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EC number: 915-586-1 | CAS number: -
- 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
Repeated dose toxicity: oral
Administrative data
- Endpoint:
- short-term repeated dose toxicity: oral
- Type of information:
- experimental study
- Adequacy of study:
- key study
- Study period:
- 20 November 2018 to 29 July 2019
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- guideline study
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 019
- Report date:
- 2019
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
- Version / remarks:
- OECD 422 Guideline for testing of chemicals adopted 29.07.16: Combined repeated dose toxicity study with the reproduction/developmental toxicity screening test.
- Deviations:
- yes
- Remarks:
- See "Any other information" for details
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- Reaction mass of 2,4-bis(xylylazo)resorcinol and 2,4-bis[(4-dodecylphenyl)azo]resorcinol and 2-[(4-dodecylphenyl)azo]-4-(2,4-xylylazo)resorcinol
- EC Number:
- 915-586-1
- Molecular formula:
- Variable; substance is a UVCB.
- IUPAC Name:
- Reaction mass of 2,4-bis(xylylazo)resorcinol and 2,4-bis[(4-dodecylphenyl)azo]resorcinol and 2-[(4-dodecylphenyl)azo]-4-(2,4-xylylazo)resorcinol
- Test material form:
- liquid: viscous
- Details on test material:
- Identification: Solvent yellow 175
Batch Number: TE2245
EC Number: 915-586-1
Purity: 100% (UVCB*)
Physical State/Appearance: Black viscous liquid with orange tinge
Expiry Date: 06 September 2020
Storage Conditions: Room temperature, in the dark
Constituent 1
- Specific details on test material used for the study:
- No further details specified in the study report.
Test animals
- Species:
- rat
- Strain:
- Wistar
- Details on species / strain selection:
- Recognized by international guidelines as a recommended test system.
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Species: Hannover Wistar Rat (HsdHan®:WIST)
Supplier: Envigo RMS, S.L.
Breeder: Envigo RMS B.V., Kreuzelweg 53, 5961 NM Horst, Netherlands
Total number of animals ordered 44: males and 48 females
Total number of animals in the study: 40 males and 40 females (80 in total). In addition, 4 spare males and 8 spare females. Each group started with 10 males and 10 females per group.
Age (at treatment start): Males: 9 to 10 weeks; Females: 10 to 12 weeks
Body-weight range (at treatment start): Males: 288-347 g; Females: 192-227 g
Identification
- Acclimatization: F0 => Cage card and ear tattoo
- Treatment: F0 => Cage card and individual ear tattoo; F1 offspring – Back mark (animals were observed daily together with pup status and the back mark was checked)
Randomization: Method based on the similarity of mean body weights among groups. Before treatment starts and after the estrous cycle examination done during pre-treatment, females number 74 and 103 that did not show 4-5 day cycles were replaced with those females available from the spare group that most closely resemble their body weight.
Allocation: The animals were allocated at random to four treatment groups. Spare animals were used and/or animals were exchanged. The rejected animals took no further part in the study after commencement of treatment.
Animal Care
Acclimatization: From five days after arrival and pre-treatment start. After acclimatization period, the animals were subjected to a pre-test period.
Veterinary examination: During acclimatization (at arrival), the animals were examined by a veterinary surgeon. Only animals without any visible signs of illness were used for treatment. Before treatment start, the animals were not inspected due to an oversight and as a consequence, a veterinary inspection was done on treatment day 2 in order to confirm their health status.
Additional inspections were done to those animals showing signs of toxicity before their sacrifice in order to determine their health status.
Environmental enrichment program: Different types of material specific to this species were supplied to reduce stress, enhance wellbeing and improve behavior.
Husbandry
Room number: 3 and 111
Conditions: Optimum hygienic conditions behind a barrier system: air-conditioned with a minimum of 15-20 air changes per hour, and continuously monitored environment with ranges for temperature of 20-24 ºC and for relative humidity between 35 and 60%. 12 hours fluorescent light/12 hours dark.
Accommodation: Cages with standard, granulated, S8-15 sawdust bedding (J. Rettenmaier & Söhne)
Premating period (maximum 5 animals/cage) Makrolon type-IV cages
Mating period (one male and one female/cage) Makrolon type-III cages
Postmating, gestation and lactation periods (individual) Makrolon type-III cages
Diet: Pelleted standard Teklad 2014C rat/mouse maintenance diet ad libitum (supplied by Envigo RMS, S.L.). Pelleted standard Teklad 2018C rat/mouse maintenance diet (supplied by Envigo RMS, S.L.) ad libitum, for lactating females and pups (until sacrifice).
Water: Tap water in bottles ad libitum.
Administration / exposure
- Route of administration:
- oral: gavage
- Details on route of administration:
- Oral gavage was used as the administration route as recommended by the OECD 422 guideline, in order to deliver accurate doses. In addition, oral ingestion is a possible route of human exposure to the test item.
- Vehicle:
- corn oil
- Details on oral exposure:
- Vehicle
Identification: Corn oil
Supplier: Sigma-Aldrich
Reference: C8267
Batch number: MKBW9504V MKCG3257
Expiry date (retest date): 11 January 2019 14 December 2020, 16 January 2021 (2 years from the date of opening of the container)
Storage conditions: Stored at ambient conditions (20 ± 5ºC)
Safety precautions: Routine hygienic procedures (nitrile gloves, goggles, facemask)
Test Item Preparation and Analysis
Formulation
Group 1: Vehicle control
Group 2: Solvent Yellow 175; 20 mg/mL
Group 3: Solvent Yellow 175; 60 mg/mL
Group 4: Solvent Yellow 175; 200 mg/mL
Dose volume: 5 mL/kg/day
Concentration range to be validated: 1 mg/mL to 200 mg/mL
Frequency of dose formulation preparation: No more than 7 days between preparation and administration based on stability data.
Storage of dose formulations: At room temperature (20 ± 5 ºC) and in the absence of light.
Stability of dose formulations: At room temperature (20 ± 5 ºC) and in the absence of light for 8 days.
Safety precautions: Safety precautions were taken according to the test item hazard class and the results of the risk assessment
Method of Preparation
Aliquoting of test item
1) The container with the test item (in its original container) was immerse in a water bath, and the test item was heated to 70-80 ºC until it become liquid.
2) The test item only allows two heating cycles.
3) The density of the test item was calculated.
4) The test item was aliquoted for each preparation day in single-use containers.
5) Aliquots were stored at 20 ± 5 ºC until use.
Formulation preparation (High Concentration / Dose)
1) The aliquot containing the test item (weighed in advance and stored under the same conditions as the test item) was taken.
2) The required amount of corn oil was added at room temperature.
3) The formulation was heated to 60-70 ºC until the mixture was homogenous (the time spent, temperature and the equipment used were recorded in the raw data).
4) The formulation net weight was recorded.
5) Formulation was mixed using a magnetic stirrer during 10 minutes. A sample, when necessary, was taken at this point.
6) The rest of the formulations were prepared by dilution in a descending order of concentration.
Formulation dilution:
1) The requested volume of the most concentrated formulation was taken and diluted with vehicle to obtain the final volume and the desired concentration.
2) Formulations were then mixed using a magnetic stirrer during 10 minutes. A sample, when necessary, was taken at this point.
3) Formulations were maintained under agitation before (in Animal House) and during administration in order to assure a homogenous suspension.
When dose formulations were prepared to be administered over several days, the stock formulation was mixed for 10 minutes at room temperature before dividing it into the aliquots required.
Formulations or aliquots of dose formulations were stored at room temperature (20 ± 5 ºC).
NOTE: test item and vehicle density were not taken into account for formulations preparation. - Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analytical method Before commencement of treatment, an analytical method (M0384_HPLC_DFA_Solvent Yellow 175_Formulation_Vehicle_ISV) was validated in the present study. Formulations at two concentration levels (target concentrations: 1 and 200 mg/mL) were prepared and the following parameters were determined:
• System suitability (SST)
• Linearity
• Accuracy/repeatability
• Homogeneity
• Specificity
• Limit of Quantification (LOQ) and Limit of Detection (LOD)
• Stability [autosampler, formulations (20 ± 5 ºC, in the absence of light, for 8 days)]
This method also includes the procedure followed and the acceptance criteria for the analysis of administered formulations.
