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Description of key information

The acute oral LD50 of FAT 40032 in rats of both sexs observed over a period of 14 days is greater than 5000 mg/kg bw. While the acute dermal LD50 based on available data with a read across substance, is considered to be >2000 mg/kg bw.  

    
    
    
    
    
    
    
    
    
    
    
    

the acute oral LD50 of FAT 40032/C in rats of both sexes observed over a period of 14 days is greater than 5000 mg/kg.

the acute oral LD50 of FAT 40032/C in rats of both sexes observed over a period of 14 days is greater than 5000 mg/kg.

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:
1984
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Justification for type of information:
None
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Principles of method if other than guideline:
None
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
Code: FAT 40032/C
Batch: EN 94031.32
Stability: guaranteed by the sponsor until November 1988
Description: solid
Species:
rat
Strain:
other: Rat, Tif:RAIf(SPF), 1/Tif x RII 2/Tif
Sex:
male/female
Details on test animals or test system and environmental conditions:
Species and Strain: Rat, Tif:RAIf(SPF), 1/Tif x RII 2/Tif
Source: CIBA-GEIGY LTD. Tierfarm, 4334 Sisseln, Switzerland
Initial Body Weight Range: 176-227 g
Initial Age: 7-8 weeks
Individual Identification: by colour code using picric acid

Husbandry: The animals were kept under conventional laboratory conditions. They were caged in groups of 5 in Macrolon cages type 4 with standardized soft wood bedding (Société Parisienne des sciures, Pantin).
The animal room was air conditioned: temperature 22±3 °C, relative humidity 55±15 %, 12 hours light/day, approximately 15 air changes/h.
Diet: Rat food, NAFAG No. 890, NAFAG AG, Gossau, SG (Switzerland), and water were provided ad libitum.
Route of administration:
oral: gavage
Vehicle:
other: Distilled water containing 0.5 % carboxymethylcellulose and 0.1 % polysorbate 80 (prepared by Pharmaceutical Division, Ciba-Geigy Ltd.).
Details on oral exposure:
Administration: oral, by gastric intubation (gavage)
Observation: 14 days or until all symptoms have disappeared, whichever lasts longer
Doses:
A single dose of 5000 mg/kg bw.
No. of animals per sex per dose:
5 males and 5 females
Control animals:
no
Details on study design:
None
Statistics:
None
Preliminary study:
None
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
None
Clinical signs:
Dyspnoea, exophthalmos, ruffled fur and curved body position were seen, being common symptoms in acute tests. In addition, a transient diarrhoea was observed, for about two days after the administration the ears and extremities appeared to be hyperaemic.
Body weight:
None
Gross pathology:
No gross lesions were found at necropsy.
Other findings:
None

None

Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral LD50 of FAT 40032 in rats of both sexes observed over a period of 14 days is >5000 mg/kg bw.
Executive summary:

FAT 40032/C was evluated for acute toxicity via oral route using Tif. RAI rats according to OECD Guideline 401. No deaths occurred. Dyspnoea, exophthalmos, ruffled fur and curved body position were seen, being common symptoms in acute tests. In addition, a transient diarrhoea was observed, for about two days after the administration the ears and extremities appeared to be hyperaemic. In conclusion, the acute oral LD50 of FAT 40032/C in rats of both sexes observed over a period of 14 days is greater than 5000 mg/kg bw.

 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
5 000 mg/kg bw
Quality of whole database:
Guideline study.

