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Administrative data

Description of key information

According to EU standards, no classification for oral exposure is required.
Oral LD50 = 2830 mg/kg bw (male/rat)
Based on weight of evidence for acute dermal toxicity no acute dermal toxicity can be anticipated.

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:
comparable to guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
analytical purity of the test substance not reported, weekly body weight was not determined, necropsy was not performed on the deceased or surviving animals
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Wistar
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Winkelmann, Borchen
- Age at study initiation: ca. 9 weeks
- Mean body weight at study initiation: 181 g
- Diet (e.g. ad libitum): Altromin R (Altromin GmbH, Lange)
- Water (e.g. ad libitum): Tap water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±1.5
- Humidity (%): 60±5
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
other: Lutrol
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): 20 ml/kg bw

DOSAGE PREPARATION: The test substance was dissolved in Lutrol by stirring on a magnetic-stirrer at room temperature.
Doses:
1000, 1500, 2000, 3100, 3500, 4000, 5000, 5500 mg/kg bw
No. of animals per sex per dose:
10
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing:
The animals were checked for mortality or toxic effects twice daily on weekdays and once daily on weekends or holidays.
The body weight of the animals was determined prior to substance administration and at the end of the 14-days observation period.
- Necropsy of survivors performed: no
Statistics:
Calculation of LD50 was performed with probit analysis (Fink and Hund, Arzneim.-Forsch. 15: 624, 1965).
Sex:
male
Dose descriptor:
LD50
Effect level:
2 830 mg/kg bw
Based on:
test mat.
95% CL:
2 380 - 3 270
Mortality:
see table below
Clinical signs:
The symptoms observed in all dose groups were increased diuresis, salivation, sedation, dyspnoea, lateral and prone position, decreased bw-gain, and decreased general condition.
Body weight:
All rats at all dosage levels gained weight during the 14-day observation period, though final bw were decreased in treated animals (see above).
Gross pathology:
not done

Dose (mg/kg bw)

Mortalities

Time of death

1000

0/10

-

1500

1/10

2d

2000

2/10

2d

3100

4/10

3h-7d

3500

7/10

2d

4000

9/10

2d

5000

9/10

3h-2d

5500

10/10

3h-3d

Interpretation of results:
GHS criteria not met
Conclusions:
The LD50 (oral, rat) was determined to be 2830 mg/kg bw.
Executive summary:

In a study, comparable to OECD 401 (analytical purity of the test substance not reported, weekly body weight was not determined, necropsy was not performed on the deceased or surviving animals), groups of 10 male rats per dose were administered with 1000, 1500, 2000, 3100, 3500, 4000, 5000, 5500 mg/kg bw of test substance dissolved in lutrol in a volume of 20 ml/kg bw. The animals were observed for 14 days post administration.

Dose related mortalities were observed. The clinical signs were increased diuresis, salivation, sedation, dyspnoea, lateral and prone position, decreased bw-gain, and bad general condition. The acute LD50 of the test substance was found to be 2830 mg/kg bw.

Based on test results the test substance is non toxic according to EU classification (DSD and GHS).

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
2 830 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Oral exposure route:

In the key study (Bayer, 1978) performed similar to the OECD guideline 401, dose related mortalities were observed between 3h-7d after exposure to 1000 -5500 mg/kg bw. The LD50 was reported to be 2830 mg/kg bw for male rates. Observed clinical signs of toxicity were e.g. increased diuresis, salivation, sedation, dyspnoea and lateral and prone position. Necropsy was not performed on the deceased or surviving animals.

In the supporting study (CIBA-Geigy LTD., 1984), 4,4'-sulphonyldiphenol was tested in an acute oral toxicity test in 5 male and 5 female rats according to OECD guideline 401 with a limit dose of 5000 mg/kg bw. Acute oral administration was followed by a 14 day post-treatment observation period. All animals survived. Dyspnoea, exophthalmus, ruffled fur and curved body position were seen, being common symptoms in acute tests. In this assay 4,4'-sulphonyldiphenol resulted in practically no acute toxicity when administered orally at 5000 mg/kg bw to male and female albino rats (LD50 > 5000 mg/kg bw).

Other studies with minimal description of methods and results (Reliability 4) reported LD50 values of >2000 mg/kg bw (Office of Environmental Chemicals Safety Environmental Health Bureau, 1999), >3200 mg/kg bw in male rats, 2540 mg/kg bw in female rats and >1600 mg/kg bw in male mice (Eastman-Kodak Co., 1983).

 

Inhalation exposure route:

In accordance with column 2 of REACH Annex VIII, the test acute toxicity after inhalation (required in section 8.5) does not need to be conducted as acute toxicity studies for oral application are available and in a weight of evidence a reliable assessment of the acute dermal toxicity LD50 is possible (see IUCLID5 section 7.2.3).