Analysis of the formulations administered: The formulations prepared at three different concentrations were analyzed twice over the course of the study to verify its correct preparation - Duration of treatment / exposure:
- Males: 2 weeks before pairing up to necropsy after a minimum of 5 weeks
Females: 2 weeks before pairing, then throughout pairing and gestation until days 13-15 of lactation (until the day before sacrifice) - Frequency of treatment:
- Once daily
- F0 males: Two weeks prior to mating start until the day before sacrifice (for five weeks of dosing). They were then killed.
- F0 females: Two weeks prior to mating start until day 13/15 of lactation, including the day before sacrifice.
Doses / concentrationsopen allclose all
- Dose / conc.:
- 0 mg/kg bw/day (nominal)
- Dose / conc.:
- 100 mg/kg bw/day (nominal)
- Dose / conc.:
- 300 mg/kg bw/day (nominal)
- Dose / conc.:
- 1 000 mg/kg bw/day (nominal)
- No. of animals per sex per dose:
- 20 animals per dose group (10 male/10 female)
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- Dose levels The doses were chosen based on the preliminary results obtained in non-GLP Study RN78JF 14-day Oral (Gavage) Dose-Range Toxicity Study for OECD 422 conducted at Envigo CRS, S.A.U.
As no toxicity was obtained at the administered doses in RN78JF, then:
- The high dose was selected as no toxicity was observed in the preliminary study at 1000 mg/kg/day and considering it as a limit dose to be tested.
- Intermediate and low dose levels were selected considering approximately a 3-fold interval between doses. - Positive control:
- Not required for the study.
Examinations
- Observations and examinations performed and frequency:
- Serial Observations/Measurements
The observations listed below were recorded.
Additional observations and examinations were performed on animals judged to be in extremis, or showing signs of ill health or unusual findings.
Viability / Mortality / Cage-side Observations
Animals and their cages: Visually inspected twice daily for evidence of reaction to treatment or ill-health.
Blood sampling for hematology or blood chemistry analysis were not performed on animals that died or were sacrificed prematurely.
Body Weight
Detailed in table for. See “any other information” for details.
Food Consumption
Detailed in table for. See “any other information” for details.
Clinical Signs
Detailed in table for. See “any other information” for details.
Sensory Reactivity and Grip Strength
Detailed in table for. See “any other information” for details.
Motor Activity
Detailed in table for. See “any other information” for details.
In-life Sampling and Analysis
Hematology, Peripheral Blood
Conditions: Males and females were deprived of food from 6-8 hours before blood extraction. Pups were removed from the dam the day before this procedure.
Samples were collected under light general anesthesia.
Anesthetic: Isoflurane.
Sample site: Retro-orbital sinus
Anticoagulant/Sample volume: EDTA/0.5 mL; Citrate/0.5 mL
Routine hematology parameters are measured by the Advia 120. Coagulation parameters are measured using a STA Compact.
All samples were examined for the following characteristics, when possible:
Using EDTA as anticoagulant
Hematocrit (Hct); Hemoglobin concentration (Hb); Erythrocyte count (RBC); Absolute reticulocyte count (Retic); Total leucocyte count (WBC) Differential leucocyte count (N: neutrophils, L: lymphocytes, E: eosinophils, B: basophils, M: monocytes, LUC: large unstained cells); Platelet count (Plt); Mean cell haemoglobin (MCH); Mean cell volume (MCV); Mean cell hemoglobin concentration (MCHC)
Using citrate as anticoagulant
Prothrombin time (SPT); Activated partial thromboplastin time (SAPT)
Blood Chemistry
Conditions: Males and females were deprived of food from 6-8 hours before blood extraction.
Samples collected under light general anesthesia.
Anesthetic: Isoflurane
Sample site: Retro-orbital sinus
Anticoagulant/Sample volume: Lithium heparin/0.8 mL
Routine biochemistry parameters were measured using the Cobas 6000 analyzer.
Electrophoretic parameters were performed by HYDRASIS LC from Sebia.
The albumin/globulin ratio was derived from the total protein value from the Cobas 6000 and the albumin value generated by the HYDRASYS LC from Sebia.
All samples were examined for the following characteristics:
Using lithium heparin as anticoagulant
Alkaline phosphatase (ALP); Alanine amino-transferase (ALT); Aspartate amino-transferase (AST); Glucose (Gluc); Bilirubin – total (Bili); Cholesterol – total (Chol); HDL; LDL; Triglycerides (Trig); Creatinine (Creat); Creatine kinase (CK); Urea; Total protein (Total Prot); Albumin (Alb); Albumin/globulin ratio; Protein electrophoretogram; Sodium (Na); Potassium (K); Chloride (Cl); Calcium (Ca); Phosphorus (Phos); Bile acids (Bi Ac) - Sacrifice and pathology:
- Necropsy
F0 Males: After final investigations completed (after 5 weeks of treatment)
F0 Females failing to produce viable litter (not pregnant): Day 25-26 after mating
F0 Females whose litters die before Day 13: On or after day last offspring dies
Females killed at Termination: Day 14-16 of lactation
Note: All animals that exhibit signs of undue stress or discomfort as judged by the animal welfare officer and study director were sacrificed immediately for ethical reasons. The Sponsor was informed. The reason for sacrifice is included in the report.
Method of Sacrifice
All surviving F0 animals: By intraperitoneal injection of sodium pentobarbital. Each animal will be subsequently exsanguinated.
Organ Weights
Detailed in table form. See “Any other information”-Pathological parameters.
Data collection: For bilateral organs, left and right organs were weighed together. Organ weights were not recorded for animals sacrificed prematurely.
Macroscopic Pathology
Detailed in table form. See “Any other information”-Pathological parameters.
Blood sampling required: specific details are included in this section as regards animals from which samples are required for the analysis of thyroid hormone levels (see Thyroid Hormone Analysis). Blood samples are also required at termination from specific adult animals for the evaluation of hematology and blood chemistry parameters and details relating to these examinations are included in Hematology, Peripheral Blood and Blood Chemistry of report.
Premature decedents (Sacrificed for Welfare Reasons): females 90 and 91 at 300 mg/kg/day and females 101 and 109 at 1000 mg/kg/day
Checks: retained tissues
Scheduled termination
F0 animals (five males and five surviving lactating females with a surviving litter per group): Blood sampling required from all males and females (see Thyroid Hormone Analysis).
Complete necropsy: all animals.
Checks: retained tissues.
Number of uterine implantation sites counted and checked.
Remaining F0 males and females / Females not pregnant/ fail to litter and litter death: Limited list.
Checks: retained tissues.
Number of uterine implantation sites counted and checked.
For females whose litter dies or those in which the whole litter needs was sacrificed because female was not taking maternal care: including evaluation of mammary tissue.
Fixation
Detailed in table form. See “Any other information”-Pathological parameters.
Fixatives: Standard - 10% Neutral Buffered Formalin. Testes and epididymides: Initially in modified Davidson’s fixative. Eyes: Davidson’s fixative.
Histology
Detailed in table form. See “Any other information”-Pathological parameters.
Processing - Full list: All adult animals sacrificed or dying prematurely (sacrificed for welfare reasons) from groups 1, 3 and 4. The five males selected in Groups 1 and 4 and five lactating females with a surviving litter selected in Groups 1 and 3 and the two females sacrificed at the end of the study in Group 4, at scheduled termination.
Processing – Abnormalities only: All adult animals
Routine staining: Stained with hematoxylin and eosin, except testes which are also stained with periodic acid-Schiff, according to Envigo CRS, S.A.U. internal SOPs.
Special staining: None
Extension of Initial Examination: The five F0 males selected in Groups 2 and 3: thyroids, kidneys and thymus. The five F0 lactating females with a surviving litter selected in Group 2: thymus, cecum and stomach. - Other examinations:
- Thyroid Hormone Analysis
Sequence of blood sampling on each occasion: In order to minimize any effect of the time of day on blood sampling, the samples were obtained within a comparable range of time according to the organization of the laboratory, thus allowing satisfactory comparisons between the groups.
Conditions: Following 6-8 hours of deprivation of food (except animals sacrificed for welfare reasons and those not confirmed to be not pregnant until necropsy, which were not fasted)
Anesthetic: Isoflurane
Sample site: retro-orbital sinus
Sample Identification
Primary tube
Kind of sample (blood); Study Number; Animal / Litter identification / Sex; Date of sampling; Day of extraction (At term /Lactation day 4 / Lactation day 13; Group of treatment; Aliquot number (1/1)
Secondary tube
Kind of sample (serum T4 / plasma TSH); Study Number; Animal / Litter identification / Sex; Date of sampling; Day of extraction (At term / Lactation day 4/ Lactation day 13; Group of treatment; Aliquot number (1/2 and 2/2)
Separation and storage: Centrifugation at 4 ºC for 10 minutes at 2000 g.
