Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Read Across: One Generation reproduction toxicity study, a calcium sulfonate read across substance (CAS 115733-09-0), NOAEL (for p) and f1 > 500 mg/kg bw/day.

Link to relevant study records

Reference

Endpoint:

one-generation reproductive toxicity

Remarks:

based on test guideline (migrated information)

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
In this justification, the read-across (bridging) concept is applied, based on the chemical structure of the potential analogues, their toxicokinetic behaviour and other available (eco-)toxicological data.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
C20-24 calcium sulfonate and Benzenesulfonic acid, C14-24-branched and linear alkyl derivs., calcium salts (CAS 115733-09-0) are members of a category of chemicals described as alkaryl sulfonates, which was established as part of the U.S. Environmental Protection Agency High Production Volume (HPV) Challenge Program. The substances of this category have a common functional group - the salt of aryl sulfonic acid. Furthermore, they all have a divalent alkaline earth metal, one or more linear and/or branched alkyl groups of variable chain length and branching characteristics or extended heterocyclic carbon system from the sulfonated benzene ring. Finally, they have common precursors and/or the likelihood of common breakdown products via physical and biological processes, resulting in structurally similar chemicals, and similar physicochemical properties, environmental fate, ecotoxicity and mammalian toxicity.
Concerning their reproductive toxicity, it is believed that both substance will be metabolised by the same mechanisms by mammalian organisms. Therefore they are expected to follow the same pattern. For the detailed procedure of the read-across principle and justifications, please refer to the analogue approach justification depicted below and the separate Read-Across Statement (Chemservice S.A., 2017).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Source chemical: Benzenesulfonic acid, C14-24-branched and linear alkyl derivs., calcium salts (CAS 115733-09-0, EC No none)
Target chemical: Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts (C20-24 calcium sulfonate, CAS No none, EC No none)

3. ANALOGUE APPROACH JUSTIFICATION
C20-24 calcium sulfonate and Benzenesulfonic acid, C14-24-branched and linear alkyl derivs., calcium salts (CAS 115733-09-0) are UVCB substances that are produced using similar manufacturing process and raw materials and are manufactured in mineral oil. They are members of a category of chemicals described as alkaryl sulfonates, which was established as part of the U.S. Environmental Protection Agency High Production Volume (HPV) Challenge Program. These substances are similar in that they have a common functional group, the salt of aryl sulfonic acid. TOXMATCH and OECD Toolbox QSAR structure similarity assessments using Tanimoto distance fingerprint, Hellinger distance atom environment, Euclidian distance and Dice calculations indicate that these substances are very similar. Likewise, they have similar physicochemical properties, similar environmental fate characteristics, and similar ecotoxicity and mammalian toxicity profiles. For example, these substances can dissociate only in the presence of strong acids such as in the stomach but are not expected to dissociate under environmental conditions. For further details on this, please refer to the separate Read-Across Statement (Chemservice S.A., 2017). The similar toxicity profiles indicate that they have a similar MOA. C20-24 calcium sulfonate and Benzenesulfonic acid, C14-24-branched and linear alkyl derivs., calcium salts (CAS 115733-09-0) are classified as Skin Sens Cat. 1B and Skin Irrit 2, respectively.
The similar findings (refer to data matrix outlined below and the separate Read-Across Statement) for both substances support the conclusion that similar molecules are expected to be formed from both substances, and in consequence, similar effects can be reasonably expected. Hence, the analogue may perfectly serve as a read-across substance for the C20-24 calcium sulfonate and vice versa. So, based on the WOE of these data, the available data on CAS 115733-09-0 can be used to cover the systemic endpoints currently lacking for C20-24 calcium sulfonate and read across is scientifically justified, making further testing obsolete.

