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EC number: 607-654-1 | CAS number: 252285-60-2
- 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
![](https://echa.europa.eu/o/diss-blank-theme/images/factsheets/A-REACH/factsheet/print_toxicological-information.png)
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:
- 02 July 2009 to05 October 2009
- Reliability:
- 1 (reliable without restriction)
- Rationale for reliability incl. deficiencies:
- other: Compliant to OECD 407 and GLP guideline
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 010
- Report date:
- 2010
Materials and methods
Test guidelineopen allclose all
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)
- Deviations:
- no
- Qualifier:
- according to guideline
- Guideline:
- EU Method B.7 (Repeated Dose (28 Days) Toxicity (Oral))
- Deviations:
- no
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Details on test material:
- Name: Triazin UV-Absorber
Constituent 1
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- Species and strain: CRL: (WI) BR rats
Source: TOXI COOP Ltd., Cserkesz u. 90. 1103 Budapest, Hungary
Hygienic level: SPF at arrival; standard laboratory conditions during the study
Justification of strain: Wistar rat as a rodent is one of the standard strains for repeat-dose toxicity studies
Number of animals: 35 male and 35 female rats
5 rats/sex/group, 4 Main groups (Groups 1 to 4);
5 rats/sex/group, 2 Recovery groups (Groups 1 and 4)
5 rats/sex/group, 1 Positive control group (Group 5)
Age of animals: Young adult rats, 7-8 weeks old at onset of treatment
Body weight: The weight variation did not exceed +/- 20 percent of the mean weight/sex at onset of treatment with the test item;
240-283 g males, 169-208 g females
Acclimation period: 8 days
Animal health: Only healthy animals were used for the test, as certified by the veterinarian. Females were nulliparous and non-pregnant.
Cage type: Type III. polypropylene/polycarbonate
Bedding: Laboratory Animal Bedding produced by Brandenburg Holzfaserstoffe Gmbh& Co.KG, Arkeburger Str. 31, 49424 Goldenstedt, Germany.
Light: 12 hours daily, from 6.00 a.m. to 6.00 p.m.
Temperature: 121.1 – 24.6°C
Relative humidity: 38-69 %
Ventilation: 15-20 air exchanges/hour
Housing/Enrichment: Rodents were group-housed (up to 5 animals/sex/cage), to allow social interaction, and with deep wood sawdust bedding, to allow digging and other normal rodent activities.
The temperature and relative humidity were recorded twice daily; no deviations from the intended range occurred during the study.
Animals received ssniff® SM R/M-Z+H "Autoclavable complete feed for rats and mice – breeding and maintenance" produced by ssniff Spezialdiäten GmbH, D-59494 Soest Germany ad libitum, and tap water from municipal supply, as for human consumption from 500 ml bottle ad libitum.
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- polyethylene glycol
- Details on oral exposure:
- The test item was formulated in PEG400 at concentrations of 15.6, 62.5 and 250 mg/mL. Formulations were prepared at the appropriate frequency for use within 72 hours as documented in the raw data, while stored refrigerated, according to stability assessment results
- Analytical verification of doses or concentrations:
- yes
- Details on analytical verification of doses or concentrations:
- Analysis of formulations (concentration, homogeneity) and assessment of test item stability in this vehicle under the conditions employed in the study was performed in the Analytical Laboratory of LAB Research Ltd.
Concentration and homogeneity of formulations were evaluated by UV-HPLC method on duplicate samples collected from the top, middle and bottom of test item solutions, and one sample from the control taken and analyzed fresh during the first and last weeks of treatment. Dose formulations were homogenous. The measured (actual) concentrations varied between 98% and 106% of the nominal concentrations. No test item was detected in the control solution samples. - Duration of treatment / exposure:
- 29 days
- Frequency of treatment:
- daily
Doses / concentrations
- Remarks:
- Doses / Concentrations:
15.625, 62.5, and 250 mg/mL
Basis:
other: formulation analytics (UV-HPLC ): 98% and 106% of nominal concentrations
- No. of animals per sex per dose:
- Groups 1 to 4: 5 animals/sex/main group
Groups 1 and 4: 5 animals/sex/recovery group
Group 5: 5 animals/sex positive control - Control animals:
- yes, concurrent vehicle
- Details on study design:
- Rationale for dose-selection: Acute oral toxicity testing at a dose level of 2000 mg/kg in the rat did not result in any signs of test item-related toxicity. The median lethal dose level (LD50) was above 2000 mg/kg for oral administration in the female rat. Based on these results and due to experience with similar compounds, dose levels of 62.5, 250, and 1000 mg/kg/day were selected for use in the study.