Due to the negligible vapor pressure exposure towards considerable 4,4'-sulphonyldiphenol vapor concentrations at room temperature does not need to be anticipated. Furthermore aerosol exposure to 4,4'-sulphonyldiphenol does not occur, e.g. since formation from production and processing (polymerization) processes can be excluded due to the high integrity of the systems and no spray processes of dissolved 4,4'-sulphonyldiphenol are supported.

4,4'-sulphonyldiphenol is a crystalline powder and approx. 60% of the particles are less than 100 µm in size, and approx. 2% of the particles are less than 10 µm in size (Granulometry; BASF AG, 2009). For open handling of the solid substance it can therefore be anticipated that only a limited amount of the substance can reach the alveolar region of the lung (respirable fraction <2%, see IUCLID5 section 4.5). For open handling of the solid substance OELs for inert dusts apply (e.g. MAK value for inert dusts,4 mg/m3for inhalable fraction), resulting in sufficient level of protection in absence of significant acute systemic (oral/dermal) and local (dermal/ocular) toxicity of 4,4'-sulphonyldiphenol.

 

Dermal exposure route:

 

According to the REACH legislation (Annex VIII) a second acute toxicity study is required and should be linked to the potential exposure situation. According to Annex VIII, 8.5.3, an acute dermal toxicity study is required if

(1) inhalation is unlikely (correct for 4,4'-sulphonyldiphenol see above) and

(2) dermal exposure is likely (only relevant for solid substance) and

(3) a substance is expected, based on its physico-chemical properties to be adsorbed dermally to a significant percentage.

 

In an acute dermal toxicity study the LD50 of 4,4'-sulphonyldiphenol was reported to be greater than 1000 mg/kg bw with guinea pigs (Eastman Kodak Co., 1983). Furthermore, repeated dermal application to the clipped backs of guinea pigs was reported not to produce an exacerbated response. Due to limited description of methods and results in the available report the reliability of this study can unfortunately not be conclusively validated. Therefore further substance specific data shall apply by means of a weight of evidence for acute dermal toxicity. In addition to the acute dermal study and in accordance to Annex VIII, 8.5.3 (3), a reliable prediction of the potential acute dermal toxicity and the respective classification and labeling of the substance can be substantiated based on an additional validation of the physico-chemical properties and data generated in other acute toxicity studies on alternative routes of exposure.

 

Based on the physico-chemical properties of 4,4'-sulphonyldiphenol a significant skin penetration, dermal adsorption and by this systemic bioavailability does not need to be anticipated:

Dry particulates first have to dissolve into the surface moisture of the skin before uptake may occur. Due to the rather low water solubility of 1.1 g/l (at 20°C) it can be anticipated that only a minor share is dissolving. The potential for dermal permeation of dissolved substances is mainly dependent on the molecular weight and the Pow, and can be predicted by in silico equations (e.g. DERMWIN v2.00). 4,4'-sulphonyldiphenol is a polar organic molecule with a molecular weight of 250.27 g/mol and a log Pow of 1.2. The dermal permeability coefficient (Kp) was calculated as 0.000387 cm/hr indicating a very low dermal uptake.

 

The acute dermal LD50 can furthermore be estimated based on a route to route extrapolation from oral data. 4,4'-sulphonyldiphenol revealed an LD50 value in an acute oral toxicity study of 2830 mg/kg bw in rats leading to no classification according to CLP with regard to acute oral toxicity (Bayer, 1978).

For the route to route extrapolation taken into account the physico-chemical properties of the substance the following assumptions can be considered as a reliable worst case scenario:

Oral bioavailability: 100 %

Dermal bioavailability: 25 %

Acute oral toxicity LD50: 2830 mg/kg bw

Based on this scenario a dermal LD50 of > 2000 mg/kg bw (11320 mg/kg bw) can be extrapolated.

 

Based on this weight of evidence the performance of a new dermal toxicity animal assay is not expected to generate additional relevant data with respect to hazard classification for acute dermal toxicity and is therefore not in accordance to the principles of animal welfare.

 

The chosen approach described is in line with a recent publications (Creton, St. et al, Critical reviews in Toxicology, 2010, Vol. 40 No.1, pages 50-83; Moore, Regulatory Toxicology and Pharmacology, 2013, 66, 30-37), in which the general benefit of performing acute dermal toxicity studies is questioned, in particular if there are no indications for a substance to be more toxic via dermal than via oral route.

 

Consequently, 4,4'-sulphonyldiphenol has not to be classified and labeled with regard to acute dermal toxicity according to Regulation (EC) No 1272/2008 (CLP) and directive 67/548/EC (DSD).

 

Justification for classification or non-classification

Based on the results of the acute oral toxicity study, and a weight of evidence for acute dermal toxicity , 4,4`-sulphonyldiphenol has not to be classified according to Directive 67/548/EEC (DSD) and Regulation (EC) No 1272/2008 (CLP).