All available plasma/serum was transferred to appropriately labelled polypropylene cryotubes using plastic disposable pipettes.
The plasma/serum samples were stored at -80 ± 10 ºC, pending analysis.
Samples were sent in dry ice to the responsible scientist for their analysis.
Total number of samples: Terminal samples: 80 per parameter, 160 in total
Total: 114
Analysis: Samples from adult males were assessed for Thyroxine (T4) levels.
Sampling started on 22 January 2019 and analysis ended on 28 February 2019.
Method Thyroxine (T4)
Bioanalysis
Serum samples were analyzed at Envigo CRS, S.A.U. according to method
M0333_HPLC_BA_T4T3_Rat_Serum_Samples validated in Envigo GLP Study
SN83QL Thyroxine T4 / Triiodothyronine T3: Validation of an LC-MS/MS
Bioanalytical Method in Rat Serum and re-validated in Envigo GLP Study
NN19MX Thyroxine T4 / Triiodothyronine T3: Revalidation of an LC MS/MS
Bioanalytical Method in Rat Serum and cross validated in Envigo GLP Study
WF90VR 3,3,5’-Triiodo-L-Thyronine (T3) and Thyroxine (T4): Cross Validation of a Bioanalytical Method for the Determination of the Biomarker 3,3,5’-Triiodo-L-Thyronine (T3) and Thyroxine (T4) in Rat Serum using Liquid Chromatography with Tandem Mass Spectrometric Detection (LC-MS/MS).
GLP Study FF58YR (carried out at Envigo CRS Limited, UK) investigates the stability of samples for a storage period of up to one year. To date, T4 stability has been proven for 387 days at -70 ± 10 ºC.
Results and discussion
Results of examinations
- Clinical signs:
- effects observed, treatment-related
- Description (incidence and severity):
- There were no other signs of evident toxicity based on clinical signs in the surviving animals. Dark feces and yellow urine were considered related to the test item color.
Salivation recorded during the administration period was related to taste aversion (from gavage dosing) - Mortality:
- mortality observed, treatment-related
- Description (incidence):
- No mortality was recorded among males. However, two females at 300 mg/kg/day and another two at 1000 mg/kg/day were sacrificed for welfare reasons between gestation days 22 and 23, showing signs of difficulty during parturition. In addition, one female at 100 mg/kg/day, three females at 300 mg/kg/day and six females at 1000 mg/kg/day were sacrificed as they lost their corresponding litters during late gestation and early lactation phases.
- Body weight and weight changes:
- no effects observed
- Description (incidence and severity):
- No effects were observed in body weight.
- Food consumption and compound intake (if feeding study):
- no effects observed
- Description (incidence and severity):
- No effects were observed in food consumption.
- Food efficiency:
- not examined
- Water consumption and compound intake (if drinking water study):
- not examined
- Ophthalmological findings:
- not examined
- Haematological findings:
- effects observed, non-treatment-related
- Description (incidence and severity):
- There were no effects on coagulation. The decrease observed in mean hematocrit, hemoglobin, red blood cells and the corresponding increase in reticulocytes observed in the test-item-administered males was considered not relevant based on the fact that they were within the historical control data and/or there was no dose-effect relation.
- Clinical biochemistry findings:
- no effects observed
- Description (incidence and severity):
- There were no relevant effects on biochemistry, considering that all statistically significant mean values observed in biochemistry were within the historical control data.
- Urinalysis findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Description (incidence and severity):
- There were no relevant effects on behavioral parameters (sensory reactivity, grip strength and motor activity).
- Immunological findings:
- not examined
- Organ weight findings including organ / body weight ratios:
- effects observed, treatment-related
- Description (incidence and severity):
- In males, adjusted epididymides, liver and thyroids and parathyroids weights were higher than in Controls. These differences were not dose-related and were within/close to that observed in the historical control range.
A dose-related trend towards a decrease in adjusted thymus weight was observed. Significant differences were observed at 300 and 1000 mg/kg/day.
Adjusted uterus, cervix and oviducts weight in females was higher than in Controls in all test item-administered groups (100, 300 and 1000 mg/kg/day), attaining statistical significance with respect to Control at 300 and 1000 mg/kg/day. Differences were dose-related.
At 1000 mg/kg/day, mean adjusted brain weight was found to be statistically higher than that recorded in the Control group. However, based on the fact that the mean value corresponds to a sample size of only two females in the group, it cannot be considered relevant. - Gross pathological findings:
- effects observed, treatment-related
- Description (incidence and severity):
- The macroscopic examination performed 5-8 weeks after treatment revealed the following changes in the stomach, cecum, thymus and kidneys of treated females.
Stomach: A small dark area in the nonglandular mucosa was noted in a female receiving 1000 mg/kg/day.
Cecum: A small cecum was seen in a female receiving 1000 mg/kg/day.
Thymus: A small thymus was seen in some females receiving 1000 mg/kg/day. Only one female given 100 mg/kg/day showed a similar change.
Kidneys: Pale kidneys were seen in a female given 1000 mg/kg/day.
Yellow coloration of the adipose tissue and/or gastric mucosa in treated animals (all male dose groups and high dose group females) were attributed to the test item color.
All the other gross findings were considered to be incidental and unrelated to the test item. A small spleen was noted in a female receiving 1000 mg/kg/day. However, it was not available for histological examination. - Neuropathological findings:
- not examined
- Histopathological findings: non-neoplastic:
- effects observed, treatment-related
- Description (incidence and severity):
- Changes that were considered to be related to treatment with the test item were seen in male thyroids and kidneys, female stomach and cecum, and thymus of both males and females.
Thyroid glands: Minimal hypertrophy of follicular cells was seen in three of the examined males given 1000 mg/kg/day, in one male given 300 mg/kg and in one male given 100 mg/kg.
Kidneys: An increased incidence and severity of hyaline droplet accumulation was detected in the kidneys of males given 1000 mg/kg/day compared with controls.
Stomach: A minimal focal erosion of the glandular stomach was seen in one female given 1000 mg/kg.
Cecum: Moderate regenerative hyperplasia of the crypts along with minimal apoptosis were seen in one female given 1000 mg/kg.
Thymus: Minimally to slightly decreased cortical/medullary cellularity was noted in the thymus of some of the examined males given 300 or 1000 mg/kg/day.
This change was also seen in all treated female groups, with a higher incidence and severity at 1000 mg/kg (minimal to severe) compared with the corresponding males and lower dose females. At 100 or 300 mg/kg, it was of minimal severity. In one of the examined females given 100 mg/kg where a smaller thymus was seen at necropsy, no tissue was present at microscopic examination.
In the single female given 1000 mg/kg where no decreased cellularity was detected, there was a minimal degree of cortical/medullary lymphocyte apoptosis.
Findings of an Uncertain Relationship to Treatment: Changes that were of unclear relationship to treatment with the test item were seen in female kidneys.
Kidneys: One of the examined females receiving 1000 mg/kg showed marked multifocal acute/subacute necrosis of cortical and, to a lesser extent, medullary tubules, along with marked multifocal tubular basophilia. - Histopathological findings: neoplastic:
- not examined
- Other effects:
- effects observed, non-treatment-related
- Description (incidence and severity):
- All other histological findings were considered to be incidental and unrelated to the test item.
A minimal increase in adipocytes was seen in the bone marrow of one of the examined males given 1000 mg/kg/day compared with controls. However, given its isolated occurrence and in the lack of changes in the spleen, it was considered to be most probably incidental, as a result of normal individual variation.
An increased mucification of the cervix and the vagina occurred in a single of the examined females, which was given 300 mg/kg. This correlated with increased organ weights of this specific animal, and was considered to be incidental.
In the testes, seminiferous tubules were evaluated with respect to their stage in the spermatogenic cycle and the integrity of the various cell types present within the different stages. No cell or stage-specific abnormalities were noted in the examined males treated at 1000 mg/kg/day.