During the acclimation period, the animals were assigned to their respective dose groups by randomization based on body weights. Animals were randomly allocated to the control and dose groups based on the most recent actual body weight. SPSS/PC+ software was used in order to verify homogeneity/variation among/within groups. Males and females were randomized separately.
Main animals underwent necropsy on Day 28 (start of treatment, Day 0), after 29 days of treatment. Recovery animals were treated for 29 consecutive days, followed by a 14-day recovery/observation period after the last dose and were then euthanized and subjected to a necropsy examination. - Positive control:
- The positive control rats (Group 5) for the Mammalian Erythrocyte Micronucleus Test were administered Cyclophosphamide by oral gavage, at a dose level of 15 mg/kg bw on Day 27, at 10 mL/kg, 1.5 mg/mL, approximately 24 hours prior to scheduled necropsy on Day 28.
Examinations
- Observations and examinations performed and frequency:
- Clinical Observations and Functional Observation Battery
Animals were inspected for signs of morbidity and mortality twice daily (at the beginning and end of each working day). General clinical observations were made once a day, after the treatment at approximately the same time, and daily during the recovery period. Detailed clinical observations were made on all animals outside the home cage in a standard arena, once prior to the first exposure and once weekly thereafter. Observation was performed on the skin, fur, eyes and mucous membranes, autonomic activity (lachrymation, piloerection, pupil size, respiratory pattern, occurrence of secretions and excretions), circulatory and central nervous system, somatomotor activity and behaviour pattern, changes in gait, posture and response to handling. Special attention was directed towards the observation of tremors, convulsions, salivation, diarrhoea, lethargy, sleep and coma.
Sensory reactivity to different type of stimuli (e.g. auditory, visual and proprioceptive), assessment of grip strength and motor activity were conducted on all animals towards the end of treatment period on Day 26. General physical condition and behaviour of animals were tested. A modified Irwin test was performed. A detailed assessment of any potentially treatment-related neurotoxic effects was made on the basis of these measurements.
Oestrus cycle evaluation
Prior to necropsy, vaginal smears were taken from all females, stained with 1% aqueous methylene blue solution and examined with a light microscope, in order to provide information regarding the stage of oestrus cycle at the time of sacrifice and assist in histological evaluation of oestrogen sensitive tissues.
Body weight measurement
Individual body weight was recorded with precision of 1 g at randomization (Day 7), on the first day of treatment (Day 0), then at least weekly and prior to necropsy (fasted for scheduled necropsy).
Food consumption measurement
Animal food consumption was determined by re-weighing the non-consumed diet with a precision of 1 g on Day 0 (pre-treatment, start on Day -7) then at least weekly. The weekly and mean daily food consumption was calculated.
CLINICAL PATHOLOGY
Blood samples for clinical pathology evaluation (haematology, coagulation, and clinical biochemistry) were collected immediately prior to the scheduled necropsy, by heart puncture under pentobarbital anaesthesia. After an overnight period of food deprivation of animals, three samples were taken from each animal: one for haematology (1.2 mL blood; tube contained K3-EDTA as anticoagulant, 1.6 mg/mL blood), one for determination of blood clotting times (1.2 mL blood; APTT and PT; tube contained sodium citrate as anticoagulant) and the third one to obtain serum samples (at least 2.4 mL blood as practical, in a tube with no anticoagulant) for clinical chemistry.
