Sodium 4(or 5)-methyl-1H-benzotriazolide

Endpoint summary

Description of key information

One orale subaute toxicity study is available, giving a NOAEL of 150 mg/kg bw/day.

As the former read-across to the proposed analogueous substance Benzotriazole (CAS 95-14-7) proofed to be
scientifcly not adequate, a read-across based on a category developed in OECD QSAR Toolbox 
was used to fulfill the data gap which arose. 
Category read-across Predictions taking into account studies with durations > 28 d
resulted in dose descriptors for the two main constituents.
While 4-Methyl-1H-Benzotriazole was predicted to have a NOAEL/NOEL of 435 resp. 168 mg/kg bw/day,
the results for 5-Methyl-1H-Benzotriazole are more consistent:
Ttwo predictions were made, one included substances for which a NOEL is available and one prediction
with substances with a NOAEL.
Both predictions resulted in a NOEL/NOAEL for 5-Methyl-1H-Benzotriazole (repeated dose toxicita, duration > 28 d) of
19 mg/kg bw/day.
However this information cannot be used for Hazard conclusion, as the approach does not give information on target organ(s) and 
details of effects. 
As a test is proposed, the information from this read across approach could be used for dose selection.



In a prenatal developmental toxicity study, a NOAEL of 90 mg/kg bw/day for systemic toxicity was determined.
For Hazard and risk assessment the lowest dose descriptor available is used.
A recalculation from the constituent to the substance, taking into account the typical concentration of the constituent
is not performed.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

Sodium Tolyltriazolate is expected to have a similar repeated dose toxicity over 28-days compared to the analogue Tolyltriazole resulting in a similar no observed adverse effect level (NOAEL), which is 150 mg/kg bw/day. The NOAEL of Tolyltriazole was determined in a well performed study. The source chemical Tolyltriazole is sufficiently similar to read-across towards Sodium Tolyltriazolate.

Reason / purpose for cross-reference:

read-across source

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Wistar

Frequency of treatment:

daily

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

in 450 mg/kg bw groups

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
one animal (450 mg/kg bw, female) died during the study
after the daily application, all animals in the dose group of 450 mg/kg bw showed apathy

BODY WEIGHT AND WEIGHT GAIN
no findings

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
no findings

HAEMATOLOGY
no findings in the dose groups 50 and 150 mg/kg bw
reduced levels of eryhtocytes, hematocrit and hemoglobine in the male dose group 450 mg/kg bw

CLINICAL CHEMISTRY
Raised activity of alanin-aminotransferase in male/female dose group 450 mg/kg bw
Reduced concentration of the plasma protein concentration in male/female dose group 450 mg/kg bw

ORGAN WEIGHTS
no findings

GROSS PATHOLOGY
two male and one female animal had pale kidneys

HISTOPATHOLOGY: NON-NEOPLASTIC
no findings


OTHER FINDINGS

Dose descriptor:

NOAEL

Effect level:

ca. 150 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical biochemistry

haematology

Critical effects observed:

not specified

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 P_OW(0-2).

 

The difference between the neutral species and the salts in respect to log P_OWis 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 LOAEL_chronicof 325 mg/kg bw for Benzotriazole and a NOAEL_sub-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 NOAEL_{Reprotox-screening}of 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

Conclusions:

In doses up to 150 mg/kg bw / day, no adverse effects were observed.
A dose of 450 mg/ kg bw/day lead to apathy after gavage, to a changed blood count and raised plasma activity of transaminases GOT and GPT

Executive summary:

For Tolyltriazole a well-conducted in vivo study is available showing a NOAEL of 150 mg/kg bw for the 28 days repeated dose toxicity. This means that a similar result for Sodium Tolyltriazolate can be anticipated.

 

Sodium Tolyltriazolate has a NOAEL of 150 mg/kg bw for the 28 days repeated dose toxicity.

 

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:

adverse effect observed

Dose descriptor:

NOAEL

150 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The study is a well conducted GLP-Study following the OECD-Guideline

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Mode of Action Analysis / Human Relevance Framework

based on the available data, no mode of action can be identified.

Justification for classification or non-classification

Based on the available data and the low severity of effects observed in experimental studies, criteria for classification is not met.