Effect levels
- Key result
- Dose descriptor:
- NOAEL
- Effect level:
- 100 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- histopathology: non-neoplastic
- mortality
Target system / organ toxicity
- Key result
- Critical effects observed:
- not specified
- Lowest effective dose / conc.:
- 100 mg/kg bw/day (nominal)
- System:
- gastrointestinal tract
- Organ:
- oesophagus
- parathyroid gland
- stomach
- thymus
- thyroid gland
Any other information on results incl. tables
F0 Body weight – Males – group mean values (g)
|
Control |
Solvent Yellow 175 |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
Group /Sex |
|
Day |
Day |
||||||
P1 |
P8 |
1 |
8 |
15 |
22 |
29 |
36 |
||
Statistics test |
Av |
Av |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
|
1M |
Mean SD N |
260.7 4.93 10 |
287.7 8.49 10 |
315.3 11.62 10 |
334.5 15.74 10 |
351.6 6.65 10 |
366.0 16.78 10 |
382.4 18.13 10 |
391.8 15.96 10 |
2M |
Mean SD N % of 1M |
262.9 9.36 10 101 |
290.4 9.46 10 101 |
319.0 14.48 10 101 |
334.6 15.84 10 100 |
350.4 20.39 10 100 |
364.1 22.34 10 99 |
377.9 26.57 10 99 |
386.7 27.96 10 99 |
3M |
Mean SD N % if 1M |
261.8 13.22 10 100 |
286.9 14.42 10 100 |
317.5 18.88 10 101 |
333.3 22.87 10 100 |
351.6 23.31 10 100 |
363.8 24.91 10 99 |
382.1 26.85 10 100 |
391.3 28.85 10 100 |
4M |
Mean SD N % of 1M |
261.8 9.56 10 100 |
290.3 11.95 10 101 |
317.9 14.47 10 101 |
337.2 17.83 10 101 |
356.2 20.21 10 101 |
370.0 22.57 10 101 |
387.1 27.40 10 101 |
398.7 29.50 10 102 |
F0 Body weight – Pregnant Females – group mean values (g)
|
Control |
Solvent Yellow 175 |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
Group /Sex |
|
Day |
Day |
|
Day |
Day |
|
|
|
Day |
|
|
|
P1 |
P8 |
1 |
8 |
1 |
0 |
7 |
14 |
20 |
1 |
4 |
13 |
||
Statistics test |
Av |
Av |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
|
1F |
Mean SD N |
184.2 5.05 9 |
197.8 6.63 9 |
210.0 8.45 9 |
216.9 10.33 9 |
226.6 10.97 |
225.3 10.97 9 |
250.4 14.04 9 |
284.4 14.35 9 |
337.5 17.28 9 |
251.3 19.18 9 |
266.9 17.11 9 |
298.9 11.67 |
2F |
Mean SD N % of 1F |
187.1 6.85 9 102 |
202.5 7.61 9 102 |
214.1 7.90 9 102 |
217.1 6.31 9 100 |
227.0 6.94 9 100 |
231.1 6.40 9 103 |
257.9 5.51 9 103 |
283.1 6.87 9 100 |
329.5 11.77 9 98 |
247.2 17.40 9 98 |
268.5 10.05 8 101 |
287.3 12.78 8 96 |
3F |
Mean SD N % if 1F |
185.0 8.20 10 100 |
198.5 7.08 10 100 |
211.6 8.63 10 101 |
217.6 8.48 10 100 |
228.8 9.22 10 101 |
229.0 9.84 10 102 |
253.4 1.47 10 101 |
279.6 9.19 10 98 |
326.8 12.97 10 97 |
256.8 12.68 8 102 |
270.4 6.70 5 101 |
288.5 6.74 5 96 |
4F |
Mean SD N % of 1F |
184.9 7.24 10 100 |
196.6 9.02 10 99 |
211.8 10.62 10 101 |
219.2 11.13 10 101 |
229.9 8.53 1 101 |
231.4 8.97 10 103 |
256.4 10.73 10 102 |
279.4 14.73 10 98 |
326.5 10.23 10 97 |
237.4 24.10 6 94 |
271.6 12.96 3 102 |
286.9 2.53 2 96 |
F0 Cage signs – Males – group distribution of observations
|
Control |
Solvent Yellow 175 |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
Category |
Observation |
Day |
|
Number of animals affected |
|||
Group/Sex: Initial no: |
1M 10 |
2M 10 |
3M 10 |
4M 10 |
|||
Normal
Excreta
Excreta |
Within normal limits
Feces abnormal color, Dark
Urine abnormal color, Yellow |
P1 P2 P3 P4 P5 P5 P7 P8 P9 P10 P11 P12 P13 P14 P15 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37
3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 |
|
10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 5
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 |
10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 5
8 8 8 9 9 9 9 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 5 |
10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 5
9 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 5 |
10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 5
10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 5 |
F0 Cage signs – Pregnant Females – Pre-test/Treatment – group distribution of observations
|
Control |
Solvent Yellow 175 |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
Category |
Observation |
Day |
|
Number of animals affected |
|||
Group/Sex: Initial no: |
1F 9 |
2F 9 |
3F 10 |
4F 10 |
|||
Normal
Excreta
Excreta
Excreta |
Within normal limits
Feces abnormal color, Dark
Urine abnormal color, White
Urine abnormal color, Yellow |
P1 P2 P3 P4 P5 P5 P7 P8 P9 P10 P11 P12 P13 P14 P15 1 2 3 4 5 6 7 8 9 10 11 12 13 14
3 4 5 6 7 8 9 10 11 12 13 14
3 4 5 6 7 8 9 10
3 4 5 6 7 8 9 10 11 12 13 14 |
|
9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9
0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 |
9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 9 0 0 0 0 0 0 0 0 0 0 0
9 9 9 9 9 9 9 9 9 9 9 9
0 0 0 0 0 0 0 0
9 9 9 9 9 9 9 9 9 9 9 9 |
10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 0 0 0 0 0 0 0 0 0 0 0
10 10 10 10 10 10 10 10 10 10 10 10
1 1 1 1 1 1 1 1
9 9 9 9 9 9 9 10 10 10 10 10 |
10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 10 0 0 0 0 0 0 0 0 0 0 0
10 10 10 10 10 10 10 10 10 10 10 10
0 0 0 0 0 0 0 0
10 10 10 10 10 10 10 10 10 10 10 10 |
F0 Detailed signs – Males – group distribution of observations
|
Control |
Solvent Yellow 175 |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
Category |
Observation |
Day |
|
Number of animals affected |
|||
Group/Sex: Initial no: |
1M 10 |
2M 10 |
