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Acute Toxicity: dermal

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Administrative data

Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1984

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes

Test material

Constituent 1
Reference substance name:
Sodium methylbenzyltriazole
IUPAC Name:
Sodium methylbenzyltriazole
Constituent 2
Chemical structure
Reference substance name:
Sodium 4(or 5)-methyl-1H-benzotriazolide
EC Number:
265-004-9
EC Name:
Sodium 4(or 5)-methyl-1H-benzotriazolide
Cas Number:
64665-57-2
Molecular formula:
C7H7N3.Na
IUPAC Name:
sodium 4(or5)-methylbenzotriazol-1-ate
Test material form:
other: solution
Details on test material:
- Name of test material (as cited in study report): Preventol CI 7-50
- Molecular formula (if other than submission substance): C7H6N3Na
- Molecular weight (if other than submission substance): 155.13 g/mol
- Smiles notation (if other than submission substance): [Na+].CC1=C2N=N[N-]C2=CC=C1; [Na+].CC1=CC=C2[N-]N=NC2=C1
- InChl (if other than submission substance): InChI=1S/C7H6N3.Na/c1-5-2-3-6-7(4-5)9-10-8-6;/h2-4H,1H3;/q-1;+1; InChI=1S/C7H6N3.Na/c1-5-3-2-4-6-7(5)9-10-8-6;/h2-4H,1H3;/q-1;+1
- Structural formula attached as image file (if other than submission substance):
- Substance type: organic
- Physical state: solved
- Lot/batch No.: 150-5-45
- Storage condition of test material: tighty closed container

Test animals

Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Small Stock, Inc., Pea Ridge, Arkansas
- Age at study initiation: no data
- Weight at study initiation: 2.6 to 2.8 kg
- Fasting period before study: no
- Housing: stainless steel cages, individual
- Diet: Purina Rabbit Chow ad libitum
- Water: ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.5 - 23.33
- Humidity (%): 35 - 55 %
- Air changes (per hr): no data
- Photoperiod (hrs dark / hrs light): 12

Administration / exposure

Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Details on dermal exposure:
TEST SITE
- Area of exposure: backs of animals
- Type of wrap if used: gauze, hypoallergenic tape, plastic, tape and elastic bandage

REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes, with paper towel and water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: twice daily, weighing on the day of treatment, 7 and 14 days after
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
no statistics performed

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
no mortalities occured
Clinical signs:
ataxia in all animals, salivation and a nasal discharge in some. These signs were not noted any longer at the 24-hour observation period.
Edema was noted only on day 1.
Erythema and discoloration of the back were apparent from day 1 to day 14.
Body weight:
Day: 0 7 14
males: 2.7 2.8 3.1
females: 2.6 2.7 2.9
Gross pathology:
no systemic signs of toxicity except signs of toxicity of the integumentary system: Erythema and discoloration of the back

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 (equivalent to OECD TG 402). The study results receive reliability 2.


 


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


 


See separate document

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
For Sodium Tolyltriazlate a well-conducted in vivo study is available showing no dermal toxicity up to the limit dose of 2000 mg/kg bw.
Executive summary:

For Sodium Tolyltriazolate a well-conducted in vivo study is available showing no dermal toxicity up to the limit dose of 2000 mg/kg bw.