Haematology and Blood Clotting Times
The following parameters were evaluated in all animals:
Red Blood Cell (erythrocyte) count, White Blood Cell (leukocyte) count, Haemoglobin concentration, Haematocrit, Mean Corpuscular (erythrocyte) Volume, Mean Corpuscular (erythrocyte) Haemoglobin, Mean Corpuscular (erythrocyte) Haemoglobin Concentration, Red Cell (erythrocyte) volume (%) Distribution Width, Platelet (thrombocyte) count, Mean Platelet Thrombocyte volume, Reticulocyte count, Neutrophil, Lymphocyte, Monocyte, Basophil, Eosinophil, Large Unstained Cells, Partial Thromboplastin Time, Prothrombin Time,
Clinical chemistry
The following parameters were evaluated in all animals:
Glucose Blood sugar concentration, T-BIL Total Bilirubin concentration, Urea Urea concentration, Chol. Cholesterol concentration, Creat. Creatinine concentration, Phos. Phosphorus concentration, Sodium concentration, Potassium concentration, Calcium concentration, Chloride concentration, Total Protein concentration, Albumin concentration, Alb/glob ratio, Aspartate Aminotransferase activity, Alanine Aminotransferase activity, Alkaline. Phosphatase – activity, Gamma Glutamyltransferase -activity, Bile acids - Sacrifice and pathology:
- Terminal procedures
Following blood sample collection for clinical pathology evaluation, necropsy and macroscopic examination was performed on every Main Study or Recovery animal euthanized at the end of the treatment or recovery periods, with the exception of positive control Group 5 animals (Mammalian Erythrocyte Micronucleus Test in Bone Marrow Cells), for which bone marrow was collected from the right femur immediately after euthanasia, after which the carcasses were discarded without further examination. Surviving animals were euthanized by exsanguination under pentobarbital anaesthesia.
Macroscopic examination
After exsanguination the external appearance was examined, cranium, thoracic and abdominal cavities were opened and the appearance of the tissues and organs was observed macroscopically.
Any abnormality was recorded with details of the location, colour, shape and size, as appropriate.
On completion of the macroscopic examination and organ weight measurements according to OECD 407 were evaluated.
Organ weight measurement
The following organs were weighed and recorded: with precision of 0.01 g, liver, kidneys, testes, epididymides, uterus, including cervix, prostate, seminal vesicle with coagulating glands as a whole, thymus, spleen, brain and heart; with precision of 0.001 g, ovaries, adrenals.
Paired organs were weighed together. Absolute organ weights were measured, and relative organ weights to the body and brain weights were calculated and are reported.
Histopathology
Full histopathology was performed in Group 1 (Control) and Group 4 (High Dose), main and recovery animals and on all organs and tissues with macroscopic findings. Representative tissue samples were embedded into paraffin and slides were prepared, then stained with haematoxylin-eosin/phloxine and examined with light microscope. As no microscopic findings recorded in High Dose animals were considered potentially treatment-related, no further histology examination was performed on other tissues or organs from the lower dose levels. - Statistics:
- Data were collected using the software PROVANTIS v.7 or recorded on the appropriate forms from the relevant SOPs of LAB Research Ltd., then tabulated using the software PROVANTIS v.7, Microsoft Office Word and/or Excel, as appropriate.
Numerical data obtained during the conduct of the study were subjected as appropriate to calculation of group means and standard deviations. The statistical analysis was performed using SPSS PC+4.0 software. The heterogeneity of variance between groups was checked by Bartlett's homogeneity of variance test. Where no significant heterogeneity was detected, a one-way analysis of variance was carried out. If the obtained result was positive, Duncan's Multiple Range test was used to assess the significance of inter-group differences. Where significant heterogeneity was found, the normal distribution of data was examined by Kolmogorov-Smirnov test. If the data was not normal distributed, the non-parametric method of Kruskal-Wallis One-Way analysis of variance was used. If there was a positive result, the inter-group comparisons were performed using Mann-Whitney U-test. The frequency of clinical observations and necropsy and histopathology findings was calculated as applicable.