3M 10 |
4M 10 |
|||
Normal
Behavior
Build (Deformity)
Coat
Skin
Skin color |
Within normal limits
Salivation
Swollen area, Forelimb digit(s)
Hair loss, Dorsal surface
Encrustation, Upper dorsal surface
Abnormal color, Blue, Forelimb – right |
P1 P8 1 8 12 13 15 22 25 28 29 30 31 32 33 34 35 36
12 13 25 28 30 31 32 33 34 35 36
7 8 15 22 29 36
3 8 9 13 15 22 25 29 32 33 35 36
3 8 9 13 15 22 25 29 30 31 32 33 34 35 36
7 8 15 22 29 36 |
|
10 10 10 10 0 0 10 10 0 0 10 0 0 0 0 1 0 9
0 0 0 0 0 0 0 0 1 0 0
0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 0 |
10 10 10 10 0 0 9 9 0 0 9 0 0 0 1 2 1 9
0 0 0 0 0 0 0 0 1 1 2
0 0 0 0 0 0
0 0 1 0 1 1 0 1 0 0 0 1
0 0 1 0 1 1 0 1 0 0 0 0 0 0 1
0 0 0 0 0 0 |
10 10 10 9 0 0 9 8 3 0 8 0 5 6 2 0 4 8
0 0 4 0 1 6 7 3 4 3 1
1 1 1 1 1 1
0 0 0 0 0 0 0 0 0 0 0 0
0 0 0 0 0 1 1 1 1 1 1 1 1 1 1
1 1 1 1 1 1 |
10 10 10 9 2 3 9 9 5 1 9 2 3 6 2 5 6 9
2 4 6 1 2 2 7 3 5 7 4
0 0 0 0 0 0
1 1 0 1 1 1 1 1 1 1 1 1
1 1 0 1 1 1 1 1 0 0 1 1 0 1 1
0 0 0 0 0 0 |
F0 Detailed signs – Pregnant Females – Pre-Test/Treatment - group distribution of observations
|
Control |
Solvent Yellow 175 |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
Category |
Observation |
Day |
|
Number of animals affected |
|||
Group/Sex: Initial no: |
1F 9 |
2F 9 |
3F 10 |
4F 10 |
|||
Normal
Behavior
Breathing
Skin |
Within normal limits
Salivation
Labored
Encrustation, Buccal cavity |
P1 P8 1 8 11 12
11 12
11
1 8 |
|
9 9 9 9 1 0
1 0
1
0 0 |
9 9 9 9 0 0
0 0
0
0 0 |
10 10 9 9 0 0
0 0
0
1 1 |
10 10 10 10 0 1
0 1
0
0 0 |
FOB: Sensory activity – group mean values
|
Control |
Solvent Yellow 175 |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
Group /Sex |
Estimuli |
Pinna reflex (1-3) |
Blink reflex |
Pupil closure reflex |
Proprioception (right leg) (1-3) |
Tail pinch response (1-4) |
Auditory Startle reflex (1-4) |
Righting reflex (1-4) |
|
Grade |
2 |
Both eye pass |
Both eye pass |
1 |
3 |
3 |
1 |
1M |
No. of animals |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
2M |
No. of animals |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
3M |
No. of animals |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
4M |
No. of animals |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
1F |
No. of animals |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
2F |
No. of animals |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
3F |
No. of animals |
5 |
5 |
5 |
5 |
5 |
5 |
5 |
4F |
No. of animals |
2 |
2 |
2 |
2 |
2 |
2 |
2 |
FOB: Grip Strength – group mean values (g)
|
Control |
Solvent Yellow 175 |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
Group /Sex |
Grip strength |
Forelimb 1 (g) |
Forelimb 2 (g) |
Forelimb 3 (g) |
Forelimb Mean (g) |
Hindlimb 1 (g) |
Hindlimb 2 (g) |
Hindlimb 3 (g) |
Hindlimb Mean (g) |
|
Statistical test |
|
|
|
Wi |
|
|
|
Wi |
1M |
Mean SD N |
607.30 108.022 5 |
70.12 342.716 5 |
903.48 300.741 5 |
760.30 212.162 5 |
728.94 269.227 5 |
612.64 178.493 5 |
745.58 283.905 5 |
695.72 212.186 5 |
2M |
Mean SD N % of 1M |
897.18 386.111 5 148 |
1260.28 278.776 5 164 |
842.84 390.873 5 93 |
1000.10 205.105 5 132 |
617.78 144.105 5 85 |
609.50 138.034 5 99 |
601.06 215.249 5 81 |
609.45 76.243 5 88 |
3M |
Mean SD N % of 1M |
770.84 258.477 5 127 |
648.84 133.218 5 84 |
848.68 349.208 5 94 |
756.12 149.906 5 99 |
869.30 343.094 5 119 |
918.96 247.299 5 150 |
822.66 259.808 5 110 |
870.31 177.572 5 125 |
4M |
Mean SD N % of 1M |
812.70 431.720 5 134 |
814.00 292.471 5 106 |
887.30 270.406 5 98 |
838.00 215.373 5 110 |
745.84 260.695 5 102 |
667.06 210.799 5 109 |
692.5 130.550 5 93 |
701.79 165.624 5 101 |
1F |
Mean SD N |
405.46 101.983 5 |
504.56 126.230 5 |
460.28 113.901 5 |
456.77 83.930 5 |
492.42 137.485 5 |
381.44 57.296 5 |
391.30 95.192 5 |
421.72 89.226 5 |
2F |
Mean SD N % of 1F |
611.94 183.364 5 151 |
584.72 186.129 5 116 |
524.24 124.122 5 114 |
573.63 128.028 5 126 |
675.56 78.452 5 137 |
520.02 165.705 5 136 |
603.80 126.418 5 154 |
599.79** 67.315 5 142 |
3F |
Mean SD N % of 1F |
732.38 144.501 5 181 |
591.20 145.061 5 117 |
477.78 53.726 5 104 |
600.45 74.231 5 131 |
707.20 186.008 5 144 |
658.54 153.719 5 173 |
596.02 137.910 5 152 |
653.92** 80.454 5 155 |
4F |
Mean SD N % of 1F |
498.10 109.036 2 123 |
646.25 164.827 2 128 |
410.20 9.051 2 89 |
518.18 94.304 2 113 |
672.70 101.965 2 137 |
705.55 192.404 2 185 |
653.65 63.145 2 167 |
677.30** 119.171 2 161 |
FOB: Motor activity – group mean values (beam counts)
|
Control |
Solvent Yellow 175 |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
Group /Sex |
Motor activity |
10 (min) |
20 (min) |
30 (min) |
40 (min) |
50 (min) |
60 (min) |
Total (min) |
|
Statistical test |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
1M |
Mean SD N |
380.6 136.21 5 |
219.8 152.06 5 |
114.8 104.57 5 |
169.4 133.62 5 |
122.6 138.02 5 |
165.6 141.67 5 |
1172.8 699.69 5 |
2M |
Mean SD N % of 1M |
463.6 103.02 5 122 |
253.8 133.90 5 115 |
135.4 88.02 5 118 |
199.4 149.18 5 118 |
132.6 98.05 5 108 |
55.4 54.43 5 33 |
1240.2 359.40 5 106 |
3M |
Mean SD N % of 1M |
543.6 137.25 5 143 |
327.0 178.69 5 149 |
138.2 80.50 5 120 |
125.4 89.21 5 74 |
175.8 85.15 5 143 |
110.2 135.67 5 67 |
1420.2 236.97 5 121 |
4M |
Mean SD N % of 1M |
448.2 175.81 5 118 |
215.2 83.28 5 98 |
184.0 91.44 5 160 |
146.8 128.64 5 87 |
