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EC number: 265-004-9 | CAS number: 64665-57-2
- 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
Toxicity to reproduction
Administrative data
- Endpoint:
- screening for reproductive / developmental toxicity
- Remarks:
- based on test type (migrated information)
- Type of information:
- migrated information: read-across from supporting substance (structural analogue or surrogate)
- Adequacy of study:
- weight of evidence
- Reliability:
- 2 (reliable with restrictions)
- Rationale for reliability incl. deficiencies:
- other: see 'Remark'
- Remarks:
- Sodium Tolyltriazolate has similar reproductive and developmental dose toxicity compared to the analogue Benzotriazole resulting in similar no observed adverse effect level (NOAEL), because Benzotriazole was tested for fertility and developmental toxicity in a Repro-screening study (OECD 421) up to toxic doses and did not show reproductive and developmental dose toxicity. The source chemical Benzotriazole is sufficiently similar to read-across towards Sodium Tolyltriazolate.
Data source
Reference
- Reference Type:
- study report
- Title:
- Unnamed
- Year:
- 2 012
Materials and methods
Test guideline
- Qualifier:
- according to guideline
- Guideline:
- OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
- GLP compliance:
- yes (incl. QA statement)
- Limit test:
- no
Test material
- Reference substance name:
- 1H-1,2,3-Benzotriazole
- IUPAC Name:
- 1H-1,2,3-Benzotriazole
- Reference substance name:
- Benzotriazole
- EC Number:
- 202-394-1
- EC Name:
- Benzotriazole
- Cas Number:
- 95-14-7
- Molecular formula:
- C6H5N3
- IUPAC Name:
- 1H-Benzotriazole
- Test material form:
- other: needles
- Details on test material:
- - Name of test material (as cited in study report): 1,2,3-Benzotriazole-REACH 01
- Molecular formula (if other than submission substance): C6H5N3
- Molecular weight (if other than submission substance): 119.14 g/mol
- Smiles notation (if other than submission substance): c12c(cccc1)N=NN2
- InChl (if other than submission substance): 1S/C6H5N3/c1-2-4-6-5(3-1)7-9-8-6/h1-4H,(H,7,8,9)
- Structural formula attached as image file (if other than submission substance):
- Substance type: organic
- Physical state: solid
- Analytical purity: 99.87 %
- Lot/batch No.: 111254/112649
- Expiry date: November 2012
- Storage condition of test material: room temperature
Constituent 1
Constituent 2
Test animals
- Species:
- rat
- Strain:
- Wistar
- Sex:
- male/female
- Details on test animals or test system and environmental conditions:
- TEST ANIMALS
- Source: Charles River, Sandhofer Weg 7, 97633 Sulzfeld, Germany
- Age at study initiation: P 10-11 wks
- Weight at study initiation: (P) Males: 294- 351 g; Females: 196 - 225 g;
- Fasting period before study: non
- Housing: females single, males in groups of three
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 6 to 9 days
ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22+-3°C
- Humidity (%): 30-70%
- Air changes (per hr):10
- Photoperiod (hrs dark / hrs light):12/12
Administration / exposure
- Route of administration:
- oral: gavage
- Vehicle:
- polyethylene glycol
- Details on exposure:
- PREPARATION OF DOSING SOLUTIONS:
Instructions for test item preparation:
1. Weigh required amount of the test item into an appropriate vial on an analysis scale.
2. Add PEG400 up to the required volume to produce the application suspension as
stated in the laboratory work sheets.
3. Stir until suspension is a consistent emulsion; vortex if necessary.
4. Stir immediately before each dose will be drawn into the application syringe.
According to the Sponsor the test item is stable in PEG400 for seven days at concentrations
of 12,5 g/l and 50 g/l. The highest concentration of the test item suspension was prepared
once every 6 or 7 days and stored in a dark place at room temperature. Daily, a serial
dilution (1 in 4) of the highest concentration was made to produce the further application
solutions. The test item preparation was intended for an application volume of 4 ml per kg
body weight.
