Registration Dossier

Administrative data

Description of key information

Rat oral LD50: 7562 mg/kg bw

Rat inhalation LD50 > 1895 mg/m3

Rat dermal LD50 > 2000 mg/kg bw

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: Study conducted according to internationally accepted testing guidelines.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Principles of method if other than guideline:
Rats were dosed at concentrations of 3170, 4640, 6000, 7750 and 10000 mg/kg bw and observed for 14 day post-treatment period in order to evaluated the substance acute oral toxicity.
GLP compliance:
no
Remarks:
Pre GLP.
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
other: Tif. RAIf (SPF)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 160 to 180 g.
- Fasting period before study: the rats were starved during one night before starting the treatment.
- Housing: segregated and housed in MacroIon cages (Type 3) in groups of 5.
- Diet: ad libitum, rat food, NAFAG, Gossau SG.
- Health: healtly rats.
- Water: ad libitum.
- Acclimatization: at leas 4 days.

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 1 °C
- Humidity: approx. 55 ± 5 %.
- Photoperiod: 14 hours light cycle day.
Route of administration:
oral: gavage
Vehicle:
CMC (carboxymethyl cellulose)
Remarks:
2%
Details on oral exposure:
TEST SOLUTION
- Preparation: before treatment the suspension was homogeneously dispersed with an Ultra-Turrax.
- During treatment: the suspension was kept stable with a magnetic stirrer.
Doses:
3170, 4640, 6000, 7750 and 10000 mg/kg bw
No. of animals per sex per dose:
20 males and 20 females; 5 x sex x dose.
Details on study design:
- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: yes; survivors killed and autopsied after an observation period of 14 days.
Statistics:
LD50 including 95 % confidence limits were calculated by the probit analysis method (Goulden A., Methods of Statistical Analysis, John Wiley and Sons, 1960, 3rd printing, pages 404-408).
Sex:
male/female
Dose descriptor:
LD50
Effect level:
7 562 mg/kg bw
Based on:
test mat.
95% CL:
6 651 - 8 598
Clinical signs:
Within 2 hours after treatment the rats in all dosage groups showed sedation, dyspnoea, exophthalmus, curved or ventral position and ruffled fur. The survivor animals recovered within 7 to 8 days.
Gross pathology:
No substance related gross organ changes were seen.

Rate of deaths

Dose
mg/kg
Conc. % of formulation N. of animals Died within
1 hr 24 hrs 48 hrs 7 days 14 days
M F M F M F M F M F M F
3170 30 5 5 0 0 0 0 0 0 0 0 0 0
4640 50 5 5 0 0 0 0 1 0 1 0 1 0
6000 50 5 5 0 0 0 1 0 1 0 1 0 1
7750 50 5 5 0 0 3 2 3 2 3 2 3 2
10000 50 5 5 1 2 4 5 4 5 4 5 4 5
Interpretation of results:
not classified
Remarks:
Migrated information According to the CLP Regulation. Criteria used for interpretation of results: EU
Conclusions:
LD50: 7562 (95 % CL: 6651-8598) mg/kg bw
Executive summary:

Method

Rats were dosed at concentrations of 3170, 4640, 6000, 7750 and 10000 mg/kg bw and observed for 14 day post-treatment period in order to evaluated the substance acute oral toxicity.

Result

LD50: 7562 (95 % CL: 6651-8598) mg/kg bw.

