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EC number: 235-428-9 | CAS number: 12225-21-7 This substance is identified in the Colour Index by Colour Index Constitution Number, C.I. 19140:1.
- Life Cycle description
- Uses advised against
- Endpoint summary
- Appearance / physical state / colour
- Melting point / freezing point
- Boiling point
- Density
- Particle size distribution (Granulometry)
- Vapour pressure
- Partition coefficient
- Water solubility
- Solubility in organic solvents / fat solubility
- Surface tension
- Flash point
- Auto flammability
- Flammability
- Explosiveness
- Oxidising properties
- Oxidation reduction potential
- Stability in organic solvents and identity of relevant degradation products
- Storage stability and reactivity towards container material
- Stability: thermal, sunlight, metals
- pH
- Dissociation constant
- Viscosity
- Additional physico-chemical information
- Additional physico-chemical properties of nanomaterials
- Nanomaterial agglomeration / aggregation
- Nanomaterial crystalline phase
- Nanomaterial crystallite and grain size
- Nanomaterial aspect ratio / shape
- Nanomaterial specific surface area
- Nanomaterial Zeta potential
- Nanomaterial surface chemistry
- Nanomaterial dustiness
- Nanomaterial porosity
- Nanomaterial pour density
- Nanomaterial photocatalytic activity
- Nanomaterial radical formation potential
- Nanomaterial catalytic activity
- Endpoint summary
- Stability
- Biodegradation
- Bioaccumulation
- Transport and distribution
- Environmental data
- Additional information on environmental fate and behaviour
- Ecotoxicological Summary
- Aquatic toxicity
- Endpoint summary
- Short-term toxicity to fish
- Long-term toxicity to fish
- Short-term toxicity to aquatic invertebrates
- Long-term toxicity to aquatic invertebrates
- Toxicity to aquatic algae and cyanobacteria
- Toxicity to aquatic plants other than algae
- Toxicity to microorganisms
- Endocrine disrupter testing in aquatic vertebrates – in vivo
- Toxicity to other aquatic organisms
- Sediment toxicity
- Terrestrial toxicity
- Biological effects monitoring
- Biotransformation and kinetics
- Additional ecotoxological information
- Toxicological Summary
- Toxicokinetics, metabolism and distribution
- Acute Toxicity
- Irritation / corrosion
- Sensitisation
- Repeated dose toxicity
- Genetic toxicity
- Carcinogenicity
- Toxicity to reproduction
- Specific investigations
- Exposure related observations in humans
- Toxic effects on livestock and pets
- Additional toxicological data
Endpoint summary
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
- 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
- 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 or test system 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
- 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
- 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.
Reference
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
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.
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Link to relevant study records
- 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
- 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 or test system and environmental conditions:
- Details on test animal
TEST 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 polycarbonate
Solid-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 week
ENVIRONMENTAL 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 by
HPLC. 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-80
0 mg/kg bw/day -10 male and 10 female
71.3 mg/kg bw/day -10 male and 10 female
214.9 mg/kg bw/day -10 male and 10 female
642.9 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 data
Litter 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 effects
Details 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.
Reference
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.
Additional information
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