VEHICLE
- Justification for use and choice of vehicle (if other than water):
As the test item’s solubility in water and corn oil is poor, polyethylene glycol 400 (PEG400)
will be used as an organic solvent. PEG400 has already been used as vehicle for the
subacute oral toxicity study of the surrogate substance Methylbenzotriazole. PEG400 is a
commonly used pharmaceutical excipient (e.g. suppositories, capsules or tablets) and also
frequently used in toxicological work to improve the solubility of otherwise poorly soluble
compounds. The LD50 of PEG is 51,3 g/kg body weight, and the maxiumum recommended
daily uptake is a quarter of the LD50.
- Concentration in vehicle: 50 g/l
- Amount of vehicle (if gavage): 4 ml/kg
- Lot/batch no. (if required): K43386003
- Purity: Not applicable - Details on mating procedure:
- - M/F ratio per cage: 1.0
- Length of cohabitation: 14 days
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy
- After 14 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged: single - Analytical verification of doses or concentrations:
- not specified
- Duration of treatment / exposure:
- Depending on the female performance at least 46 days:
- Frequency of treatment:
- daily
- Details on study schedule:
- 14 days pre-mating
up to 14 days until mating
an average of 21 days of gestation
between 8-14 days of lactation
Doses / concentrationsopen allclose all
- Remarks:
- Doses / Concentrations:
12.5 mg/kg bw/day
Basis:
nominal conc.
- Remarks:
- Doses / Concentrations:
50 mg/kg bw/day
Basis:
nominal conc.
- Remarks:
- Doses / Concentrations:
200 mg/kg bw/day
Basis:
nominal conc.
- No. of animals per sex per dose:
- 12
- Control animals:
- yes, concurrent vehicle
- Details on study design:
- - Dose selection rationale:
In a previously performed dose range finding study4, the test item was administered at three
doses up to 200 mg/kg body weight over a time period of at least six weeks which produced
no acute toxic effects in the test animals. In accordance with the Study Monitor, 200 mg/kg
was determined as high dose for this study followed by two graduated (1 in 4) serial dilutions
thereof (50 mg/kg, 12,5 mg/kg) assigned as medium and low dose.
The high dose was chosen based on following arguments:
In an acute toxicological assessment quoted in the material safety sheet on the test item,
560 mg/kg wasdetermined as the LD50. A subacute oral toxicity study for the surrogate substance Methylbenzotriazole (study report indicates LD50 value at 720 mg/kg) showed signs of toxicity at a dose level of 450 mg/kg. Thus, 200 mg/kg were determined as high dose for the dose range finding study. Two graduated 1:2 v/v) serial dilutions thereof (100 mg/kg, 50 mg/kg) were assigned as medium and low dose for this assay.
Examinations
- Parental animals: Observations and examinations:
- CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
DETAILED CLINICAL OBSERVATIONS: No
BODY WEIGHT: Yes
- Time schedule for examinations: once weekly
FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Time schedule for examinations: once weekly
WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): Yes
- Time schedule for examinations: once weekly - Sperm parameters (parental animals):
- Parameters examined in P male parental generations:
testis weight, epididymis weight - Litter observations:
- STANDARDISATION OF LITTERS
- Performed on day 4 postpartum: yes
- If yes, no maximum set for pups/litter.
PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of gross anomalies, weight gain - Postmortem examinations (parental animals):
- SACRIFICE
- Male animals: All surviving animals approximately four weeks post-mating
- Maternal animals: All surviving animals between days 8 and 14 post-partum
GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.
HISTOPATHOLOGY / ORGAN WEIGHTS
The tissues indicated below were prepared for microscopic examination and weighed, respectively:
Epididymides, Testes, Ovaries, Uterus, Adrenal glands, Lymph nodes, Heart - Postmortem examinations (offspring):
- no postmortem examinations of offspring
- Statistics:
- Spread sheet calculations were performed using Microsoft® Excel® 2011 for Mac.
Food- and water consumption of male animals were documented sorted by experimental
groups, whereas the body weight was documented for each animal individually. Body weight,
food- and water consumption, litter size and litter weight were documented for each female
animal individually.
