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Diss Factsheets

Administrative data

Description of key information

LD50 oral > 2000 mg/kg bw
LD50 dermal > 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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
From July 27th to August 19th, 2005
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted according to internationally accepted testing guidelines and performed in compliance with Good Laboratory Practice. Justification for read across approach is given in the endpoint summary and in the read across justification report attached to the Section 13 of this dossier.
Qualifier:
according to guideline
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Version / remarks:
adopted 17th December 2001
Qualifier:
according to guideline
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Version / remarks:
April 29, 2004
GLP compliance:
yes (incl. QA statement)
Test type:
acute toxic class method
Limit test:
yes
Species:
rat
Strain:
other: HanRcc:WIST (SPF))
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd, Laboratory Animal Services CH-4414 Füllinsdorf / Switzerland.
- Age at study initiation: 11-13 weeks.
- Weight at study initiation: 174.2 - 199.7 g.
- Fasting period before study: the animals received a single dose of the test item after being fasted for approximately 18 to 19 hours (access to water was permitted). Food was provided again 3 hours after dosing.
- Housing: Makrolon type-4 cages with wire mesh tops and standard softwood bedding ('Lignocel' Schill AG, CH-4132 Muttenz/Switzerland).
- Diet: pelleted standard Provimi Kliba 3433 rat/mouse mainte-nance diet, batch no. 25/05 (Provimi Kliba AG, CH-4303 Kaiseraugst/Switzerland) ad libitum.
- Water: community tap water from Füllinsdorf ad libitum.
- Acclimation period: under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.

ENVIRONMENTAL CONDITIONS
- Temperature: continuously monitored environment with ranges for room temperature 22 ± 3 °C.
- Humidity: between 30-70 % (values above 70 % during cleaning process possible).
- Air changes: 10-15 air changes per hour.
- Photoperiod: automatically controlled light cycle of 12 hours light and 12 hours dark.
- Other: music during the daytime light period.
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
purified
Details on oral exposure:
VEHICLE
Purified water was found to be a suitable vehicle. The vehicle was chosen after a non-GLP solubility trial which was performed before the study initiation date. This formulation trial is excluded from the GLP statement of compliance.

DOSE FORMULATION
Dose levels are in terms of the test item. The dose formulations were made shortly before each dosing occasion using a magnetic stirrer, a spatula and an Ultra-Turrax (Janke & Kunkel, D-79219 Staufen) as homogenizers.
The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle added (weight : volume).
Homogeneity of the test item in the vehicle was maintained during administration using a magnetic stirrer.

TREATMENT
- Application volume: 10 ml/kg body weight.
- Rationale: oral administration was considered to be an appropriate application method as it is a possible route of human exposure during manufacture, handling and use of the test item.
Doses:
2000 mg/kg body weight
No. of animals per sex per dose:
2 goups of 3 female each one.
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: mortality and viability were controlled daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15. Body weights were recorded on test days 1 (prior to administration), 8 and 15.
- Necropsy of survivors performed: all animals were killed at the end of the observation period by an intraperitoneal injection of Vetanarcol at a dose of at least 2.0 ml/kg body weight (equivalent to at least 324 mg sodium pentobarbitone/kg body weight) and discarded after macroscopic examinations were performed. No organs or tissues were retained.
- Other examinations performed: clinical signs were daily observed during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1. Once daily during days 2-15.
Statistics:
No statistical analysis was used.
Sex:
female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred during the study.
Clinical signs:
No clinical signs were observed during the course of the study.
Body weight:
The body weight of the animals was within the range commonly recorded for this strain and age.
Gross pathology:
No macroscopic findings were recorded at necropsy.

MORTALITY / CLINICAL SIGNS

Dose mg/kg bw Animal N. Sex Signs Test days
1 2 3 4 5 6 7 8 9 10 11 12 13 14
0.5* 1* 2* 3* 5*
2000 1 F No clinical signs √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √
2 F No clinical signs √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √
3 F No clinical signs √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √
2001 4 F No clinical signs √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √
5 F No clinical signs √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √
6 F No clinical signs √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √ √

Key: √ noted

* Examinations were performed approximately 0.5, 1, 2, 3 and 5 hours after treatment.

No clinical signs were evident in any animal during the acclimatization period.

BODY WEIGHTS

Dose mg/kg bw Animal N. Sex Day 1 (treatment) Day 8 Day 15
2000 1 F 180.3 197.9 211.8
2 F 174.2 203.2 214.2
3 F 199.7 222.8 233.2
2001 4 F 176.1 199.7 212.3
5 F 176.1 204.1 218.0
6 F 194.2 218.5 228.3

Body weights are presented in grams.