4. DATA MATRIX
There is mainly data available on the toxicological properties of the analogues CAS 61789-86-4 / its overbased version CAS 68783-96-0 and for CAS 70024-69-0 / its overbased version CAS 70024-71-4. Data on Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts covers merely the physico chemical properties. Hence, the identification and discussion of common properties of the analogues and the C20-24 calcium sulfonate will be mainly based on this physicochemical data.
The available data for the following physico-chemical properties, which are relevant for absorption into living organisms, are very similar. The substances are rather huge molecules and have a similar molecular weight range, which triggers already similarities in their absorption behaviour. Furthermore, the physico-chemical properties like their partition coefficient, water solubility and vapour pressure are similar. Regarding the application of these substances, the substances are usually solved in an inert mineral oil to enable handling. The C20-24 calcium sulfonate and all analogous substances are hydrolytically stable in the natural environment and at least CAS 70024-69-0 and CAS 61789-86-4 are not readily biodegradable, and the available data suggests this to apply also for C20-24 calcium sulfonate. Taking into account the vast amount of data available for partition coefficient data on various calcium sulfonates it can be concluded that they do not have a significant potential for bioaccumulation in aquatic and terrestrial organisms. However, they are expected to be adsorbed to a significant extent to the sediment and soil and to be thereby not bioavailable, which was confirmed by the results of short-term toxicity tests to fish, daphnia and algae for CAS 70024-71-4; CAS 115733-09-0 and CAS 61789-64-4, in which the lowest LL50 was already > 100 mg/L WAF.
For the following toxicological endpoints there is data available derived from CAS 70024-69-0/ CAS 70024-71-4, Analogue of CAS 70024-69-0, CAS 115733-09-0, CAS 61789-86-4/ CAS 68783-96-0 and CAS 75975-85-8: Acute toxicity, Skin irritation / corrosion, Eye irritation /corrosion, Skin sensitization, Repeated dose toxicity, Genetic toxicity in vitro and in vivo and Toxicity to reproduction (fertility / developmental toxicity). Furthermore a rather extensive data package is available concerning the human sensitization potential of numerous analogous substances. For the acute oral toxicity, the values for all read across substances are very high, all LD50 values being above 2000 mg/kg (reaching in older tests up to greater than 20,000 mg/kg) and the values for the substances can be considered as similar within normal biological variations. The substances are also not toxic via the inhalation or the dermal route of exposure. Regarding Skin/Eye Irritation, the available data on CAS 70024-69-0 and CAS 61789-86-4 shows both substances to be not irritating to the skin or the eyes. The skin sensitization data in animals and humans (for CAS 75975-85-8; CAS 61789-86-4 and EC 939-141-6) evaluated in a weight-of-evidence approach indicates that low TBN calcium sulfonates (TBN < 300) are skin sensitizers with a specific concentration limit (SCL) of 10% and that high TBN calcium sulfonates (TBN ≥ 300) are not skin sensitizers. Last but not least, the available genetic toxicity data for Analogue of CAS 70024-69-0, CAS 61789-86-4 and its overbased version CAS 68783-96-0 prove all of these substances to be not mutagenic. The NOAELs derived for the endpoints Repeated dose toxicity (Analogue of CAS 70024-69-0 and CAS 61789-86-4) and Toxicity to reproduction (fertility / developmental toxicity for CAS 115733-09-0)) have been also found to be in a similar range.
For further details please refer to the seperate Read-Across Statement (Chemservice S.A., 2017) and/or the robust study summaries of the respective studies in this IUCLID file.

Reason / purpose for cross-reference:

read-across source

Analytical verification of doses or concentrations:

yes

Clinical signs:

no effects observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Other effects:

not specified

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

There were no remarkable findings in F0 males, with the exception of post dosing salivation.
In F0 females there were no remarkable findings with the exception of negative ammonium sulphide staining in two high dose and one mid dose animal.

Dose descriptor:

NOAEL

Effect level:

> 500 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: No significant adverse effects occurred at 500 mg/kg/bw (highest dose tested).

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

no effects observed

There were no remarkable observations in F1 animals.

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

> 500 mg/kg bw/day (actual dose received)

Sex:

male/female

Basis for effect level:

other: No adverse effects occurred in animals in the top dose group, therefore a NOAEL cannot be identified from this study.

Reproductive effects observed:

not specified

Results of the homogeneity analysis indicate that the test article was homogeneous in the vehicle and stable for ten days when stored under ambient conditions. Concentration analysis confirmed that the test article was at the appropriate concentration in the dosing solutions.

Results

F0 Generation:

F0 males exhibited a dose related increase in post dosing salivation and dark material around the nose in the mid and high dose groups The remaining F0 male parameters were unremarkable including: mean body weight and food consumption, mating and fertility indices, absolute and relative organ weights, sperm evaluation parameters and macro- and microscopic pathology.

The clinical signs of the F0 females were generally unremarkable. There were no toxicologically meaningful differences between the control low, mid and high dose groups with respect to F0 female mean body weights, body weight change, food consumption, mating and fertility indicies, precoital intervals or gestation length. A macroscopic finding observed in two high dose and one mid female sacrificed on post mating day 25 was a finding of negative ammonium sulfide staining in animals that failed to deliver and were euthanized on gestation day 25.