Descriptive statistics
The arithmetic mean, standard deviation and median were calculated for all grouped
numerical data originating from monitoring the body weight, food- and water consumption,
organ weights (gross pathology) and litter size and weight (for details see appendix). Where
appropriate, detailed column statistics were applied (minimum / maximum data, 25%
quantiles, standard error, upper and lower confidence interval 95%).
Deductive statistics
If appropriate, the respective test item groups were compared to the vehicle group by
assessing statistical significance using a two-tailed unpaired Student´s t-test. For all
calculations, the significance level was set to 0,05.
For some analysis parameters that returned statistical significances in the t-test, further
deductive statistics were applied as outlined in the schematic decision tree displayed in the
appendix. Most statistical hypotheses in this study were best characterised as “many to
one”– a vehicle control vs. three treatment groups, respectively. Therefore the adequate
analysis method was a One-Way ANOVA (Analysis of variance), followed by a post hoc
Dunnett´s t-test. In case a sufficient number of values per group were available a Bartlett´s
test for equal variances was applied on the data. For all calculations, the significance level
was set to 0,05. These further deductive statistics then were performed using Graph Pad
Prism for Mac, Version 5.01. Statistical data and analyses were documented in the appendix. - Reproductive indices:
- not calculated
- Offspring viability indices:
- not calculated
Results and discussion
Results: P0 (first parental generation)
General toxicity (P0)
- Clinical signs:
- no effects observed
- Body weight and weight changes:
- no effects observed
- Food consumption and compound intake (if feeding study):
- no effects observed
- Organ weight findings including organ / body weight ratios:
- no effects observed
- Histopathological findings: non-neoplastic:
- no effects observed
- Other effects:
- no effects observed
Reproductive function / performance (P0)
- Reproductive function: oestrous cycle:
- not examined
- Reproductive function: sperm measures:
- not examined
- Reproductive performance:
- no effects observed
Effect levels (P0)
- Dose descriptor:
- NOAEL
- Effect level:
- > 200 mg/kg bw/day
- Based on:
- test mat.
- Sex:
- male/female
- Basis for effect level:
- other: overall effects
Results: F1 generation
General toxicity (F1)
- Clinical signs:
- no effects observed
- Mortality / viability:
- no mortality observed
- Body weight and weight changes:
- no effects observed
- Sexual maturation:
- not examined
- Organ weight findings including organ / body weight ratios:
- not examined
- Gross pathological findings:
- not examined
- Histopathological findings:
- not examined
Overall reproductive toxicity
- Reproductive effects observed:
- not specified
Any other information on results incl. tables
1. Source Chemical(s)
Benzotriazoles have two fused rings, one 1,2,3-triazole and one benzene ring. In Tolyltriazole, the benzene ring is substituted with one methyl group, while in Benzotriazole all substituents are hydrogen.
The Benzotriazoles can be deprotonated at the Nitrogen, leading to the conjugated base as sodium salt.
The differences in the chemical structure (from Benzotriazole to Tolyltriazole) are not expected to change the toxicological properties significantly.
The sodium salts are more basic than the neutral substances (Benzotriazole and Tolyltriazole) and present therefore irritant and corrosive properties, as seen in in vivo studies. Nevertheless, systemic effects are expected to be comparable between the salts and the neutral substances due to the fact that in physiological environment (pH 6-8) protonation of the slat occurs and the neutral species is yielded.
2. Purity/impurities
The impurities in the target substance do not indicate toxicological relevence to this endpoint. The impurities are all below 1 %.
The excess sodium hydroxide of sodium benzotriazolate and sodium tolyltriazolate increases the toxicological irritation/corrosion properties as seen in valid in vivo tests. Further on, it is assumed that no other influence then the basic reservoir is changed by this impurity
3. Analogue approach justification
According to Annex XI, 1.5 a read-across approach can be used to fill the data gap when certain criteria are fulfilled. The fulfillment of these criteria is discussed below. The information from the REACH technical guidance document R.6 are used for this assessment as well as ECHA's Practical guide 6 on category and read-across approaches (ECHA REACH TGD; ECHA, 2009).
