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Description of key information

The substance has an oral LD50 of 500 mg/kg bw. 
In an acute dermal toxicity test for an analogue 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 LD50 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
Study period:
The study was performed between 23 October 2012 and 15 November 2012.
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted to GLP and in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficiencies, which do not effect the quality of the relevant results.
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.1100 (Acute Oral Toxicity)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other:  Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 2000
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals or test system and environmental conditions:
Female Wistar (RccHan:WIST) strain rats were supplied by Harlan Laboratories UK Ltd., UK. On receipt the animals were randomly allocated to cages. The animals were nulliparous and non pregnant. After an acclimatisation period of at least five days the animals were selected at random and given a number unique within the study by indelible ink marking on the tail and a number written on a cage card. At the start of the study the animals were eight to twelve weeks of age. The bodyweights fell within an interval of ±20% of the mean initial bodyweight of the first treated group.

The animals were housed in groups of three in suspended solid floor polypropylene cages furnished with woodflakes. With the exception of an overnight fast immediately before dosing and for approximately three to four hours after dosing, free access to mains drinking water and food (2014C Teklad Global Rodent diet) was allowed throughout the study. The diet, drinking water and bedding were routinely analysed and were considered not to contain any contaminants that would reasonably be expected to affect the purpose or integrity of the study.

The temperature and relative humidity were set to achieve limits of 19 to 25°C and 30 to 70% respectively. Any occasional deviations from these targets were considered not to have affected the purpose or integrity of the study. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give twelve hours continuous light (06:00 to 18:00) and twelve hours darkness.
Route of administration:
oral: gavage
Vehicle:
other: distilled water
Details on oral exposure:
VEHICLE
- Concentration in vehicle:
33.8 mg/ml (for 338 mg/kg dose level (equivalent to 300 mg active ingredient/kg).
225.3 mg/ml (for 2253 mg/kg dose level (equivalent to 2000 mg active ingredient/kg).


MAXIMUM DOSE VOLUME APPLIED: 10 ml/kg


DOSAGE PREPARATION:
For the purpose of the study, test concentrations were adjusted to allow for the stated water content (11.2%) of the test item. The test item was freshly prepared, as required, as a solution at the appropriate concentration in distilled water.
The test item was formulated within two hours of being applied to the test system. It is assumed that the formulation was stable for this duration.

Doses:
2253 and 338 mg/kg bodyweight (equivalent to 2000 and 300 mg active ingredient/kg bodyweight, respectively).
No. of animals per sex per dose:
6 females at 338 mg/kg bodyweight (equivalent to 2300 mg active ingredient/kg bodyweight).
3 females at 2253 mg/kg bodyweight (equivalent to 2000 mg active ingredient/kg bodyweight, respectively).
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days

- Frequency of observations and weighing: The animals were observed for deaths or overt signs of toxicity ½, 1, 2 and 4 hours after dosing and subsequently once daily for up to fourteen days.
Individual bodyweights were recorded prior to dosing and seven and fourteen days after treatment or at death.

- Necropsy of survivors performed: yes - At the end of the observation period the surviving animals were killed by cervical dislocation. All animals were subjected to gross pathological examination. This consisted of an external examination and opening of the abdominal and thoracic cavities for examination of major organs. The appearance of any macroscopic abnormalities was recorded. No tissues were retained.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 300 - < 2 000 mg/kg bw
Based on:
act. ingr.
Mortality:
Individual mortality data are given in Table 1.

One hour after dosing animals treated at a dose level of 2253 mg/kg (equivalent to 2000 mg active ingredient/kg bodyweight) were found dead or killed for humane reasons, due to the occurrence of clinical signs of toxicity that exceeded the moderate severity limit set forth in the UK Home Office Project Licence.

There were no deaths at a dose level of 338 mg/kg (equivalent to 300 mg active ingredient/kg bodyweight).
Clinical signs:
Individual clinical observations are given in Table 2 and Table 3.

Signs of systemic toxicity noted at a dose level of 2253 mg/kg (equivalent to 2000 mg active ingredient/kg bodyweight) were prostration and increased respiratory rate or laboured respiration.

Signs of systemic toxicity noted at a dose level of 338 mg/kg (equivalent to 300 mg active ingredient/kg bodyweight) were ataxia, hunched posture, lethargy, ptosis, prostration and increased lachrimation. All animals treated at a dose level of 338 mg/kg (equivalent to 300 mg active ingredient/kg bodyweight) appeared normal one day after dosing.
Body weight:
Individual bodyweights and weekly bodyweight changes are given in Table 4 and Table 5.

The surviving animals showed expected gains in bodyweight over the study period.
Gross pathology:
Individual necropsy findings are given in Table 6 and Table 7.

Abnormalities noted at necropsy of animals treated at a dose level of 2253 mg/kg (equivalent to 2000 mg active ingredient/kg bodyweight) were abnormally red lungs, dark liver, haemorrhage and epithelial sloughing of the gastric mucosa and gaseous small intestine. No abnormalities were noted at necropsy of animals treated at a dose level of 338 mg/kg (equivalent to 300 mg active ingredient/kg bodyweight).

