at dose level 0.15%compare to control.Significant change were observed in the neurobehaviur test ,Swimming direction at PND7 and time taken of olfactory orientation at PND 14 in F2 generation male at dose level 0.15% and 0.45% respectively and surface righting at PND7 in female offspring at dose level 0.15 %compare to control.
Dose descriptor:
NOAEL
Effect level:
643.8 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant effect were observed onthe litter size or sex ratio at birth,litter weight and viability index of offspring
Remarks on result:
other: No developmental toxic effects was observed
Dose descriptor:
LOAEL
Effect level:
214.9 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
not specified
Basis for effect level:
other: neurobehavioural changes
Remarks on result:
other: neurobehavioural changes was observed
Abnormalities:
not specified
Developmental effects observed:
not specified
Treatment related:
not specified
Relation to maternal toxicity:
not specified
Dose response relationship:
not specified
Relevant for humans:
not specified
Conclusions:
NOAEL was found to be 642.8 mg/kg/day (0.45%) for Tartrazine in both F1and F 2generation (Crlj: CD1 male and female mice when their dams were exposed to test chemical by oral diet.
Executive summary:

A three generation reproductive toxicity study was conducted for Tartrazine(1934-21-0) in (Crlj: CD1 male and female mice.The design of the study was based on the guidelines issued by ICH[12]and OECD[13]adapted for mice The test materialwas given to male and female mice in the diet at levels of 0 (control), 0.05%, 0.15%, and 0.45%(0, 71.3, 214.9 and 642.8 mg/kg/day)from 5 weeks of ageof the F0 generation to 9weeks of age of the F2 generation. 10 male and 10 female in each dose group.Clinical sign ,body weight, food consumption,chemical intake ,reproductive and neurobehavioral parameters were measured. Thelitter size or sex ratio at birth,litter weight and viability index of offspring were also observed..No. of females examined, No. of pregnant females, No. of litters No. of offspring, Average litter size, Average litter weight, Total sex ratio (male/female) and Average sex ratio (male %) were also observed.Exploratory behavior of mice was measured in an animal movement analyzing system ANIMATE AT- at 8 weeks of in the F0.

 

InParents,movement activity of exploratory behavior at 8 weeks of age, no variables of measurement showed a significant adverse effect of tartrazine in male and female mice of treated group compare to contol.No significant change was observed in themale and female mice during the preconception or mating periods in all treated group compare to control.Even the average body weight of dams showed no significant adverse effect during the gestation or lactation period in treated group compare to control.No significant change was observed in the food consumption ofmale and female mice during the preconception, mating periods, gestation and lactation period in all treated group compare 0,0.05%, 0.15%, and 0.45%to control.No significant change was observed in the chemical intake ofmale and female mice during the preconception, mating periods, gestation and lactation period in all treated group compare 0,0.05%, 0.15%, and 0.45%to control. Abortion was observed in four dams, one dam each in the lowdosed(0.05%) and middle-dosed groups(0.15), and two dams in the high-dosed groups (0.45%). One dam in the high-dosed group(0.45%)killed its all offspring during the first week of lactation. One dam in the control(0%) group had not nursed its offspring during the first week of lactation.

 

In the F1 generation,In the,0.05%dosed group, the average body weight of male and female offspring was increased significantly throughout the lactation period .In the0.15%dosed group, the average body weight of male offspring was increased significantly at PND 7.In the0.45%dosed group, the average body weight of male offspring was increased significantly at PND 21.No significant change was observed in themale and female mice during the preconception or mating periods in all treated group compare to control in F1 generation.

The averagebody weight of dams showed no significant adverse effect during the gestation or lactation period in all treated group0,0.05%, 0.15%, and 0.45% compare to control.No significant change was observed in the food consumption of F1male and female mice during the preconception ,mating periods, gestation and lactation period in all treated group compare 0,0.05%, 0.15%, and 0.45%to control.The development of swimming direction at postnatal day (PND) 7 was accelerated significantly in male offspring in a dose-related manner. Surface righting at PND 7 was affected significantly in female offspring in dose-related manner. Several variables in exploratory behavior showed significant tendencies to be affected in the treatment groups in male offspring at 3 weeksof age.