Results and discussion
Results of examinations
- Clinical signs:
- no effects observed
- Mortality:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Food efficiency:
- no effects observed
- Ophthalmological findings:
- no effects observed
- Haematological findings:
- no effects observed
- Clinical biochemistry findings:
- no effects observed
- Behaviour (functional findings):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Gross pathological findings:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Details on results:
- High dose recovery male 4008 was found dead on Day 10. Prior to death, no clinical signs were noted in this animal. At necropsy, white creamy material in the oral cavity and trachea, and enlarged mottled lungs were recorded. In the absence of any clinical changes in other animals and based on the macroscopic findings noted, the death of this animal was considered due to a dosing error (misgavage) and not ascribed to Triazin UV-Absorber administration.
There were no changes that could be ascribed to Triazin UV-Absorber administration noted in the body weight and body weight gain, animal food consumption, or clinical pathology parameters (haematology, coagulation and clinical chemistry) evaluated at the completion of the 29-day treatment period (all dose levels) or at the end of a 14 day recovery period (control, and 1000 mg/kg bw/day animals).
There were no test item related changes in the female oestrus cycle examined prior to necropsy. No macroscopic or microscopic changes or changes in the organ weights related to Triazin UV-Absorber administration were recorded in either main or recovery animals examined. No induction of micronuclei in bone marrow erythrocytes was observed, thus, there was no evidence of any genotoxic activity of the test item.
Effect levels
- Dose descriptor:
- NOAEL
- Effect level:
- 1 000 mg/kg bw/day (nominal)
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: There were no adverse effects in parameters investigated
Target system / organ toxicity
- Critical effects observed:
- not specified
Applicant's summary and conclusion
- Conclusions:
- Triazin UV-Absorber administered daily by oral gavage for at least 28 days in Wistar rats did not lead to test item related mortality or clinical adverse effects, including animal behaviour, general physical condition, reactions to different type of stimuli, grip strength or motor activity, at dose levels of 62.5, 250, or 1000 mg/kg bw/day during either the treatment or 14-day recovery/observation periods.
There were no changes that could be ascribed to Triazin UV-Absorber administration noted in the body weight and body weight gain, animal food consumption, or clinical pathology parameters (haematology, coagulation and clinical chemistry) evaluated at the completion of the 28-day treatment period (all dose levels), or at the end of a 14 day recovery period (control, and 1000 mg/kg bw/day animals).
There were no test item related changes in the female oestrus cycle examined prior to necropsy. No macroscopic or microscopic changes or changes in the organ weights related to Triazin UV-Absorber administration were recorded in either main or recovery animals examined. No induction of micronuclei in bone marrow erythrocytes was observed, thus, there was no evidence of any genotoxic activity of the test item.
In conclusion, under the conditions of this study, the no observed effect level (NOEL) for Triazin UV-Absorber is considered to be 1000 mg/kg bw/day. - Executive summary:
The toxicity of Triazin UV-Absorber administered daily for at least 28 days by oral gavage to CRL:(WI)BR rats and the reversibility of any treatment-related changes was evaluated following a 14-day recovery period. In addition, the test item was evaluated for genotoxic effects by examiningthe induction ofmicronuclei in bone marrow erythrocytes of treated and control animals.
Triazin UV-Absorberor the vehicle/control only was administered to sixty Wistar rats (20 male and 20 female Main animals, and 10 male and 10 female Recovery animals)according to the following experimental design:
Group No.
Group Designation
Dose Level
(mg/kg/day)Conc. (mg/mL)
Dose volume
(mL/kg)
Number of Animals
Main
Recovery
Male
Female
Male
Female
1
Control
0
0
4
5
5
5
5
2
Low Dose
62.5
15.6
5
5
-
-
3
Mid Dose
250
62.5
5
5
-
-
4
High Dose
1000
250
5
5
5
5
5
Positive Control*
0
0
10
5
5
-
-
*MNT: 15 mg/kg bw/day Cyclophosphamide PO (10 mL/kg, 1.5 mg/mL) approximately 24 h prior to scheduled necropsy
Main animals underwent necropsy on Day 28 (start of treatment, Day 0), after 29 days of treatment. Recovery animals were treated for 28 consecutive days, they were euthanized and subjected to a necropsy examination following a 14-day recovery/observation period after the last dose. Control animals received the vehicle item solution only (PEG400), at the same volume as the high dose animals.