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
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:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Reason / purpose for cross-reference:
read-across source
Qualifier:
according to guideline
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Qualifier:
according to guideline
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Qualifier:
according to guideline
Guideline:
EPA OTS 798.1100 (Acute Dermal Toxicity)
Qualifier:
according to guideline
Guideline:
other: Testing Methods for New Chemical Substances according to the Revised Japanese Chemical Substance Law (March 31, 1987).
Test type:
standard acute method
Limit test:
yes
Specific details on test material used for the study:
None
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., Wölferstrasse 4, 4414 Füllinsdorf/Switzerland
- Age at study initiation: males: 9 weeks, females: 11 weeks
- Weight at study initiation: males: 253.6 - 286.2 g; females: 196.6 - 212.8 g
- Housing: during acclimatization in groups of five in Makrolon type-4 cages (size: 33 x 55 x 20 cm) with standard softwood bedding ("Lignocel", Schill AG, CH-4132 Muttenz). During treatment and observation individually in Makrolon type-3 cages (size: 22 x 37.5 x 15 cm) with standard softwood bedding.
- Diet (e.g. ad libitum): Pelleted standard Kliba 343, Batch no.73/94 rat maintenance diet ("Kliba", Klingentaimuehie AG, CH-4303 Kaiseraugst) available ad libitum.
- Water (e.g. ad libitum): community tap water from Füllinsdorf, available ad libitum.
- Acclimation period: one week under laboratory conditions, after health examination. Only animals without any visual signs of illness were used for the study.

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity (%): 36-64
- Air changes (per hr): 10-15
- Photoperiod (hrs dark / hrs light): 12/12, music during light period
Type of coverage:
semiocclusive
Vehicle:
water
Remarks:
bi-distilled water
Details on dermal exposure:
TREATMENT
Approximately 24 hours before treatment, the backs of the animals were clipped with an electric clipper, exposing an area of approximately 10 % of the total body surface. Only those animals without injury or irritation on the skin were used in the test.
On test day 1, the test article was applied at a dose of 2000 mg/kg body weight evenly on the intact skin with a syringe and covered with a semi-occlusive dressing. The dressing was wrapped around the abdomen and fixed with an elastic adhesive bandage. Application volume/ kg body weight: 4.0 mL/kg. Twenty-four hours after the application the dressing was removed and the skin was washed with lukewarm tap water and dried with disposable paper towels.

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:
Mortality / Viability*: Four times during test day 1 and daily during days 2-15.
Body Weights: On test days 1 (pre-administration), 8 and 15.
Clinical Signs: Each animal was examined for changes in behaviour and appearance (with special emphasis on the application area, except for the time when the semi-occlusive dressing was in place) four times during day 1, and once daily during days 2-15. All abnormalities were recorded, (general behaviour, respiration, eyes, motor susceptibility, nose, motility, body posture, skin)

* The computerised system does not show that the mortality/viability checks were recorded at the same time as the clinical signs.

- Necropsy of survivors performed:
Necropsies were performed by experienced prosectors. At the end of the observation period all animals were anesthetized by intraperitoneal injection of NARCOREN (Rhone Merieux GmbH, D-88417 Laupheim) at a dose of at least 2.0 mL/kg body weight (equivalent to at least 320 mg/kg sodium pentobarbitone/kg body weight) and sacrificed by exsanguination. The animals were examined macroscopically.
Statistics:
The LOGIT-Model could not be used as no deaths occurred.
Key result
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
There were no deaths as a result of treatment with the test article.
Clinical signs:
No clinical signs of systemic toxicity were observed during the observation period.
Discoloration of the skin at the application site was evident in all animals after the removal of the dressing on test day two and persisted until study termination.
Body weight:
Slight loss of body weight (2.2 and 2.0 g) was noted in female animals no. 7 and 9 respectively during the first observation week. The other animals gained weight over the observation period.
Gross pathology:
No organ abnormalities were observed at necropsy.

None

Interpretation of results:
GHS criteria not met
Conclusions:
The toxicity of the read across substance was estimated to be greater than 2000 mg/kg bw.
Executive summary:

In a GLP compliant dermal toxicity study, performed according to OECD guideline 402, Wistar rats (5/sex) were administered the read across substance (2000 mg/kg bw). The test substance was dissolved in water and applied on the skin with a syringe and covered with a semi-occlusive dressing for 24 hours. The treated skin was washed after 24 hours and a 14-day observation period followed. No mortality, clinical signs of systemic toxicity, or organ abnormalities were observed during this period. The pigment in the test article caused a discolouration of the skin at the application site which persisted throughout the observation period. There were no test article-related effects on the body weight of the animals during the observation period. The minimal to slight loss of body weight in two female animals during the first observation week was considered to be a consequence of the semi-occlusive dressing. Commonly female animals prove to be more sensitive in relation to effects on body weight caused by semi-occlusive dressing than males. The mean lethal dose of test substance after single dermal administration to rats of both sexes, observed over a period of 14 days, could not be estimated, because no deaths occurred at the maximal dose of 2000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
2 000 mg/kg bw
Quality of whole database:
A Guideline study.