 

In the F2 generation, In the 0.05% dosed group, the average body weight of female offspring was affected significantly at birth and was increased significantly at PNDs 14 and 21, and that of male offspring was increased significantly at PNDs 7, 14 and 21. In 0.15% dosed group, the average body weight of male offspring was increased significantly throughout the lactation period, and that of female offspring was increased significantly at PNDs 7, 14 and 21. There was no sex-related difference in average body weight during the lactation period.No significant change was observed in the food consumption of F2male and female mice during the preconception, mating periods, gestation and lactation period in all treated group compare 0,0.05%, 0.15%, and 0.45%to control.No significant change was observed in the chemical intake of F2male and female mice during the preconception, mating periods, gestation and lactation period in all treated group 0,0.05%, 0.15%, and 0.45%compareto control.The development of swimming direction at PND 7was accelerated significantly in the 0.45%dosed group in male offspring. Time taken of olfactory orientation at PND 14 was accelerated significantly in male offspring in a dose-related manner. Several variables in exploratory behavior showed significant tendencies to be affected in the treatment groups in male offspring at 3 weeks of age, and in males at 8 weeks of age. The dose levels of tartrazine in the present study produced a few adverse effects on neurobehavioral parameters throughout generations in mice .But no adverse effect were observed on reproductive parameter in all generations of (Crlj: CD1 male and female mice in all treated group 0,0.05%, 0.15%, and 0.45% compareto control. Therefore NOAEL was considered to be 642.8 mg/kg/day (0.45%) for Tartrazine(1934-21-0) in both F1and F 2 generation (Crlj: CD1 male and female mice for developmental effect.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The data is K2 level as the data has been obtained from the experimental study from the journal of 'Food and Chemical Toxicology'.
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

In different studies, aluminium tris(4-{[3-carboxy-5-oxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazol-4-yl]diazenyl}benzenesulfonate) (12225-21-7) has been investigated for developmental toxicity to a greater or lesser extent. Often are the studies based on in vivo experiments and estimated data in rodents, i.e. most commonly in rats for aluminium tris(4-{[3-carboxy-5-oxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazol-4-yl]diazenyl}benzenesulfonate) (12225-21-7) also been compared with the experimental studies performed on structurally similar read across substance Tartrazine(1934-21-0).

Another experimental study conducted by T. F. X. COLLJNS, T. N. BLACK, L. H. BROWN and P. BULHACK (Food Chem Toxic, Vol. 28, No. 12, pp. 821-827, 1990)on structurally similar read across substance Tartrazine(1934-21-0). Developmental toxicity study was observed for Tartrazine (1934-21-0) in female Osborne-Mendel rats, when they were exposed at the concentration of0, 60,100, 200, 400, 600 or 1000mg/kg body weight/day on days 0-19 of gestation by oral gavage.259 female rats were used in the study.  All the animals were observed for Clinical sign and weight daily. Food consumption was observed weekly. Water intake was not measured. The foetuses were grouped by litter for identification. 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 than 70% of the average weight of the concurrent male or female controls was considered tobe a runt. External visceral and sternebral variations were also observed. On day 20 of gestation, the females were examined for gross abnormalities for the last time before being killed by CO2 asphyxiation. Caesarean sections were performed, corpora lutea were counted and the uteri were opened and examined in situ. The uterine positions of all implantation sites were noted and their condition (early or late resorptions, alive or dead foetuses) was determined. Approximately half of the foetuses were examined for skeletal variations after being fixed in alcohol, cleared and stained with Alizarin Red S by a modification of Dawson's method. The remaining foetuses were fixed in Bouin's solution and sectioned according to the method of Wilson in order to detect internal visceral variations. Specific sternebral variation were observed in all fetuses like Incomplete , Bipartite, Missing and Malaligned. Specific soft tissue variation like Hydroureter, Enlarged renal pclvis,Ectopic kidney ,Haemorrhages , Hydrocephalus ,Ectopic/incomplete descended testes ,Ectopic ovary ,Microphthalmia ,Anophthalmia ,Oedema and Defective heart valve were observed .Skeletal variation like 15 rib,l4th rib l3th rib ,l2th rib, Ribs, fused Ribs, wavy ribs, Centra. red. on. Centra, misshapen , Centra, bipartite ,Centra, missing Centra, fused wI dorsal arches ,Vertebrae. missing Caudal oss ibcation ,Dorsal arches, red Dorsal arches, fused Interparietal, red. oss. , Pariewl, red ,Frontal, red oss. ,Nasal red. oss. Supraoccipital, red. Oss, Supraoccipitaf. bipartite Hyoid. Red oss.Squuamosa, red. Zygomatic, red. ms. ,Pubis, red oss. Metacarpals, red. Scapula. red oss. ,Scapula, curved ,Clavicle, misshapen Maxillary, red. oss. were observed .