102.8 140.37 5 84 |
226.0 252.44 5 136 |
1323.0 477.98 5 113 |
1F |
Mean SD N |
132.0 56.87 5 |
302.6 122.48 5 |
198.2 128.05 5 |
159.2 85.72 5 |
175.8 70.38 5 |
181.6 55.30 5 |
1149.4 104.94 5 |
2F |
Mean SD N % of 1F |
200.8* 41.55 5 152 |
169.8 93.86 5 56 |
179.4 27.12 5 91 |
132.6 61.80 5 83 |
220.6 194.49 5 125 |
165.4 80.55 5 91 |
1068.6 323.12 5 93 |
3F |
Mean SD N % of 1F |
317.8** 52.83 5 241 |
207.12 67.78 5 68 |
130.4 86.83 5 66 |
192.0 125.49 5 121 |
217.0 51.57 5 123 |
209.8 144.22 5 116 |
1274.2 323.68 5 111 |
4F |
Mean SD N % of 1F |
293.0** 12.73 2 222 |
259.0 89.10 2 86 |
110.5 51.62 2 56 |
263.0 31.11 2 165 |
213.0 57.98 2 121 |
159.5 60.10 2 88 |
1298.0 21.21 2 113 |
F0 Hematology and Coagulation – group values
|
Control |
Solvent Yellow 175 |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
Group /Sex |
|
Hct L/L |
Hb g/dL |
RBC x1012/L |
Retic x1012/L |
MCH pg |
MCHC g/dL |
MCV fL |
WBC x109/L |
N x109/L |
L x109/L |
|
Statistical test |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
1M |
Mean SD N |
0.457 0.0160 5 |
15.1 0.59 5 |
8.79 0.194 5 |
0.117 0.0192 5 |
17.2 0.74 5 |
33.1 0.48 5 |
52.1 1.85 5 |
5.31 2.266 5 |
0.90 0.266 5 |
4.22 2.008 5 |
2M |
Mean SD N |
0.419** 0.0240 5 |
14.0* 0.69 5 |
8.00* 0.570 5 |
0.144 0.0244 5 |
17.6 0.71 5 |
33.4 0.31 5 |
52.5 1.91 5 |
6.82 1.122 5 |
1.21 0.360 5 |
5.45 1.216 5 |
3M |
Mean SD N |
0.422** 0.0181 5 |
14.2* 0.67 5 |
8.18* 0.229 5 |
0.156* 0.0302 5 |
17.4 0.51 5 |
33.7 0.21 5 |
51.5 1.27 5 |
5.60 3.497 5 |
1.06 0.282 5 |
4.40 3.426 5 |
4M |
Mean SD N |
0.422** 0.0131 5 |
14.2* 0.38 5 |
8.29* 0.336 5 |
0.174** 0.0204 5 |
17.1 0.83 5 |
33.6 0.49 5 |
51.0 2.30 5 |
7.77 1.303 5 |
1.11 0.326 5 |
6.47 1.174 5 |
Group /Sex |
|
E x109/L |
B x109/L |
M x109/L |
LUC x109/L |
Plt x109/L |
SPT Secs |
SAPT Secs |
|
||
|
Statistical test |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
|||
1M |
Mean SD N |
0.05 0.021 5 |
0.00 0.005 5 |
0.09 0.042 5 |
0.03 0.015 5 |
749 37.4 5 |
16.9 0.76 5 |
18.8 2.80 5 |
|||
2M |
Mean SD N |
0.03** 0.004 5 |
0.00 0.004 5 |
0.09 0.030 5 |
0.04 0.015 5 |
749 98.6 5 |
16.8 1.04 5 |
18.7 4.48 5 |
|||
3M |
Mean SD N |
0.02** 0.009 5 |
0.00 0.004 5 |
0.09 0.036 5 |
0.03 0.034 5 |
774 61.8 5 |
16.2 0.87 5 |
18.6 3.00 5 |
|||
4M |
Mean SD N |
0.02** 0.011 5 |
0.01 0.005 5 |
0.11 0.047 5 |
0.06 0.011 5 |
800 82.6 5 |
16.8 0.43 5 |
19.7 1.25 5 |
|
Control |
Solvent Yellow 175 |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
Group /Sex |
|
Hct L/L |
Hb g/dL |
RBC x1012/L |
Retic x1012/L |
MCH pg |
MCHC g/dL |
MCV fL |
WBC x109/L |
N x109/L |
L x109/L |
|
Statistical test |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
1F |
Mean SD N |
0.440 0.0191 5 |
14.6 0.47 5 |
7.86 0.419 5 |
0.209 0.0506 5 |
18.5 0.82 5 |
33.1 0.97 5 |
56.0 1.48 5 |
5.97 1.512 5 |
2.81 1.288 3 |
2.99 0.714 3 |
2F |
Mean SD N |
0.409 0.0196 5 |
13.9 1.07 5 |
7.50 0.429 5 |
0.180 0.0377 5 |
18.6 1.02 5 |
34.0 1.57 5 |
5.95 1.067 5 |
5.95 1.067 5 |
2.46 0.297 5 |
3.21 0.813 5 |
3F |
Mean SD N |
0.437 0.0106 4 |
14.7 0.32 4 |
7.76 0.167 4 |
0.132 0.0573 4 |
18.9 0.70 4 |
33.6 0.17 4 |
56.4 2.11 4 |
5.57 1.436 4 |
1.77 0.954 4 |
3.54 0.772 4 |
4F |
Mean SD N |
0.433 0.0099 2 |
14.1 1.63 2 |
7.87 0.078 2 |
0.184 0.0926 2 |
17.9 1.84 2 |
32.5 2.90 2 |
55.0 0.71 2 |
4.31 3.288 2 |
1.65
1 |
4.61
1 |
Group /Sex |
|
E x109/L |
B x109/L |
M x109/L |
LUC x109/L |
Plt x109/L |
SPT Secs |
SAPT Secs |
|
||
|
Statistical test |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
|||
1F |
Mean SD N |
0.04 0.010 3 |
0.00 0.006 3 |
0.17 0.047 3 |
0.05 0.030 3 |
817 241.8 5 |
16.2 0.67 4 |
24.6 1.84 4 |
|||
2f |
Mean SD N |
0.03 0.015 5 |
0.01 0.005 5 |
0.20 0.106 5 |
0.05 0.019 5 |
859 198.3 5 |
15.9 0.51 5 |
25.3 5.34 5 |
|||
3F |
Mean SD N |
0.03 0.017 4 |
0.00 0.005 4 |
0.18 0.083 4 |
0.05 0.012 4 |
786 156.1 4 |
15.5 0.30 4 |
21.3 2.65 5 |
|||
4F |
Mean SD N |
0.02
1 |
0.01
1 |
0.25
1 |
0.10
1 |
612 116.7 2 |
16.7 0.42 2 |
31.3 9.19 2 |
F0 Clinical Biochemistry – group values
|
Control |
Solvent Yellow 175 |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
Group /Sex |
|
ALP U/L |
ALT U/L |
AST U/L |
CK U/L |
Bi Ac μmol/L |
Urea mmol/L |
Creat μmol/L |
Gluc mmol/L |
Chol mmol/L |
HDL mmol/L |
|
Statistical test |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
1M |
Mean SD N |
138 32.6 5 |
45 12.3 5 |
62 12.0 5 |
199 138.3 5 |
37.1 19.10 5 |
4.10 0.974 5 |
25 2.6 5 |
9.23 0.651 5 |
2.06 0.388 5 |
1.67 0.279 5 |
2M |
Mean SD N |
115 26.6 5 |
47 15.8 5 |
75 15.1 5 |
301 108.3 5 |
18.2 12.69 5 |
4.56 0.499 5 |
31* 4.0 5 |
8.78 2.028 5 |
1.77 0.198 5 |
1.33 0.116 5 |
3M |
Mean SD N |
121 35.5 5 |
43 9.7 5 |
72 6.7 5 |
195 34.2 5 |
21.5 15.61 5 |
4.16 0.388 5 |
29 2.2 5 |
7.94 1.003 5 |
2.24 0.201 5 |
1.76 0.154 5 |
4M |
Mean SD N |
115 16.4 5 |
68 54.6 5 |
83 28.1 5 |
299 243.0 5 |
29.5 6.08 5 |
4.30 0.318 5 |
26 1.5 5 |
9.10 0.504 5 |
2.30 0.310 5 |
1.873 0.172 5 |
Group /Sex |
|
LDL mmol/L |
Trig mmol/L |
Na mmol/L |
K mmol/L |
Cl mmol/L |
Ca mmol/L |
Phos mmol/L |
Total Prot g/L |
Alb g/L |
Al g/L |
|
Statistical test |
Wi |
Wi |
Wi |
Wi |
Sh |
Wi |
Wi |
Wi |
Wi |
Wi |
1M |
Mean SD N |
0.34 0.124 5 |
0.60 0.054 5 |
141 0.5 5 |
4.0 0.20 5 |
99 0.9 5 |
2.56 0.071 5 |
1.93 0.173 5 |
61 1.1 5 |
33 0.8 5 |
11 0.8 5 |
2M |
Mean SD N |
