Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Description of key information
Other studies: non studies available
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Reproduction

In an OECD 421 study (Reproduction/Developmental Toxicity Screening Test) on BPS, reduced food intake and body weight gain from day 3 after start of administration to the time of necropsy were observed in males and females of the high dose group. At necropsy, abdominal distension of the caecum was observed in males and females of the mid and high dose group, mostly with mucoepithelial cell necrosis, which might be a reaction of the absorptive epithelium to physical stimulus.

Similar results were found in the 28-day repeated dose oral toxicity study in rats, therefore, indicating that the effects might be similar changes caused by the test substance BPS.

The reproductive toxicity NOAEL was set at 60 mg/Kg bw/day, LOAEL of 300 mg/Kg bw/day (prolonged estrous cycle, decreased fertility index number of live offspring) while the parental toxicity NOAEL is 10 mg/Kg bw/day, the LOAEL 60 mg/Kg bw/day (cecum distension, diffuse hyperplasia of mucosal epithelium).1 2 3

To validate these observations from a screening assay and to address concerns about the potential for adverse effects on fertility an extended one generation reproductive toxicity study (OECD 443) on the oral route of exposure is ongoing.1

2,4'-sulfonyldiphenol CAS 5397-34-2 is considered non toxic for the reproduction, 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 high water solubility, the substance would be expected to be absorbed into systemic circulation to a minimal extent. For these reasons, repro/developmental toxicity studies have not been performed.4

There are studies for the chemically related hydrotrope substances that looked at reproductive organs and the development of offspring. Hydrotropes are the salt form of the sulphonic acids and therefore, are used as read-across for this endpoint. The 90 -day oral rat and oral mouse studies and the 2-year chronic dermal rat and mouse studies with the closely related compound sodium xylenesulfonate (CAS No. 1300-72-7) included examination of sex organs of both sexes. No treatment related effects on reproductive organs were reported at doses roughly equivalent to those in the developmental toxicity study. The 1994 study with calcium xylenesulphonate (CAS No. 28088-63-3) did not follow a specific guideline but was fully documented and conducted in accordance with GLP requirements. No adverse effects were reported. The NOAEL for both maternal and foetal toxicity was the highest dose tested - 3000 mg/kg bw/day which is equivalent to 936 mg active ingredient per kilogram body weight per day. The conclusion of the study was no indications of developmental toxicity including teratogenesis.5

Several developmental toxicity studies in rats and mice conducted via the gavage route on phenol are available. The only developmental effect reported in these studies was decreased fetal body weight. The pathological examinations showed no treatment-related lesions in the kidneys, spleen, liver, thymus, or reproductive organs.6

 

1ECHA Registration Dossier 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.


Short description of key information:
Toxic on fertility: non toxic

Effects on developmental toxicity

Description of key information
Toxic on developmental: non toxic
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Developmental toxicity

In an OECD 421 study (Reproduction/Developmental Toxicity Screening Test) on BPS, reduced food intake and body weight gain from day 3 after start of administration to the time of necropsy were observed in males and females of the high dose group. At necropsy, abdominal distension of the caecum was observed in males and females of the mid and high dose group, mostly with mucoepithelial cell necrosis, which might be a reaction of the absorptive epithelium to physical stimulus.

Similar results were found in the 28-day repeated dose oral toxicity study in rats, therefore, indicating that the effects might be similar changes caused by the test substance BPS.

The reproductive toxicity NOAEL was set at 60 mg/Kg bw/day, LOAEL of 300 mg/Kg bw/day (prolonged estrous cycle, decreased fertility index number of live offspring) while the parental toxicity NOAEL is 10 mg/Kg bw/day, the LOAEL 60 mg/Kg bw/day (cecum distension, diffuse hyperplasia of mucosal epithelium).1 2 3

Developmental study with maternal toxicity on BPS has been finalized in 2014 according to the OECD Guideline 414 (Prenatal Developmental Toxicity Study). The no observed adverse effect level (NOAEL) for maternal toxicity was set at 100 mg/kg bw/day and there were no toxicologically relevant adverse fetal findings evident.

Thus, the no observed adverse effect level (NOAEL) for prenatal developmental toxicity is 300 mg/kg bw/day.1

2,4'-sulfonyldiphenol CAS 5397-34-2 is considered non toxic for the reproduction, 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 high water solubility, the substance would be expected to be absorbed into systemic circulation to a minimal extent. For these reasonsrepro/developmental toxicity studies have not been performed.4

There are studies for the chemically related hydrotrope substances that looked at reproductive organs and the development of offspring. Hydrotropes are the salt form of the sulphonic acids and therefore, are used as read-across for this endpoint. The 90-day oral rat and oral mouse studies and the 2-year chronic dermal rat and mouse studies with the closely related compound sodium xylenesulfonate (CAS No. 1300-72-7) included examination of sex organs of both sexes. No treatment related effects on reproductive organs were reported at doses roughly equivalent to those in the developmental toxicity study. The 1994 study with calcium xylenesulphonate (CAS No. 28088-63-3) did not follow a specific guideline but was fully documented and conducted in accordance with GLP requirements. No adverse effects were reported. The NOAEL for both maternal and foetal toxicity was the highest dose tested - 3000 mg/kg bw/day which is equivalent to 936 mg active ingredient per kilogram body weight per day. The conclusion of the study was no indications of developmental toxicity including teratogenesis.5

Several developmental toxicity studies in rats and mice conducted via the gavage route on phenol are available. The only developmental effect reported in these studies was decreased fetal body weight. The pathological examinations showed no treatment-related lesions in the kidneys, spleen, liver, thymus, or reproductive organs.6

 

References:

1ECHA Registration Dossier 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 xylene sulphonate, 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.

Justification for classification or non-classification

Reproductive/developmental toxicity

In order to classify the whole mixture for the reproductive/developmental 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

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

2,4'-sulfonyldiphenol: non classified

Phenol: non classified

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, the 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 concentration of 1.8%.

According to the CLP Regulation 1272/2008/EC, 3.7 section, point 3.7.3.1., Table 3.7.2, generic concentration limits shall be used to determine if the mixture is considered to be or not toxic for the reproduction or the development.

Based on the information available, the intermediate DCB is not classified as reprotoxic or toxic for the development.

For fertility, a study was proposed, to confirm the results available on BPS (one generation reproductive toxicity study (OECD 443).