 

No significant change were observed in body weight at all treated group60, 100, 200, 400 and 600 mg/kg/day compare to control. Except at dose group 1000 mg/kg/day, where body weight increased compare to control. Initial body weight at day 0 and maternal body-weight gain during gestation did not vary significantly between treated and control groups. No significant change were observed in food consumption at all treated group60, 100, 200, 400 and 600 mg/kg/day compare to control. Except at dose group 1000 mg/kg/day, where food consumption increased compare to control. No significant changes were observed in% pregnant rats and %implantation efficiency in all treated group60, 100, 200, 400, 600 and 1000 mg/kg /day compare to control. No significant change were observed in number of implants and number of resorption sites all treated group60, 100, 200, 400, 600 and 1000 mg/kg /day compare to control.

No significant change was observed in the viability for male and female foetuses in all treated group compare to control. No significant changes were observed in the crown rump length of male and female foetuses in all treated group compare to control. No significant changes were observed in the body weight of male and female foetuses in all treated group compare to control. No significant change were observed in Specific sternebral variation all treated group60, 100, 200, 400, 600 and 1000 mg/kg /day compare to control. No significant change was observed in Specific Skeletal variation in all treated group60, 100, 200, 400, 600 and 1000 mg/kg /day compare to control. No significant change were observed in Specific soft tissue variation like Hydroureter, Enlarged renal pclvis, Ectopic kidney ,Haemorrhages , Hydrocephalus ,Ectopic/incomplete descended testes ,Ectopic ovary ,Microphthalmia ,Anophthalmia ,Oedema and Defective heart valve all treated group60, 100, 200, 400, 600 and 1000 mg/kg /day compare to control. Therefore NOAEL was considered to be 1000 mg/kg/day as no significant maternal toxicity was observed at all dose level. No significant change were observed in the clinical sign, body weight, food consumption, reproductive performance (% pregnant rats and %implantation efficiency )and gross pathology of female Osborne-Mendel rats when treated with for Tartrazine (1934-21-0)on days 0-19 of gestation by oral gavage.

Also supported by experimental study conducted by T. F. X. COLLJNS, T. N. BLACK, L. H. BROWN and P. BULHACK (Food Chem Toxic, Vol. 30, No. 4, pp. 263-268, 1992) on structurally similar read across substance Tartrazine(1934-21-0). Developmental toxicity study was observed for Tartrazine(1934-21-0) in female Osborne-Mendel rats, when they were exposed at the concentration of0.05, 0.1, 0.2, 0.4 or 0.7% (67.4, 131.8, 292.4, 567.9 and 1064.3mg/kg/day) on days 0-19 of gestation. They were administered test material by using distilled water as vehicle. Distilled water served as the control. On mating days ,two females were randomly placed in cage with one male at approx. 16.30hr. The following morning, the presence of sperm in the vaginal smear was considered to be evidence of copulation and the sperm positive females were considered to be at day 0 of gestation. Morbidity and mortality were observed daily. Clinical sign and abnormality in behaviour was also observed daily. The rats were weighed and fluid consumption was measured daily. Food consumption was measured weekly. On day 20 of gestation, the females were examined for gross abnormalities for the last time before being killed by CO2 asphyxiation. Caesarean sections were performed and the uterus of each female was opened and examined in situ for the presence and position of resorption sites and fetuses (dead or alive), number of corpora lutea and number of implantation sites. Viability of fetuses, each live fetus was promptly weighed, sexed and examined for gross external malformations, and the crown-rump length was measured. Any fetus that weighed less than 70% of the average weight of the concurrent male or female controls was considered to be a runt. Approximately half of the fetuses were examined for skeletal variations after being fixed in alcohol, cleared and stained with Alizarin Red S by a modification of Dawson's method. The remaining fetuses were fixed in Bouin's solution, serially sectioned according to the method of Wilson and examined for internal visceral variations. Approximately half of the fetuses were examined for skeletal variations after being fixed in alcohol, cleared and stained with Alizarin Red S by a modification of Dawson's method. The remaining fetuses were fixed in Bouin's solution, serially sectioned according to the method of Wilson and examined for internal visceral variations.