0.35 0.067 5 |
0.43 0.181 5 |
143 0.9 5 |
3.8 0.30 5 |
100 0.2 5 |
2.47 0.053 5 |
1.91 0.115 5 |
60 2.0 5 |
32 0.8 5 |
10 0.8 5 |
3M |
Mean SD N |
0.40 0.093 5 |
0.51 0.249 5 |
142 1.7 5 |
4.1 0.24 5 |
100 1.9 5 |
2.50 0.052 5 |
1.94 0.166 5 |
60 2.3 5 |
32 1.4 5 |
11 0.5 5 |
4M |
Mean SD N |
0.41 0.180 5 |
0.61 0.302 5 |
140* 0.9 5 |
4.3 0.27 5 |
98 1.0 5 |
2.53 0.043 5 |
1.90 0.064 5 |
60 2.3 5 |
32 0.9 5 |
10* 0.7 5 |
Group /Sex |
|
a2 g/L |
Beta g/L |
Gamma g/L |
A/G Ratio |
ALB% % |
A1G% % |
A2G% % |
BGL% % |
GGL% % |
|
|
Statistical test |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
|
1M |
Mean SD N |
5 0.2 5 |
11 0.1 5 |
1 0.4 5 |
1.15 0.039 5 |
53.4 0.87 5 |
18.4 1.08 5 |
8.9 0.31 5 |
17.4 0.38 5 |
1.9 0.70 5 |
|
2M |
Mean SD N |
6 0.2 5 |
11 0.8 5 |
1 0.4 5 |
1.11 0.053 5 |
52.5 1.19 5 |
17.4 1.34 5 |
9.6 0.41 5 |
18.2* 0.73 5 |
2.2 0.59 5 |
|
3M |
Mean SD N |
6 0.4 5 |
11 0.6 5 |
1 0.3 5 |
1.13 0.060 5 |
53.0 1.30 5 |
17.6 0.73 5 |
9.3 0.56 5 |
18.6** 0.77 5 |
1.5 0.38 5 |
|
4M |
Mean SD N |
6 0.4 5 |
12** 0.4 5 |
1 0.4 5 |
1.11 0.044 5 |
52.6 0.98 5 |
16.8* 0.77 5 |
9.6 0.61 5 |
19.4** 0.15 5 |
1.5 0.54 5 |
|
Control |
Solvent Yellow 175 |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
Group /Sex |
|
ALP U/L |
ALT U/L |
AST U/L |
CK U/L |
Bi Ac μmol/L |
Urea mmol/L |
Creat μmol/L |
Gluc mmol/L |
Chol mmol/L |
HDL mmol/L |
|
Statistical test |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
1F |
Mean SD N |
101 48.1 5 |
57 21.5 5 |
72 15.8 5 |
208 61.2 5 |
47.6 46.53 5 |
7.48 1.712 5 |
31 3.1 5 |
8.34 1.213 5 |
2.52 0.384 5 |
1.91 0.318 5 |
2F |
Mean SD N |
77 15.6 5 |
59 16.3 5 |
102 38.5 5 |
199 60.5 5 |
40.3 29.48 5 |
7.21 1.491 5 |
32 4.6 5 |
7.96 0.990 5 |
2.79 0.313 5 |
1.96 0.394 5 |
3F |
Mean SD N |
89 37.8 5 |
56 18.9 5 |
88 28.3 5 |
181 61.0 5 |
61.4 64.18 5 |
7.04 1.936 5 |
28 7.2 5 |
7.88 1.695 5 |
2.45 0.313 5 |
1.96 0.283 5 |
4F |
Mean SD N |
125 5.6 2 |
80 8.1 2 |
140* 41.9 2 |
378** 59.8 2 |
104.3 79.97 2 |
7.93 0.856 2 |
29 4.2 2 |
6.91 0.608 2 |
2.43 0.134 2 |
1.83 0.078 2 |
Group /Sex |
|
LDL mmol/L |
Trig mmol/L |
Na mmol/L |
K mmol/L |
Cl mmol/L |
Ca mmol/L |
Phos mmol/L |
Total Prot g/L |
Alb g/L |
Al g/L |
|
Statistical test |
Wi |
Wi |
Wi |
Wi |
Sh |
Wi |
Wi |
Wi |
Wi |
Wi |
1F |
Mean SD N |
0.24 0.085 5 |
1.75 0.805 5 |
136 1.3 5 |
4.0 0.53 5 |
93 2.0 5 |
2.59 0.113 5 |
2.71 0.455 5 |
57 1.9 5 |
30 1.7 5 |
10 0.7 5 |
2F |
Mean SD N |
0.33 0.096 5 |
1.58 0.688 5 |
135 3.3 5 |
4.2 0.55 5 |
94 3.2 5 |
2.59 0.211 5 |
2.67 0.470 5 |
57 7.2 5 |
30 3.5 5 |
9 2.0 5 |
3F |
Mean SD N |
0.24 0.094 5 |
1.04 0.376 5 |
135 4.4 5 |
3.8 0.36 5 |
93 3.2 5 |
2.53 0.116 5 |
2.11 0.94 5 |
58 3.1 5 |
32 2.1 5 |
8 0.5 5 |
4F |
Mean SD N |
0.20 0.014 2 |
1.83 1.358 2 |
134 0.0 2 |
4.4 0.25 2 |
92 0.2 2 |
2.65 0.106 2 |
2.87 0.134 2 |
58 4.5 2 |
32 1.2 2 |
8 1.5 2 |
Group /Sex |
|
a2 g/L |
Beta g/L |
Gamma g/L |
A/G Ratio |
ALB% % |
A1G% % |
A2G% % |
BGL% % |
GGL% % |
|
|
Statistical test |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
|
1F |
Mean SD N |
6 0.6 5 |
10 0.7 5 |
1 0.3 5 |
1.09 0.099 5 |
52.2 2.22 5 |
17.6 1.19 5 |
10.5 0.98 5 |
17.5 1.09 5 |
2.2 0.48 5 |
|
2F |
Mean SD N |
6 0.6 5 |
11 1.3 5 |
1 0.3 5 |
1.08 0.067 5 |
51.8 1.60 5 |
16.0 1.59 5 |
10.9 0.63 5 |
19.1 0.95 5 |
2.1 0.28 5 |
|
3F |
Mean SD N |
6 0.4 5 |
10 0.6 5 |
1 0.6 5 |
1.27 0.070 5 |
55.9 1.38 5 |
14.3** 0.78 5 |
9.6 0.95 5 |
18.2 0.69 5 |
2.1 0.90 5 |
|
4F |
Mean SD N |
6 1.2 2 |
11 2.6 2 |
1 0.4 2 |
1.24 0.316 2 |
54.9 6.36 2 |
13.7** 1.48 2 |
10.5 1.27 2 |
19.3 3.04 2 |
1.7 0.57 2 |
F0 Macropathology – Males – group distribution of findings
|
Control |
Solvent Yellow 175 |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
|
|
Number of animals affected |
|||
Tissue/Organ and Findings |
Group/Sex No. of animals |
1M 10 |
2M 10 |
3M 10 |
4M 10 |
Number of animals within normal limits
Adipose Tissue Abnormal color
Cecum Abnormal color
Kidneys Dilated Pelvis
Lymph Node, Mandibular Abnormal color
Lymph Node, Mesenteric Abnormal color
Skin and Subcutis Deformity Scab(s)
Stomach Abnormal color
Thymus Abnormal color |
[CA]
[Ch]
[Ch]
[Ch]
[Ch]
[Ch] [Ch]
[CA]
[Ch] |
9
0
1
0
1
1
0 0
0
1 |
7
0
0
0
0
0
0 0
3
0 |
1
7**
0
0
2
1
1 1
6**
1 |
0
10**
0
2
0
0
0 1
10**
0 |
Statistic test indicated in brackets; a dash indicates statistics were not possible and a space indicates statistics were not required.
F0 Macropathology – Pregnant Females – group distribution of findings
|
Control |
Solvent Yellow 175 |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
|
|
Number of animals affected |
|||
Tissue/Organ and Findings |
Group/Sex No. of animals |
1F 9 |
2F 9 |
3F 8 |
4F 7 |
Number of animals within normal limits
Adipose Tissue Abnormal color
Adrenals Enlarged
Cecum Small
Ileum Abnormal color
Kidneys Abnormal color Dilated Pelvis
Liver Nodule
Lymph Node, Mandibular Enlarged
Lymph Node, Mesenteric Abnormal color
Spleen Small
Stomach Abnormal color Dark area(s)
Thymus Small |
[CA]
[Ch]
[Ch]
[Ch]
[Ch] [Ch]
[Ch]
[Ch]
[Ch]
[Ch]
[Ch] [Ch]
[CA] |
8
0
0
0
0
0 1
0
0
0
0
0 0
0 |
7
0
1
0
0
0 0
0
0
0
0
1 0
1 |
5
0
0
0
0
0 0
1
2
2
0
0 0
0 |
1
5**
1
1
1
1 0
0
0
0
1
2 1
3* |
Statistic test indicated in brackets; a dash indicates statistics were not possible and a space indicates statistics were not required.