See attached background material for Tables 1 -7.

Interpretation of results:
Toxicity Category IV
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 338 mg/kg bodyweight but less than 2253 mg/kg bodyweight (equivalent to greater than 300 and less than 2000 mg active ingredient/kg bodyweight, (Globally Harmonised Classification System – Acute Oral Toxicity Category 4).

The test item was classified as Acute Oral Toxicity Category 4 according to the Regulation (EC) No. 1272/2008. The Signal Word ‘Warning’ and the Hazard Statement ‘H302: Harmful if swallowed’ are therefore required.
Executive summary:

Introduction.

The study was performed to assess the acute oral toxicity of the test item following a single oral administration in the Wistar strain rat. The method was designed to be compatible with the following:

- OECD Guidelines for the Testing of Chemicals No. 423 “Acute Oral Toxicity – Acute Toxic Class Method” (adopted 17 December 2001)

-  Method B1 tris Acute Toxicity (Oral) of CommissionRegulation (EC) No. 440/2008

-  United States Environmental Protection Agency Health Effects Test Guidelines OPPTS 870.1100 Acute Oral Toxicity, 2002

-  Japanese Ministry of Agriculture, Forestry and Fisheries (JMAFF), 2000

Method. 

A group of three fasted females was treated with the test item at a dose level of 338 mg/kg bodyweight (equivalent to 300 mg active ingredient/kg bodyweight). Based on the results from this dose level, further groups of fasted females were treated at dose levels of 2253and 338 mg/kg bodyweight (equivalent to 2000 and 300 mg active ingredient/kg bodyweight, respectively). Dosing was performed sequentially.

The test item was administered orally as a solution in distilled water. Clinical signs and bodyweight development were monitored during the study. All animals were subjected to gross necropsy.

Mortality. 

During the day of dosing animals treated at a dose level of 2253 mg/kg (equivalent to 2000 mg active ingredient/kg bodyweight) were found dead or killed for humane reasons, due to the occurrence of clinical signs of toxicity that exceeded the moderate severity limit set forth in the UK Home Office Project Licence. There were no deaths at a dose level of 338 mg/kg (equivalent to 300 mg active ingredient/kg bodyweight).

Clinical Observations. 

Signs of systemic toxicity noted at a dose level of 2253 mg/kg (equivalent to 2000 mg active ingredient/kg bodyweight) were prostration and increased respiratory rate or laboured respiration. Signs of systemic toxicity noted at a dose level of 338 mg/kg (equivalent to 300 mg active ingredient/kg bodyweight) were ataxia, hunched posture, lethargy, ptosis, prostration and increased lachrimation. All animals treated at a dose level of 338 mg/kg (equivalent to 300 mg active ingredient/kg bodyweight) appeared normal one day after dosing.

Bodyweight. 

The surviving animals showed expected gains in bodyweight over the study period.

Necropsy. 

Abnormalities noted at necropsy of animals treated at a dose level of 2253 mg/kg (equivalent to 2000 mg active ingredient/kg bodyweight) were abnormally red lungs, dark liver, haemorrhage and epithelial sloughing of the gastric mucosa and gaseous small intestine. No abnormalities were noted at necropsy of animals treated at a dose level of 338 mg/kg (equivalent to 300 mg active ingredient/kg bodyweight).

Conclusion. 

The acute oral median lethal dose (LD50) of the test item in the female Wistar strain rat was estimated to be greater than 338 mg/kg bodyweight but less than 2253 mg/kg bodyweight (equivalent to greater than 300 and less than 2000 mg active ingredient/kg bodyweight), (Globally Harmonised Classification System – Acute Oral Toxicity Category 4).

The test item was classified asAcute Oral Toxicity Category 4 according to the Regulation (EC) No. 1272/2008. The Signal Word ‘Warning’ and the Hazard Statement ‘H302: Harmful if swallowed’ are therefore required.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
500 mg/kg bw
Quality of whole database:
one study available for the substance, for analogue substances (Benzotriazole, Tolyltriazole, Sodium Tolyltriazolate) comparable LD50-values were observed.

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:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well-performed study
Qualifier:
equivalent or similar to guideline
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 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
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
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. This means that a similar result for Sodium Benzotriazolate can be anticipated.

 

Sodium Benzotriazolate is not an acute dermal toxicant 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 characterization will be performed because the substance is classified for oral toxicity.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
no study available for the substance, one study available for an analogue substance (Sodium Tolyltriazolate)

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 placing on the market as solution) indicate that the inhalation route is irrelevant compared to the dermal and oral route.

Justification for selection of acute toxicity – dermal endpoint
Read across from an analogue substance (Sodium Tolyltriazolate) available

Justification for classification or non-classification

According to Regulation (EC) No 1272/2008 the substance is classified as Hazard category 4 for acute oral toxicity. For this classification the substance has to be labelled with the signal word “Warning” and GHS pictogram "GHS07".

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