 No significant change was observed in behaviour and clinical sign. No mortality was observed .Except one female in the control group of unknown causes during the study. No significant change were observed in body weight of initial maternal body weight at day 0 and weight gain during days 0-20 in all treated group0.05, 0.1, 0.2, 0.4 or 0.7% compare to control. No significant changes were observed in food consumption at all treated group0.05, 0.1, 0.2, 0.4 or 0.7% compare to control. A significant increase in the fluid consumption was observed in all treated group0.05, 0.1, 0.2, 0.4 or 0.7% compare to control. Especially in dose group 0.7% significant increase in the fluid consumption was observed. A significant increase in pregnancy rate was observed in all group compare to control. No significant change were observed in %implantation efficiency in all treated group0.05, 0.1, 0.2, 0.4 or 0.7% compare to control.

Reproductive findings at the time of caesarean sections were unremarkable. Nine litters were totally resorbed, but the resorptions were not related to dosage (0.05%, 1 litter; 0.1%, 3 litters; 0.4%, 2 litters; 0.7%, 3 litters). No significant change was observed in number of implants and number of resorption sites all treated group 0.05, 0.1, 0.2, 0.4 or 0.7% compare to control.

No significant change were observed in the viability for male and female foetuses in all treated group compare to control .Also No significant change were observed in thecrown rump length of male and female foetuses in all treated group compare to control. The body weight of male and female foetuses in all treated group no significant changes were observed compare to control. No significant change were observed in Specific sternebral variation all treated0.05, 0.1, 0.2, 0.4 or 0.7% compare to control and No significant change were observed in Specific Skeletal variation in all treated0.1, 0.2, or 0.7% compare to control. Except in dose level0.05 and 0.4%, this was considered random because they are not dose related. No significant change were observed in the specific soft tissue variation like Hydro-ureter, Enlarged renal pelvis, Haemorrhage, internal Microcephalus ,Hydrocephalus ,Eetopic tongue ,Diaphragmatic hernia ,Polydactyly Adrenal black in all treated group0.05, 0.1, 0.2, 0.4 or 0.7% compare to control .Therefore NOAEL was considered to be 1064.3 mg/kg/day as no dose-related changes were seen in maternal clinical findings, implantations, foetal viability or foetal size (weight and length). Neither visceral development nor skeletal development (sternebral and other skeletal bones) was affected by the Tartrazine. The small numbers of statistically significant increases in skeletal variations in the 0.05 and 0.4% levels are considered random because they are not dose related.When pregnant Osborne-Mendel rats were treated with Tartrazine (1934-21-0) throughout gestation by orally.

It is supported by experimental study conducted by Toyohito Tanaka, Osamu Takahashi, Shinshi Oishi, Akio Ogata (Reproductive Toxicology 26 ,156–163,2008)on structurally similar read across substance Tartrazine(1934-21-0) .A three generation reproductive toxicity study was conducted for Tartrazine(1934-21-0) in(Crlj: CD1 male and female mice. The design of the study was based on the guidelines issued by ICH[12]and OECD[13]adapted for mice The test material was given to male and female mice in the diet at levels of 0 (control), 0.05%, 0.15%, and 0.45%(0, 71.3, 214.9 and 642.8 mg/kg/day)from 5 weeks of age of the F0 generation to 9weeks of age of the F2 generation. 10 males and 10 females in each dose group. Clinical sign, body weight, food consumption, chemical intake, reproductive and neurobehavioral parameters were measured. The litter size or sex ratio at birth, litter weight and viability index of offspring were also observed. No. of females examined, No. of pregnant females, No. of litters No. of offspring, Average litter size, Average litter weight, Total sex ratio (male/female) and Average sex ratio (male %) were also observed. Exploratory behaviour of mice was measured in an animal movement analysing system ANIMATE AT- at 8 weeks of in the F0.