MACROSCOPIC FINDINGS

Dose mg/kg bw Animal N. Sex Mode of death Findings
2000 1 F Scheduled necropsy No macroscopic findings
2 F Scheduled necropsy No macroscopic findings
3 F Scheduled necropsy No macroscopic findings
2001 4 F Scheduled necropsy No macroscopic findings
5 F Scheduled necropsy No macroscopic findings
6 F Scheduled necropsy No macroscopic findings
Interpretation of results:
not classified
Remarks:
Migrated information according to the CLP Regulation (EC 1272/2008) Criteria used for interpretation of results: EU
Conclusions:
LD50 (female rat) > 2000 mg/kg body weight
Executive summary:

Two groups, each of three female HanRcc:WIST (SPF) rats, were treated with the test item by oral gavage administration at a dosage of 2000 mg/kg body weight. The test item was diluted in vehicle (purified water) at a concentration of 0.2 g/ml and administered at a volume dosage of 10 ml/kg. The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs at approximately 30 minutes, 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Mortality/viability was recorded at approximately 30 minutes, 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15. Body weights were recorded on day 1 (prior to administration) and on days 8 and 15. All animals were necropsied and examined macroscopically. All animals survived until the end of the study period. No clinical signs were observed during the course of the study. The body weight of the animals was within the range commonly recorded for this strain and age. No macroscopic findings were recorded at necropsy.

Conclusion

LD50 (female rat): greater than 2000 mg/kg body weight

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

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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
From July 27th to August 18th, 2005
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Study conducted according to internationally accepted testing guidelines and performed in compliance with Good Laboratory Practice. Justification for read across approach is given in the endpoint summary and in the read across justification report attached to the Section 13 of this dossier.
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Version / remarks:
adopted February 24, 1987
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Version / remarks:
July 31, 1992
GLP compliance:
yes (incl. QA statement)
Test type:
standard acute method
Species:
rat
Strain:
other: HanRcc:WIST (SPF)
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: RCC Ltd, Laboratory Animal Services CH-4414 Fiillinsdorfl Switzerland.
- Age at study initiation: males 7- 8 weeks; females 12-13 weeks.
- Weight at study initiation: males 219.7 - 233.0 g; females 189.4 - 217.5 g.
- Housing: during acclimatization in groups of five per sex in Makrolon type-4 cages with standard softwood bedding. Individually in Makroloh type-3 cages with standard softwood bedding ("LighoceI“, Schill AG, CH-4132 l\/Iuttenz) during treatment and observation.
- Diet: pelleted standard Provimi Kliba 3433 rat/mouse maintenance diet, batch no. 25/05 (Provimi Kliba AG, CH-4303 Kaiseraugst/ Switzerland), ad Iibitum.
- Water: community tap water from Fullinsdorf, ad libitum.
- Acclimation period: under laboratory conditions, after health examination. Only animals without any visible signs of illness were used for the study.

ENVIRONMENTAL CONDITIONS
- Temperature: 22 ± 3 °C
- Humidity: 30 - 70 % (values above 70 % during cleaning process possible).
- Air changes: 10-15 air changes per hour.
- Photoperiod: automatically controlled light cycle of 12 hours light and 12 hours dark.
- Other: music during the daytime light period.
Type of coverage:
semiocclusive
Vehicle:
water
Remarks:
deionised
Details on dermal exposure:
DOSE FORMULATION
The test item was weighed into a tared glass beaker on a suitable precision balance and the vehicle added (weight:voIume). The formulation was prepared shortly before the application using a magnetic stirrer, a spatula and an Ultra-Turrax (Janke & Kunkel, D-79219 Staufen) as homogenizers.
Homogeneity of the test item in the vehicle was maintained during administration using a magnetic stirrer.

TEST SITE
- Area of exposure: one day before treatment, the backs of the animals were clipped with an electric clipper. Only those animals without injury or irritation on the skin were used in the test.
- % coverage: exposing an area of approximately 10 % of the total body surface.
- Type of wrap if used: covered with a semi-occlusive dressing. The dressing was wrapped around the abdomen and fixed with an elastic adhesive bandage.

REMOVAL OF TEST SUBSTANCE
- Washing: the skin was flushed with lukewarm tap water and dried with disposable paper towels.
- Time after start of exposure: twenty-four hours after the application.

TEST MATERIAL
- Amount applied: on test day 1, the test item was applied at a dose of 2000 mg/kg body weight evenly on the intact skin with a syringe (application volume/kg body weight: 4 ml).

Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5 males and 5 females
Details on study design:
- Duration of observation period following administration: 14 days
- Mortality / Viability: daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15.
- Frequency of observations and weighing: on test days 1 (prior to administration), 8 and 15.
- Necropsy of survivors performed: yes. All animals were killed at the end of the observation period by an intraperitoneal injection of Vetanarcol at a dose of at least 2.0 ml/kg body weight (equivalent to at least 324 mg sodium pentobarbitone/kg body weight) and discarded after macroscopic examinations were performed. No organs or tissues were retained.
- Other examinations performed: clinical signs were recorded daily during the acclimatization period, during the first 30 minutes and at approximately 1, 2, 3 and 5 hours after administration on test day 1. Once daily during days 2-15. Local signs Once daily during days 2-15.
Statistics:
No statistical analysis was used.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No deaths occurred during the study.
Clinical signs:
No systemic or local signs of toxicity were observed during the study period.
Body weight:
The body weight ofthe animals was within the range commonly recorded for this strain and age.
Gross pathology:
No macroscopic findings were observed at necropsy.
Interpretation of results:
not classified
Remarks:
Migrated information according to the CLP Regulation (EC 1272/2008) Criteria used for interpretation of results: EU
Conclusions:
LD50 (rat) greater than 2000 mglkg body weight
Executive summary:

Five male and five female HanRcc:WIST (SPF) rats were treated with the test item at 2000 mg/kg by dermal application. The test item was diluted in vehicle (purified water) at a concentration of 0.5 g/ml and administered at a volume dosage of 4 ml/kg. The application

period was 24 hours.

The animals were examined daily during the acclimatization period and mortality, viability and clinical signs were recorded. All animals were examined for clinical signs at approximately 30 minutes, 1, 2, 3 and 5 hours after treatment on day 1 and once daily during test days 2-15. Local signs were noted once daily from test day 2 to 15. Mortality/viability was recorded at approximately 30 minutes, 1, 2, 3 and 5 hours after administration on test day 1 (with the clinical signs) and twice daily during days 2-15. Body weights were recorded on day1 (prior to administration) and on days8 and 15. All animals were necropsied and examined macroscopically.

No deaths occurred during the study.

No clinical signs were observed during the course of the study.

The body weight of the animals was within the range commonly recorded for this strain and age.

No macroscopic findings were observed at necropsy.

Conclusion

The median lethal dose of the test item after single dermal administration to rats of both sexes, observed over a period of 14 days is:

LD50 (rat): greater than 2000 mglkg body weight

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

Additional information

There are no experimental data available on the Leucophor 1501X, thus a read across approach with the structural analogous substances has been proposed.

All the substances used in a read across approach are Stilbene derivatives Fluorescent Whitening Agents salts. They display similar structural and physicochemical properties; all of them exhibit high degree of dissociation in water and very low octanol/water partition coefficients because to a higher affinity with water phase than the octanol one. The water solubility is due to the sulphonated groups in the molecules. The differences occurring in the structure formulas (i.e. substituents) are expected to not significantly impact the toxicological characterisation.Further details about the justification for read across approach are given in the report attached to the Section 13 of this dossier.

ACUTE TOXICITY - ORAL ROUTE

In all the cases investigated, the substances are clearly not harmful/toxic by oral route in rats up to 2000 and 5000 mg/kg bw. No signs of systemic toxicity were noted during the studies and no abnormalities were noted. Only in one study one male was killed one hour after dosing having sustained a broken leg. This was done for humane reasons in accordance; the death was therefore not attributed to the toxicity of the test material (Tomlinson, 1993).

ACUTE TOXICITY - INHALATION ROUTE

According to the REACH Regulation Annex VIII Column 2 (specific rules for adaptation from column 1) in addition to the oral route (8.5.1), for substances other than gases, the information mentioned under 8.5.2 to 8.5.3 shall be provided for at least one other route. The choice for the second route will depend on the nature of the substance and the likely route of human exposure. Because of the physical state and the trade forms of the substance inhalation is not an appropriate route of exposure. The substance is manufactured and used as aqueous solution, furthermore at manufacturing level, the substance is handled with suitable risk management measures and with the suitable personal protective equipments.

ACUTE TOXICITY - DERMAL ROUTE

No signs of systemic toxicity were noted during the studies performed on analogous substances. The LD50 values resulted to be greater than 2000 mg/kg bw in all the cases.

Slightly depressed bodyweight gains were observed during the first week of treatment in the study performed on analogous substance 02. The test was performed administering a dose of 5000 mg/kg bw. The bodyweight gain returned to normal during the second week, compared with controls (Kynoch and Lloyd, 1975).


Justification for selection of acute toxicity – oral endpoint
Study conducted according to internationally accepted testing guidelines and performed in compliance with Good Laboratory Practice.

Justification for selection of acute toxicity – dermal endpoint
Study conducted according to internationally accepted testing guidelines and performed in compliance with Good Laboratory Practice.

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 greater than 2000 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).

In conclusion, the test substance is not classified for oral and dermal acute toxicity, according to the CLP Regulation (EC 1272/2008).