No correction for purity ofTriazin UV-Absorberwas applied.
Ten additional Wistar rats (5 male and 5 female), Group 5, served as positive control group for the Mammalian Erythrocyte Micronucleus Test (MNT). They were treated with 15 mg/kg bw/day Cyclophosphamide by oral gavage (dose volume, 10 mL/kg, concentration, 1.5 mg/mL) on Day 27, approximately 24 h prior to scheduled necropsy on Day 28.
Parameters measured during the study includedinspection for signs of morbidity and mortality twice daily,observation of clinical signs, performed daily (general, cage side observations, after the dose administration), or weekly (detailed observations), as well as a modified Irwin test conducted on Day 26, weekly determination of body weight and body weight gain, and food consumption. Prior to necropsy, the oestrus cycle of all females was evaluated by examination of vaginal smears. In addition, blood was collected prior to terminal necropsy, for clinical pathology (haematology, coagulation and clinical chemistry) assessment. At termination, necropsy with macroscopic examination was performed. Weights of selected organs were recorded and representative tissues/organs were sampled and preserved in appropriate fixatives.
Histopathology evaluation was conducted on tissues and organs retained in fixative and processed to slides from the control and high dose animals (1000 mg/kg bw/day), and on all organs with macroscopic findings from the low and mid dose groups (62.5 and 250 mg/kg bw/day, respectively).
Analysis of formulations (concentration, homogeneity) and assessment of test item stability in this vehicle in the conditions employed on the study was performed in the Analytical Laboratory of LAB Research Ltd.
Stability tests (LAB study code 09/069-316AN) at concentrations from approximately 1 to 250 mg/mL in PEG 400 indicated an up to 24 hour stability at room temperature. In addition, under refrigerated conditions (5±3°C), the solutions were stable for up to 72 hours, with a recovery of 101% and 106%, at 1 and 250 mg/mL, respectively (acceptance range: 100 ± 10%). Concentration and homogeneity of formulations were evaluated by UV-HPLC method on duplicate samples collected from the top, middle and bottom of test item solutions, and one sample from the control, taken and analyzed fresh during the first and last weeks of treatment. Dose formulations were homogenous; the measured (actual) concentrations varied between 98% and 106% of the nominal concentrations.No test item was detected in the control solution samples.
These results were considered suitable for the study purposes.
Triazin UV-Absorber caused neither test item related mortality, nor clinical changes following administration by oral gavage, daily for at least 28 days, at up to and including 1000 mg/kg bw/day in CRL:(WI)BR rats. All the animals were normal during the 14-day recovery period. One male at 1000 mg/kg bw/day died due to a dosing failure between Day 9 and Day 10. The behaviour and the general condition of the test animals were normal during the study. There was no treatment-related effect on motor activity or in the functional observation battery tests across groups of treated male or female animals and no findings indicative of neurotoxicity were observed. Evaluation of the vaginal smears prior to necropsy showed the expected distribution of the oestrus cycle phases within the normal population of female Wistar rats. There were no toxicologically significant changes in body weight, body weight gain or animal food consumption between the control and test item treated groups.
Minor variations, on occasion attaining statistical significance, were noted in the clinical pathology parameters (haematology, coagulation, or clinical chemistry) in both main and recovery animals. However, no dose or gender-response was observed, and/or the results were within the historical range. These changes were neither considered toxicologically significant, nor indicated a Triazin UV-Absorber-related etiology.
There were no macroscopic or microscopic findings, or changes in the absolute or relative organ weights that could be ascribed to Triazin UV-Absorber-administration. No induction of micronuclei in bone marrow erythrocytes was observed, thus, there was no evidence of any genotoxic activity of the test item.
In conclusion, under the conditions of this study, the no observed effect level (NOEL) for Triazin UV-Absorber is considered to be 1000 mg/kg bw/day.
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