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Toxicological information

Acute Toxicity: dermal

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Administrative data

Endpoint:
acute toxicity: dermal
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:
Benzotriazole 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 Benzotriazole.

Data source

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

Materials and methods

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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
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 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
Key result
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

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 test (equivalent to OECD TG 402). The rest 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.

 

 

 

2.      Data matrix

 

Common names

Benzotriazole

Tolyltriazole

Sodium Benzotriazolate

Sodium Tolyltriazoloate

Chemical structure

CAS no

95-14-7

29385-43-1

15217-42-2

64665-57-2

Physicochemical data

Molecular weight

119.14

133.15

 

155.13

Physical state

Solid

Solid

 

Solid

Melting point °C

99

76-87

 

Decomposition at approx. 230-231

Boiling point °C

>350

Decomposition at approx. 195

 

Decomposition at approx. 230-231

Vapour pressure Pa (Episuite)

0.003

0.004

 

0.004 (value from Tolyltriazole)

Water solubility mg/l

20000

N/A

 

N/A

WSKOWmg/l

5957

3069

 

55000

Log KOW(meas.)

1.44

N/A

 

N/A

Log KOWWin

1.17

1.71

 

0.14

Log KOWSPARC

0.38

0.86

 

 

Environmental toxicology Endpoints

 

 

 

 

 

 

 

 

 

 

Human health endpoints

Acute oral toxicity mg/kg bw

500 (acute toxic class)

720

 

735

Acute inhalation toxicity

N/A

N/A

 

N/A

Acute dermal toxicity mg/kg bw

Read across

Read across

 

> 2000

Skin irritation

Not irritating

Not irritating

 

Corrosive

Eye irritation

Slightly irritating

Slightly irritating

 

Corrosive

Skin sensitisation

Not sensitising

Not sensitising

 

Read across

Genotoxicity – Ames test

Negative

Negative

 

Read across

Genotoxicity in vitro MLA

Negative

Negative

 

Read across

Genotoxicity in vitro chrom. aberration

Negative

Read across

 

Read across

Repeated-dose toxicity 28-day mg/kg bw

See below:
LOAEL 325

NOAEL 150

 

Read across

Repeated-dose toxicity 90-day mg/kg bw

See below:
LOAEL 325

Read across

 

Read across

Reproductive and developmental toxicity mg/kg bw

 

 

 

 

Repeated-dose toxicity 2 year mg/kg bw

LOAEL 325

-

 

-

 

 

 

 

 

 

Applicant's summary and conclusion

Conclusions:
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 Benzotriazole can be anticipated.

The target chemical is not acute dermal toxic and the derived LD50 is set at > 2000 mg/kg bw for this endpoint.
Executive summary:

Conclusions per endpoint for C&L, PBT, vPvB and dose descriptor

 

For Sodium tolayltriazolate 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 Benzotriazole can be anticipated.

 

Benzotriazole 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.