 In parents, movement activity of exploratory behaviour at 8 weeks of age, no variables of measurement showed a significant adverse effect of tartrazine in male and female mice of treated group compare to control. No significant change was observed in the male and female mice during the preconception or mating periods in all treated group compare to control. Even the average body weight of dams showed no significant adverse effect during the gestation or lactation period in treated group compare to control. No significant change was observed in the food consumption of male and female mice during the preconception, mating periods, gestation and lactation period in all treated group compare 0, 0.05%, 0.15%, and 0.45%to control. No significant change was observed in the chemical intake of male and female mice during the preconception, mating periods, gestation and lactation period in all treated group compare 0, 0.05%, 0.15%, and 0.45%to control. Abortion was observed in four dams, one dam each in the 0.05% dose group and 0.15 %dose groups and two dams in the 0.45% dose groups .One dam in the 0.45% dose group killed it’s all offspring during the first week of lactation. One dam in the control (0%) group had not nursed its offspring during the first week of lactation.

 In the F1 generation, In the,0.05%dosed group, the average body weight of male and female offspring was increased significantly throughout the lactation period .In the0.15%dosed group, the average body weight of male offspring was increased significantly at PND 7.In the0.45%dosed group, the average body weight of male offspring was increased significantly at PND 21.No significant change was observed in the male and female mice during the preconception or mating periods in all treated group compare to control in F1 generation.

The average body weight of dams showed no significant adverse effect during the gestation or lactation period in all treated group0, 0.05%, 0.15%, and 0.45% compare to control. No significant change was observed in the food consumption of F1male and female mice during the preconception, mating periods, gestation and lactation period in all treated group compare 0, 0.05%, 0.15%, and 0.45%to control. The development of swimming direction at postnatal day (PND) 7 was accelerated significantly in male offspring in a dose-related manner. Surface righting at PND 7 was affected significantly in female offspring in dose-related manner. Several variables in exploratory behaviour showed significant tendencies to be affected in the treatment groups in male offspring at 3 weeks of age.

 In the F2 generation, In the 0.05% dosed group, the average body weight of female offspring was affected significantly at birth and was increased significantly at PNDs 14 and 21, and that of male offspring was increased significantly at PNDs 7, 14 and 21. In 0.15% dosed group, the average body weight of male offspring was increased significantly throughout the lactation period, and that of female offspring was increased significantly at PNDs 7, 14 and 21. There was no sex-related difference in average body weight during the lactation period. No significant change was observed in the food consumption of F2male and female mice during the preconception, mating periods, gestation and lactation period in all treated group compare 0, 0.05%, 0.15%, and 0.45%to control. No significant change was observed in the chemical intake of F2male and female mice during the preconception, mating periods, gestation and lactation period in all treated group 0,0.05%, 0.15%, and 0.45%compareto control. The development of swimming direction at PND 7was accelerated significantly in the 0.45%dosed group in male offspring. Time taken of olfactory orientation at PND 14 was accelerated significantly in male offspring in a dose-related manner. Several variables in exploratory behaviour showed significant tendencies to be affected in the treatment groups in male offspring at 3 weeks of age, and in males at 8 weeks of age. The dose levels of tartrazine in the present study produced a few adverse effects on neurobehavioral parameters throughout generations in mice .But no adverse effect were observed on reproductive parameter in all generations of (Crlj: CD1 male and female mice in all treated group 0,0.05%, 0.15%, and 0.45% compare to control. Therefore NOAEL was considered to be 642.8 mg/kg/day (0.45%) for Tartrazine(1934-21-0) in both P and F1 generation (Crlj: CD1 male and female mice for reproductive toxicity effect.

 Thus based on the above results it can be concluded that the substance CAS: 12225-21-7 is expected to show the similar toxicological effect based on the effects observed in structurally similar read across substance Tartrazine(1934-21-0). Since no effective dose value (NOAEL) is reported to be 1000 mg/kg orally. Also there are no known evidence of adverse effect on development in human of CAS: 12225-21-7. Thus, comparing this value with the criteria of CLP regulation aluminium tris(4-{[3-carboxy-5-oxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazol-4-yl]diazenyl}benzenesulfonate) (12225-21-7) can be "Not classified" for developmental toxicity.

 

Justification for classification or non-classification

Thus, comparing this value with the criteria of CLP regulation aluminium tris(4-{[3-carboxy-5-oxo-1-(4-sulfophenyl)-4,5-dihydro-1H-pyrazol-4-yl]diazenyl}benzenesulfonate) (12225-21-7) cannot be classified as reproductive and developmental toxicant.