F0 Organ Weights – Males – group mean absolute and adjusted values (g)
|
Control |
Solvent Yellow 175 |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
Group /Sex |
|
Terminal Body weight |
Adrenals |
Brain |
Prostate, Seminal Vesicles and Coagulating Gland |
Epididymides |
Heart |
Kidneys |
Liver |
Spleen |
Testes |
Thymus |
Thyroids and Parathyroids |
|
Statistics test |
Wi |
|
|
|
|
|
|
|
|
Sh |
|
|
1M |
Mean SD N |
385.89 15.74 10 |
0.072 0.010 5 |
2.048 0.097 5 |
2.656 0.740 10 |
1.335 0.374 10 |
0.996 0.032 5 |
2.203 0.136 5 |
10.840 0.771 5 |
0.703 0.098 5 |
3.585 0.707 10 |
0.468 0.153 5 |
0.024 0.004 10 |
2M |
Mean SD N % of 1M |
382.61 25.25 10 99 |
0.077 0.013 5 108 |
2.11 0.067 5 103 |
2.923 0.488 10 110 |
1.449 0.210 10 109 |
1.018 0.099 5 102 |
2.307 0.197 5 105 |
11.732 0.693 5 108 |
0.782 0.062 5 111 |
3.818 0.221 10 106 |
0.382 0.117 5 82 |
0.032 0.004 10 131 |
3M |
Mean SD N % of 1M |
387.48 30.69 10 100 |
0.077 0.005 5 106 |
2.114 0.089 5 103 |
2.896 0.240 10 109 |
1.432 0.202 10 107 |
1.083 0.117 5 109 |
2.413 0.084 5 110 |
13.995 1.961 5 129 |
0.714 0.132 5 102 |
3.855 0.279 10 108 |
0.296 0.045 5 63 |
0.027 0.003 10 112 |
4M |
Mean SD N % of 1M |
393.30 23.97 10 102 |
0.071 0.007 5 99 |
2.094 0.045 5 102 |
2.662 0.488 10 100 |
1.593 0.145 10 119 |
1.054 0.049 5 106 |
2.341 0.072 5 106 |
13.806 1.090 5 127 |
0.785 0.124 5 112 |
3.943 0.187 10 110 |
0.259 0.033 5 55 |
0.033 0.007 10 135 |
Statistics test |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
|
Wi |
Wi |
||
1M 2M 3M 4M |
Adjusted Mean Adjusted Mean Adjusted Mean Adjusted Mean |
0.072 0.078 0.076 0.072 |
2.050 2.103 2.126 2.088 |
2.664 2.949 2.895 2.629 |
1.336 1.452 1.432 1.589* |
0.994 1.027 1.070 1.060 |
2.201 2.314 2.403 2.345 |
10.830 11.775 13.933** 13.836** |
0.702 0.786 0.708 0.788 |
|
0.467 0.387 0.290* 0.262** |
0.024 0.032* 0.027* 0.032** |
F0 Organ Weights – Pregnant Females – group mean absolute and adjusted values (g)
|
Control |
Solvent Yellow 175 |
||
Dose Group |
1 |
2 |
3 |
4 |
Dose (mg/kg/day) |
0 |
100 |
300 |
1000 |
Group /Sex |
|
Terminal Body weight |
Adrenals |
Brain |
Heart |
Kidneys |
Liver |
Ovaries |
Spleen |
Thymus |
Thyroids and Parathyroids |
Uterus and Cervix and Oviducts |
|
Statistics test |
Wi |
|
|
|
|
|
|
|
|
|
Sh |
1F |
Mean SD N |
284.48 19.99 9 |
0.100 0.016 5 |
1.950 0.094 5 |
0.918 0.039 5 |
1.682 0.094 5 |
12.289 0.746 5 |
0.093 0.012 9 |
0.706 0.051 5 |
0.237 0.053 5 |
0.027 0.004 9 |
0.624 0.073 9 |
2F |
Mean SD N % of 1F |
269.87 20.10 9 95 |
0.089 0.008 5 89 |
1.910 0.068 5 98 |
0.834 0.042 5 91 |
1.676 0.058 5 100 |
11.815 0.890 5 96 |
0.101 0.020 9 109 |
0.662 0.146 5 94 |
0.198 0.026 5 83 |
0.026 0.007 9 99 |
0.710 0.199 9 114 |
3F |
Mean SD N % of 1F |
271.16 11.94 8 95 |
0.101 0.025 5 101 |
1.966 0.076 5 101 |
0.883 0.070 5 96 |
1.758 0.086 5 105 |
12.425 1.963 5 101 |
0.101 0.023 8 108 |
0.677 0.144 5 96 |
0.237 0.081 5 100 |
0.028 0.008 8 105 |
1.006** 0.346 8 161 |
4F |
Mean SD N % of 1F |
250.54** 39.07 7 88 |
0.102 0.009 2 101 |
2.042 0.109 2 105 |
0.948 0.089 2 103 |
1.707 0.033 2 101 |
12.937 1.234 2 105 |
0.109 0.021 7 117 |
0.673 0.038 2 95 |
0.158 0.034 2 67 |
0.027 0.008 7 101 |
1.773** 1.233 7 284 |
Statistics test |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
Wi |
|
||
1M 2M 3M 4M |
Adjusted Mean Adjusted Mean Adjusted Mean Adjusted Mean |
0.100 0.090 0.101 0.102 |
1.931 1.920 1.966 2.067* |
0.908 0.839 0.883 0.961 |
1.681 1.677 1.758 1.708 |
12.398 11.761 12.427 12.794 |
0.095 0.101 0101 0.106 |
0.703 0.663 0.677 0.677 |
0.228 0.203 0.237 0.171 |
0.025 0.026 0.028 0.029 |
|
Applicant's summary and conclusion
- Conclusions:
- In conclusion, the effects of oral (gavage) administration of Solvent Yellow 175 to Wistar rats receiving 100, 300 or 1000 mg/kg/day for 14 days prior to mating and until sacrifice can be summarized as follows:
Systemic toxicity:
− Considering that among the animals administered at 300 and 1000 mg/kg/day, two females in each dose were sacrificed for welfare reasons at late gestation (showing difficulties during parturition) and taking into account the histopathological findings observed in the digestive tract, thymus and thyroids and parathyroids, the No Observed Adverse Effect Level (NOAEL) could be established at 100 mg/kg/day. - Executive summary:
The purpose of the study was to assess the general systemic toxic potential of Solvent Yellow 175 in rats, including a screen for reproductive/developmental effects and assessment of endocrine disruptor relevant endpoints, with administration of the test item by gavage for 5-8 weeks.
Three groups of 10 male and 10 female rats received Solvent Yellow 175 at the doses of 100, 300 and 1000 mg/kg/day. Males were treated continuously for two weeks before pairing up to necropsy, after a minimum of 36 consecutive days. Females were treated continuously for two weeks before pairing, throughout pairing and gestation, and until Day 13-15 of lactation (the day before sacrifice). Females were allowed to litter and rear their offspring, and litters were killed on Day 13-15 of lactation (the day before the corresponding female was killed).
During the study, mortality, clinical signs, sensory reactivity observations, grip strength, motor activity, body weight, food consumption, hematology, coagulation, blood biochemistry, organ weight and macroscopic examination were evaluated.
Results
The study results can be summarized as follows:
- Preparation of all formulations was considered correct considering the acceptance ranges as formulation results demonstrated that all formulations were within the necessary acceptance range for the nominal concentration and coefficient of variation.
- Two females at both 300 and 1000 mg/kg/day were sacrificed for welfare reasons at the end of gestation period as they showed signs of difficulty during parturition.
Between late gestation and lactation day 8, one female at 100 mg/kg/day, three females at 300 mg/kg/day and six females at 1000 mg/kg/day were sacrificed due to total litter loss.
- Administration of Solvent Yellow 175 at the dose levels of 100, 300 or 1000 mg/kg/day had no other evident toxicological effects on clinical condition than those mentioned above, or in body weight, food consumption, motor activity, sensory reactivity and grip strength. A dose related increase in gestation length at increasing dose was observed, mainly due to the difficulties observed during parturition for some females. Dark feces and yellow urine recorded from day 1 of treatment onwards in all the test-item groups were attributable to the color of the test item. Salivation was recorded occasionally in test-item- administered males and females in all test-item groups as well as in a control male and female, probably due to taste aversion (from gavage dosing).
- Although they were not considered relevant and as a dose-response effect was not recorded, the hematocrit, hemoglobin and red blood cell values of the males sacrificed after 5 weeks of treatment with the test item showed significant differences, with mean values lower than those seen in the Control group. In addition, mean reticulocyte values higher than those of Controls were also found in males (statistically significant at 300 and 1000 mg/kg/day).
- There were no relevant differences considered related to the treatment in hematology in females or in coagulation and clinical biochemistry in males and females.
- T4 analyses of samples in males sacrificed at the end of treatment, statistically lower mean values were observed in the test-item-administered groups with respect to Control, although these differences were not dose-related.
- The macroscopic examination performed at the end of lactation period revealed changes in the stomach, cecum, thymus and kidneys of treated females.
- Histopathology revealed changes that were considered related to treatment with the test item in male thyroids and kidneys, female stomach and cecum, and thymus of both males and females. Changes observed in males, i.e. decrease in thymus weight and increase in thyroids and parathyroids, correlate with these findings.
Conclusion
In conclusion, the effects of oral (gavage) administration of Solvent Yellow 175 to Wistar rats receiving 100, 300 or 1000 mg/kg/day for 14 days prior to mating and until sacrifice can be summarized as follows:
Systemic toxicity:
− Considering that among the animals administered at 300 and 1000 mg/kg/day, two females in each dose were sacrificed for welfare reasons at late gestation (showing difficulties during parturition) and taking into account the histopathological findings observed in the digestive tract, thymus and thyroids and parathyroids, the No Observed Adverse Effect Level (NOAEL) could be established at 100 mg/kg/day.
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