Quality of the experimental data of the analogues
The source chemical has been tested in a well-conducted study (According to OECD TG 407). The study results receive reliability 1.
Toxicokinetics
The source and target chemicals indicate similarity in toxicokinetic behavior based on the molecular weight (< 200), physical form (all are solids), vapor pressure (< 10 Pa) and Log POW(0-2).
The difference between the neutral species and the salts in respect to log POWis in the range of 1 and expected to be of minimal relevance. The charge of the Benzotriazolate anion in the salts will decrease the bioavailability but in contact with water the neutral species will be formed in dependence of the pH.
Reactivity towards proteins and DNA
(Q)SAR modeling
The (Q)SAR modeling as such is not used for predictivity but it is used for showing that the Benzotriazoles have the same toxicological profile according to these models.
The OECD (Q)SAR toolbox program is used to obtain the toxicological profile for the source and target substances.
The benzotriazole structures result in two alerts with regard to toxicity:
- Toxic Hazard Classification by Cramer: High (Class III)
- In vivo mutagenicity (Micronucleus) alerts by ISS: H-Acceptor-path 3-H-acceptor for DNA-binding for in vivo mutagenicity.
No alerts were found for DNA or protein binding.
The Toxic Hazard Classification by Cramer: High (Class III) is verified by the observed oral toxicity of the different benzotriazoles (data matrix).
The “in vivo mutagenicity (Micronucleus) alert by ISS” is a false positive alert as the available in vivo genetic toxicity data is negative for this endpoint.
Similarities in results for toxicological endpoints between the target and the source chemical(s) to support read-across for acute dermal toxicity
As it is presented in the data matrix the acute oral toxicity is in the same range for the target and source chemical(s).
The neutral substances (Benzotriazole and Tolyltriazole) show no skin irritation, skin sensitization properties and only mild eye irritation, the salts (Sodium benzotriazolate and sodium tolyltriazolate) show severe skin irritation / corrosion which is caused by the high basicity and the pH of a solution of these substances.
The negative genotoxicity profile is also similar between the source and the target chemical.
For Benzotriazole the Ames test, the mammalian mutation test and the mouse micronucleus test are negative.
For Tolyltriazole the Ames test and the mouse micronucleus test are negative.
Systemic toxicity is seen for Benzotriazole in a two year study and for Tolyltriazole in a 28 days-repeated dose test. No target organ was identified.
A LOAELchronicof 325 mg/kg bw for Benzotriazole and a NOAELsub-acuteof 150 mg/kg bw for Tolyltriazole was established.
Toxicity to reproduction and fertility was tested in a Screening test according to OECD Guideline 421 for Benzotriazole. In this study, a NOAELReprotox-screeningof 200 mg/kg bw/day was found. Higher doses were not tested due to the systemic toxicity of the substance.
4. Data matrix (IUCLID: „Results and discussion“)
Separate document
Applicant's summary and conclusion
- Conclusions:
- The Reproduction Toxicity was examined in a Screening study.
Up to the highest dose of 200 mg/kg bw/day, no effects on the reproduction were observed - Executive summary:
For Benzotriazole a well-conducted in vivo study is available showing a NOAEL of 200 mg/kg bw for the reproductive and developmental dose toxicity. The study was designed as screening study and no higher doses were tested in this study.
This means that a similar result for Sodium Tolyltriazolate can be anticipated.
Sodium Tolyltriazolate has a NOAEL of 200 mg/kg bw for the screening for reproductive and developmental toxicity.
A DNEL for oral, dermal and/or inhalation route can be based on this information.
Classification and labeling are / are not needed for this endpoint.
A risk characterisation will be performed because the substance is classified for orale toxicity.
This human health risk characterization will further support safe use for the reproductive and developmental toxicity endpoints.
Information on Registered Substances comes from registration dossiers which have been assigned a registration number. The assignment of a registration number does however not guarantee that the information in the dossier is correct or that the dossier is compliant with Regulation (EC) No 1907/2006 (the REACH Regulation). This information has not been reviewed or verified by the Agency or any other authority. The content is subject to change without prior notice.
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