Registration Dossier

Administrative data

Description of key information

Repeated oral toxicity: non toxic
Repeated dermal toxicity: non toxic
Repeated inhalatory toxicity: no data available

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Oral repeated dose toxicity

A 28 days Japanese test similar to OECD 407 on BPS revealed effects at 200 mg/kg bw/day.1 2

In a repeated-dose oral study on rats, effects at the 200 mg/kg bw/day included decreased body weight gain in females, increased incidences of proteinuria in males and females and urobilinogen in males, increasing kidney weight in males, and increasing incidences of hyperplasia and necrosis in cecal mucosal epithelium of males and females (LOAEL = 200 mg/kg bw/day).3

The definitive classification of BPS as a kidney toxicant (STOT- repeated dose (Cat. 2 H371/R48) based on EU and GHS standards is not possible, therefore, a full evaluation of the toxicity of BPS was proposed by the registrant, and an OECD Guideline 408 test (Repeated Dose 90-Day Oral Toxicity in Rodents) has been completed. In this recent repeated dose 90 -Day oral toxicity study in rodents (2014), the NOAEL for male rats was determined to be 100 mg/kg bw/day (nominal) based on relative body weight and atrophy of mammary gland effects while the NOAEL for female rats was determined to be 300 mg/kg bw/day (nominal) based on the following effects: regenerative anaemia, effects on liver (hypertrophy), uterus (epithelial metaplasia) and ovaries (relative weights). Based on these data, BPS is not considered a repeated dose toxicant.

2,4'-sulfonyldiphenol CAS 5397-34-2 is considered non toxic for the repeated oral dose toxicity, and no data are available.

Also, data on benzenesulfonic acid, 4-hydroxy-, sodium salt (1:1), CAS 825-90-1 is not available.

The substance is the salified form of phenol sulfonic acid, which is a very acidic substance (comparable to sulphuric acid) and is almost completely ionised in watery environments, even at low pH. In fact, taking into consideration its corrosive nature, studies would cause unnecessary harm to laboratory animals. Moreover, because of the high polarity and high water solubility, the substance would be expected to be absorbed into systemic circulation to a minimal extent. For these reasons, the 28-day study will not be performed.4

Thus, more realistic data on salified similar substances called hydrotropes, can be considered.

There are a total of 6 oral repeated dose studies for the hydrotrope sodium xylenesulphonate. Toxicological properties of this substance can be helpful (in read across as well) to understand the toxicity of sodium sulphonated phenols, part of the intermediate DCB. The key study is a 90 -day oral study, conducted in 1968 and is generally comparable to the OECD 408 guideline study. In that study, the highest dose for female rats 4092 mg active ingredient (a.i.) per kilogram body weight - resulted in a loss in relative weight of the spleen. The 2nd highest dose for females - 763 mg a.i. per kilogram body weight - had no measureable adverse effects and therefore, establishes the repeat dose oral NOAEL for the test substance. The highest oral dose for male rats - 3534 mg a.i. per kilogram body weight - had no measurable adverse effects. No adverse effects were reported in a 90 day mouse study with the same substance.5

Several studies on phenol are available, and the substance is already classified as STOT RE (category 2, H373) in the Index VI of CLP Regulation 1272/2008/EC. 6 7

Phenol is toxic for the repeated dose oral exposure, however it is present at 1.8%, concentration that do not add a repeated toxicity property to the whole mixture.

Dermal repeated dose toxicity

Considering the whole mixture of intermediate DCB, the sulfonic groups tend to bind tightly to proteins and carbohydrates of skin and part of the mixture has a big molecular dimension (tri-hydroxy).

Regarding the dermal hazard of BPS, it is less absorbed through the skin.

The estimated Kp of BPS is 0.000767 cm/hr and this value suggests that it could be less skin absorbed (EPI Suite v. 4.11).

2,4'-sulfonyldiphenol CAS 5397 -34-2 is considered non toxic for the repeated oral dose toxicity, and no data are available.

Also, data on benzenesulfonic acid, 4-hydroxy-, sodium salt (1:1), CAS 825-90-1 is not available.

The substance is the salified form of phenol sulfonic acid, which is a very acidic substance (comparable to sulphuric acid) and is almost completely ionised in watery environments, even at low pH. Taking into consideration its corrosive nature, studies would cause unnecessary harm to laboratory animals. Moreover, because of the high polarity and the water solubility, the substance would be expected to be absorbed into systemic circulation to a minimal extent. For these reasons, the 28-day study will not be performed.4

Thus, more realistic data on salified similar substances called hydrotropes, can be considered.

A category approach evaluation is available on sodium xylenesulphonate. The estimated toxicological property of this substance can be helpful (in read across as well) to understand the toxicity of sodium sulphonated phenols, part of the intermediate DCB.

This category approach defined it has no concern for the repeated dermal exposure.5

No data on phenol are available but it is considered non toxic for dermal repeated exposure.5

Inhalation repeated dose toxicity

No data is available on BPS, 2,4'-sulfonyldiphenol and related hydrotropes regarding the repeated inhalation toxicity.

References:

1ECHA Registration Dossier BPS CAS 80-09-1;

2SIDS INITIAL ASSESSMENT PROFILE, CAS 80-09-1, CoCAM 4, 16-18 April 2013;

3EPA, U.S. Environmental Protection Agency, Bisphenol A alternatives in thermal paper, Final Report, January 2014;

4HPV Assessment Report On Hydroxybenzenesulphonic acid CAS No. 1333-39-7, 2004, NOTOX;

5ECHA Registration Dossier, Sodium xylenesulphonate, CAS 1300 -72-7; ECHA Registration Dossier, Toluene sulphonic acid, CAS 104 -15 -4;

6Toxicological review of phenol. EPA, IRIS, 2002, EPA/635/R-02/006;

7 Bioassay of phenol for possible carcinogenicity. Report of the National Cancer Institute, n. 203, NTP 80-15, 1980.

Justification for classification or non-classification

Repeated dose toxicity

In order to classify the whole mixture for repeated toxicity, the available classification and the results of the reported studies of every known component has been taken into account.

4,4'-sulfonyldiphenol (BPS): non classified. Based on the NOAELs in male and female rats (2014) equal to 100 and 300 mg/kg bw respectively, BPS is not classified for repeated dose toxicity according to CLP Regulation EC n. 1272 of 2008, Annex I, Part 3, Table 3.9.3.

Benzenesulfonic acid, 4-hydroxy-, sodium salt (1:1)- hydrotropes, sodium xylenesulphonate (category approach): non classified

2,4'-sulfonyldiphenol: non classified (C&L ECHA inventory)

Phenol: H373 , no target organ indicated

Approximately 48% of the organic part of the intermediate under registration is composed by BPS.

Approximately 14% of the organic part of the mixture is the salified form of the phenol sulfonic acid (p-APS), benzenesulfonic acid, 4-hydroxy-, sodium salt (1:1). A category approach based on the hydrotropes can be taken into account for the classification of the whole intermediate mixture DCB. In fact, the properties of the salified form can be covered in read across with sodium xylenesulphonate (data available).

2,4'-sulfonyldiphenol is present at ca. 6%.

Phenol is present in a low concentration (1.8%) and for the evaluation of the repeated toxicity the presence >= 10 % shall be taken into account.

According to the CLP Regulation 1272/2008/EC, 3.9 section, point 3.9.3.4, Table 3.9.4, generic concentration limits shall be used to determine if the mixture is considered to be or not a repeated dose toxicant, oral or dermal.

Based on the information available, the intermediate DCB 58% is not classified as repeated dose toxicant.