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Administrative data

Description of key information

The substance has an oral LD50 of 720 mg/kg bw. In an acute dermal toxicity test the limit dose of 2000 mg/kg bw did not lead to mortality, the dermal LD50 is set to 2000 mg/kg bw by default.
An inhalative LC50 is not available.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well performed and documented toxicological study
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
The test item is administered oral to groups of rats in different doses.
The animals are examined for 14 days post gavage and sacrificed.
All animals found dead or sacrificed are pathological analysed.
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Bor: WISW (SPF Cpb)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Winkelmann, Borchen
- Age at study initiation: 9 (male) 14 (female)
- Weight at study initiation: 174 (male) 167 (female)
- Fasting period before study: 16 hours
- Housing: Makrolon cages type III
- Diet: Altromin R1324 ad libitum except fasting period
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +-1.5 °C
- Humidity (%): 60 +-5 %
- Photoperiod (hrs dark / hrs light): 12 h
Route of administration:
oral: gavage
Vehicle:
DMSO
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): 10 ml / kg
- Justification for choice of vehicle: DMSO is appropriate solvent for the test item
Doses:
500/630/730/800/1000/1300 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: daily, first day 1, 2, 4, 8, 24 hours
- Necropsy of survivors performed: yes
Statistics:
Calculation of LD50 and confidence interval for p < 0.05 was performed according to Rosiello, J. Tox. Environ. Health, 3, 1977, 797
Sex:
male/female
Dose descriptor:
LD50
Effect level:
ca. 720 mg/kg bw
Based on:
test mat.
95% CL:
> 700 - < 800
Mortality:
in the lowest dose group all animals survived, with increasing dose, the mortality increases up to 100 % in the highest dose group
Clinical signs:
decrease of general condition, Loss of body weight, ventral and lateral position, sedation, paralysis of rear extremities, bloodily mouth
Body weight:
no data
Gross pathology:
The animals died during the study showed an irritation of the stomach mucosa
Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
4(or5)-methyl-1H-benzotriazole is harmful to rats by oral gavage. The LD50 is 720 mg/kg bw
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
720 mg/kg bw
Quality of whole database:
The study is not conducted using an international Guideline, therefore rated with Klimisch 2.
Nevertheless all relevant information equal to a Guideline study are provided.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Remarks:
Tolyltriazle is expected not to be acute dermal toxic because the analogue Sodium Tolyltriazolate has not shown acute dermal toxicity properties in a well performed study. The source chemical Sodium Tolyltriazolate is sufficiently similar to read-across towards Tolyltriazole.
Justification for type of information:
Tolyltriazle is expected not to be acute dermal toxic because the analogue Sodium Tolyltriazolate has not shown acute dermal toxicity properties in a well performed study. The source chemical Sodium Tolyltriazolate is sufficiently similar to read-across towards Tolyltriazole.
Reason / purpose:
read-across source
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals 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
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
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

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

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.
This means that a similar result for Tolyltriazle can be anticipated.

Tolyltriazle is not acute dermal toxic and the derived LD50 is set at > 2000 mg/kg bw for this endpoint.
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. This means that a similar result for Tolyltriazle can be anticipated.

 

Tolyltriazle is not acute dermal toxic and the derived LD50 is set at > 2000 mg/kg bw for this endpoint.

A DNEL for oral, dermal and/or inhalation route can be based on this information.

Classification and labelling are / are not needed for this endpoint.

A risk characterisation will be performed because the substance is classified for orale toxicity.

 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
2 000 mg/kg bw
Quality of whole database:
The related study is not conducted using an international Guideline, therefore rated with Klimisch 2.
Nevertheless all relevant information equal to a Guideline study are provided.

Additional information

Justification for selection of acute toxicity – oral endpoint
only one study available

Justification for selection of acute toxicity – inhalation endpoint
No study concerning toxicity via the inhalation route is required as the physicochemical properties (low vapour pressure and high particle size) indicate that the inhalation route is irrelevant compared to the dermal and oral route.

Justification for selection of acute toxicity – dermal endpoint
Read across; only information available

Justification for classification or non-classification