Additional information

Acute oral toxicity

Acute oral toxicity of FAT 40032 was evaluated in three available studies. When tested upto 5000 mg/kg bw, no deaths occured in these studies.

In the study designated as key, Tif. RAI rats were administered FAT 40032/C at 5000 mg/kg bw by oral gavavge following the methodology of OECD Guideline 401. No deaths occurred. Dyspnoea, exophthalmos, ruffled fur and curved body position were seen, being common symptoms in acute tests. In addition, a transient diarrhoea was observed, for about two days after the administration the ears and extremities appeared to be hyperaemic. In conclusion, the acute oral LD50 of FAT 40032/C in rats of both sexes observed over a period of 14 days is greater than 5000 mg/kg.

Acute inhalation toxicity

Currently no study to assess acute inhalation toxicity is available. Taking the intrinsic properties of the test item (low volatility as the melting point >300 °C and high water solubility of 522.5 g/L, indicating if dust is inhaled will be trapped in the mucus) into account as well as the high LD50 values observed during acute oral toxicity studies (LD50 >5000 mg/kg bw), low toxicity is expected via the inhalation route. Considering the high water solubility of the test substance accidentally inhaled particles will most likely be trapped in the mucus and subsequently swallowed. Compared to oral ingestion subsequent gastro-intestinal absorption or excretion of non-absorbed material is considered to be the most relevant route in the body. Since this route did not result in systemic toxicity up to 5000 mg/kg bw when tested in both male and female rats, systemic toxic effects subsequent to inhalation exposure is unlikely to occur. Experience with similar chemical structures demonstrated that it is very unlikely that toxicity related to intrinsic properties of the test item only show up via the inhalation route and not via the oral-gastric route of exposure. Further, production and spray drying is performed in closed processes without isolation of reaction products. Isolated product is present in dust free granules (non-dusty solid). Therefore, the study will be waived and the intrinsic property/toxicity potential can be extrapolated from the acute oral route administration. 

Acute dermal toxicity

Currently no study to assess acute dermal toxicity of Reactive Brown 011 is available. However, the molecular weight of the substance is 938.16 g/mol, which indicates substance is too large for dermal absorption. Further, high water solubility (522.5 g/L), indicate the substance may be too hydrophilic to cross the lipid rich environment of the stratum corneum. Hence, the dermal uptake for the substance is expected to be low. The substance showed low toxicity potential in an acute oral toxicity study (LD50>5000 mg/kg bw). Since this route does not result in systemic toxicity up to 5000 mg/kg bw in both male and female rats, systemic toxic effects subsequent to dermal exposure is considered to be unlikely to occur. Similarly, absence of systemic toxicity or mortality in skin irritation as well as sensitization studies, further supports the conclusion that no adverse effects are expected via dermal route. Further experience with similar chemical substances has demonstrated that it is very unlikely that toxicity related to the intrinsic properties of the test item only show up upon dermal exposure and not after systemic application, hence, further experiments to assess dermal toxicity are not considered.

Lithium sodium salt of Reactive Black 039 (FAT 45168) was tested for acute dermal toxicity in a GLP compliant study, performed according to OECD Guideline 402. In this study, Wistar rats (5/sex) were exposed to the test substance (2000 mg/kg bw) dermally. No adverse effects were reported throughout the study. Hence, the lithium sodium salt of Reactive Black 039 was expected to pose no acute dermal hazard.

Based on the above discussion, Reactive Brown 11 (FAT 40032) is expected to pose no hazard when in contact with the skin for a short duration.

Justification for classification or non-classification

The acute oral LD50 of FAT 40032/C in rats is greater than 5000 mg/kg, while dermal LD50 can be considered to be >5000 mg/kg bw based on the read across. Hence, Reactive Brown 11 does not meet the criteria for classification according to the Regulation EC No. 1272/2008 (CLP).

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