Within 2 hours after treatment the rats in all dosage groups showed sedation, dyspnoea, exophthalmus, curved or ventral position and ruffled fur. The survivor animals recovered within 7 to 8 days.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
7 562 mg/kg bw
Quality of whole database:
The quality of the database is high, since a number of studies are available of good quality and consistent results.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
other: read-across based on grouping of substances (category approach)
Adequacy of study:
supporting study
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Particle size not specified. Justification for Read Across is reported in the endpoint summary and in the Category Justification Report attached to the Section 13 of this dossier.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 403 (Acute Inhalation Toxicity)
GLP compliance:
no
Remarks:
Pre GLP.
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Winkelmann, Borchen, Germany.
- Weight at study initiation: 180 - 200 g.
Route of administration:
inhalation: dust
Type of inhalation exposure:
not specified
Vehicle:
air
Analytical verification of test atmosphere concentrations:
yes
Remarks:
gravimetric with membrane filter.
Duration of exposure:
1 - 4 h
Concentrations:
163.3, 375, 1225 and 1895 mg/m³ air at 4 hour exposure.
1820 mg/m³ air at 1 hour exposure.
No. of animals per sex per dose:
10
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days .
- Necropsy of survivors performed: yes.
- Other examinations performed: clinical signs.
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 1 895 mg/m³ air (nominal)
Based on:
test mat.
Exp. duration:
4 h
Sex:
male/female
Dose descriptor:
LC50
Effect level:
1 820 mg/m³ air (nominal)
Based on:
test mat.
Exp. duration:
1 h
Mortality:
No mortality occuerred.
Clinical signs:
other:
Gross pathology:
No abnormalities detected.
Interpretation of results:
other: not applicable.
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
LC50 (4 h): > 1.895 mg/l air
Executive summary:

Method

Acute inhalation toxicity was assessed following the method described into the OECD guideline 403.

Results

LC50 (4 h): > 1.895 mg/l air

LC50 (1 h): 1.820 mg/l air

Conclusion

According to the CLP Regulation (EC 1272/2008), 3.1 Acute toxicity section, substances can be allocated to one of four toxicity categories based on acute toxicity by the oral, dermal or inhalation route according to the numeric criteria. Acute toxicity values are expressed as (approximate) LD50 (oral, dermal) or LC50 (inhalation) values or as acute toxicity estimates (ATE).

The inhalation LD50 value classification limit for dust is 5.0 mg/l (category 4: 1.0 < ATE ≤ 5.0 mg/l). In the current test an LD50 was non identified; considering the fact that no mortality occurred, a classification category can not be assigned. Thus, a classification according to the CLP Regulation (EC 1272/2008) is not applicable.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
Value:
1 895 mg/m³

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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted according to internationally accepted testing guidelines; the deviations do not impair the result's reliability.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: BRL, Biological Research Laboratories Ltd. Wolferstrasse 4, CH-4414 Fullinsdorf.
- Age at study initiation: males: 10 weeks; females: 12 weeks.
- Weight at study initiation: males: 228 - 234 g; females: 198 - 206 g.
- Housing: individually in Makrolon type-2 cages with standard softwood bedding.
- Diet: Kliba 343, Batches 77/90 and 78/90 rat maintenance diet ("Kliba", Klingentalmuehle AG, CH-4303 Kaiseraugst) ad libitum.
- Water: community tap water from Itingen, ad libitum.
- Acclimation period: 1 week.
Only those animals with no signs of skin injury or irritation were used in the experiment.

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3 °C
- Humidity: 40-70 %
- Photoperiod: 12/12 hrs dark / hrs light.
Type of coverage:
semiocclusive
Vehicle:
water
Details on dermal exposure:
TEST SITE
- Area of exposure: approximately 24 hours before treatment, the backs of the animals were clipped with an electric clipper.
- % coverage: approximately 10 % of the total body surface.
- Application: on test day 1, the test article was applied evenly on the skin with a syringe and covered with a semi-occlusive dressing.
- Type of wrap if used: the dressing was wrapped around the abdomen and fixed with an elastic adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing: with lukewarm tap water, dried with disposable paper towels.
- Time after start of exposure: 24 h

TEST MATERIAL
- Amountapplied: 4 ml/kg body weight was applied to the test site, for a dose of 2000 mg/kg
- Concentration: 0.5 g/ml
- Constant volume or concentration used: yes
Duration of exposure:
24 hours after the application, the dressing was removed.
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
3
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations: four times during day 1, and daily during days 2-13. Skin reactions were assessed on removal and after 48 and 72 hours and 4 and 7 days.
- Frequency of weighing: test days 1 (pre-administration), 8 and 15.
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Mortality:
No mortality occured.
Clinical signs:
No systemic signs were observed in the animals during the entire observation period.
Local symptoms: all animals had a discoulored skin (yellow), and 1 male showes scales at the back. All animals had recovered from the local signs after 8 observation days.
Body weight:
One female lost slightly weight between day 1 and 8 of the test period. The body weight gain of the further animals was not affected throughout the
study by test article treatment.
Gross pathology:
No macroscopical organ findings were observed in the animals.
Other findings:
IRRITATION
Well defined erythema (grade 2) was observed in all animals after 24 hours, as well as in 4/6 animals at 48 and 72 hours. After 24, 48 and 72 hours, the erythema scores were 2.0, 1.7 and 1.7. Except for one slight edema (grade 2) in one male after 48 hours, only very slight edema (grade 1) was observed in some animals after 24, 48 and 72 hours. After 24, 48 and 72 hours, the edema scores were 1.0, 0.7 and 0.5, respectively.
All effects were fully reversible within 7 days (all scores: 0.0). There was no staining of the treated skin.
Interpretation of results:
not classified
Remarks:
Migrated information According to the CLP Regulation. Criteria used for interpretation of results: EU
Conclusions:
LD50 > 2000 mg/kg bw.
Executive summary:

Method

Upon an acute oral single administration (2000 mg/kg bw) and a 14 day post-treatment observation period, the dermal LD50 was determined for the test substance, according to the OECD guideline 402.

Results

LD50 > 2000 mg/kg bw.

No systemic signs were observed in the animals during the entire observation period.

All animals had a discoulored skin (yellow), and 1 male showes scales at the back. All animals had recovered from the local signs after 8 observation days.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw

Additional information

Several acute toxicity studies are available: all were performed on rats and they were conducted following test procedures similar to those outlined into the OECD guideline 401. The lots tested were different, with different concentration percentages of the substance. Nevertheless, all the test clearly indicated that the substance is not harmful and thus the lowest LD50 identified has been chosen for the Risk Assessment: 7562 mg/kg bw (Ciba-Geigy Ltd., 1975).

A good GLP Klimish 1 study for acute dermal toxicity is reported (Ciba-Geigy Ltd., 1990). It was performed just at 2000 mg/Kg bw and no systemic signs were observed in the animals during the entire observation period (RCC, Research & Consulting Company AG., 1990).

Because of the physical state and the trade forms, inhalation is not an appropriate route of exposure. Acute toxicity results for the other two exposure routes indicate no concern therefore no testing was performed. One test is available on an analogous substance, performed at the maximum allowed concentration of 1890 mg/m3: no effects were observed. The analogous substance, part of the Stilbene Fluorescent Withening Agents, group 3, is the acid form of the disulphonated derivative dihydroxyethyl derivative (Justification for Read Across is reported in the Category Justification Report attached to the Section 13 of the dossier).

As a conclusion, it can be stated that the substance is not acutely toxic for all the three exposure ways.

Justification for selection of acute toxicity – oral endpoint

Several acute toxicity studies performed on rats are available and all the test clearly indicated that the substance is not harmful; thus the lowest LD50 identified has been chosen for the Risk Assessment. The study was conducted according to internationally accepted testing guidelines.

Justification for selection of acute toxicity – dermal endpoint

Study conducted according to internationally accepted testing guidelines, in GLP. Furthermore the active ingredient tested was 83 %.

Justification for classification or non-classification

According to the CLP Regulation (EC 1272/2008), 3.1 Acute toxicity section, substances can be allocated to one of four toxicity categories based on acute toxicity by the oral, dermal or inhalation route according to the numeric criteria. Acute toxicity values are expressed as (approximate) LD50 (oral, dermal) or LC50 (inhalation) values or as acute toxicity estimates (ATE).

The oral LD50 value was established to be ca 7562 mg/kg body weight, therefore the test substance is out of any classification limit for acute oral toxicity (oral acute toxicity category 4: 300 < ATE ≤ 2000 mg/kg bw).

The dermal LD50 value was established to exceed 2000 mg/kg body weight, which exceeded the highest CLP classification limit (dermal acute toxicity category 4: 1000 < ATE ≤ 2000 mg/kg bw).

The inhalation LC50 value was established to be greater than 1895 mg/m3. For powder the limit for classification is ATE > 5 mg/l i. e. 5000 mg/m3.

Since no effect was observed at the tested concentration and this was the maximum reachable concentration in the test condition, it is assumed that the substance is not classified for inhalation acute toxicity.

In conclusion, the available experimental data are adequate for classification and labelling and the test substance is non classified for oral and dermal acute toxicity, according to the CLP Regulation (EC 1272/2008).