No other remarkable findings were noted in the F0 females at necropsy and no meaningful microscopic lesions were observed in any of the treated F0 females.

F1 Generation:

No treatment related findings were noted in the F1 pups during lactation. No treatment related gross necropsy findings were evident in any of the F1 pups examined (stillborn, dead during lactation, culled or examined at scheduled sacrifice on lactation day 21.)

Conclusions:

Adverse effects did not occur in parental animals or offspring at doses up to 500 mg/kg bw/day, therefore the NOAEL was identified as > 500 mg/kg bw/day (the highest dose tested in this study). These results can be used to fulfill the information requirements for the chemical substance Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts, due to the high structural similarity of these substances. For the detailed procedure of the read-across principle and justifications, please refer to the separate Read-Across Statement (Chemservice S.A., 2017).

Executive summary:

In a 1-generation reproduction study, benzenesulfonic acid, C14-C24 branched and linear alkyl derivatives (CAS 115733 -09 -0) was administered in corn oil via oral gavage to 28 Sprague-Dawley rats/sex at dose levels of 0, 50, 167 and 500 mg/kg bw/day (Bjorn, 2004, according to OECD 415). All F0 males were dosed for 70 days prior to mating, mating (maximum 3 weeks) and through the completion of parturition. All F0 females were dosed for 14 days prior to mating, mating (maximum 3 weeks), 25 days of gestation and through day 20 of lactation. The F1 pups were treated in gestation and through day 20 of lactation (via lactation). The animals were observed twice daily for appearance and behaviour, and a detailed clinical observation was performed weekly and daily for females during gestation. Cage site observations were performed daily approximately 30 to 120 minutes post dosing. In addition, the bodyweights were determined weekly and on the day of euthanasia for males. Females were weighed after evidence of mating on gestational days 0, 7, 14 and 21 and on lactation fays 1, 4, 7, 14 and 21. Food consumption was recorded on the same days as body weights except during the mating period and during lactation. Animals were paired 1:1 for mating, after successful mating each pregnant females was caged individually. Positive evidence of mating was confirmed by the presence of sperm or a vaginal copulatory plug (day 0 of gestation). If evidence of mating was not present after three weeks, mating was discontinued. All of the surviving F0 females were allowed to deliver and rear their pups to lactation day 21. The offspring were potentially exposed to the test substance in utero and through nursing during lactation days 1-21 until euthanization on post-natal day 21. On lactation day 4 each litter was randomly culled to a maximum of eight pups, 4/sex/litter, when possible. Detailed pup examinations were performed on lactation days 0, 4, 7, 14 and 21. Pup sex was determined on lactation day 0 and verified on lactation days 4, 7, 14 and 21. Individual pup weights were determined on lactation days 1, 4, 7 14 and 21. Pups that were stillborn, cannibalized or found dead were subjected to a gross necropsy with emphasis on developmental morphology. Pups culled on day 4 were subjected to an abbreviated gross necropsy with emphasis on the reproductive system. All surviving pups were euthanized on lactation day 21 and examined macroscopically. All internal gross lesions were preserved for possible future microscopic examination.

Gross necropsies (consisting of external and internal examinations including the cervical, thoracic and abdominal viscera) were performed on death, organ weights and microscopic examinations were performed on termination. The surviving F0 dams were necropsied on lactation day 21, following a minimum of 60 days of dosing. The surviving F0 males were necropsied at the conclusion of parturition following a minimum of 96 days of dosing. F0 females that failed to deliver were necropsied on post-mating day 25 (with evidence of mating) or 25 days following the termination of the mating period (with no evidence of mating). Organ weights were determined and microscopic examinations were conducted for all surviving control and high dose F0 animals. Tissues examined microscopically included the liver, kidney, brain, right epididymides, cervix, coagulation gland, ovaries, pituitary, prostrate, seminal vesicles, testes, uterus, vagina and gross lesions. F0 animals from all groups found dead or sacrificed early were subjected to a gross necropsy and the microscopic evaluation of all tissues. Sperm was collected from all surviving F0 males and evaluated for sperm count, concentration, motility and morphology assessment. The parameters examined in P males included: testis weight, epididymis weight, sperm count in epididymides, enumeration of cauda epididymal sperm reserve, sperm motility and sperm morphology. The F1 offsprings were examined for number and sex of pups, stillbirths, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities. Moreover a gross examination of dead pups was conducted for external and internal abnormalities. So the possible cause of death fro pups born or found dead was evaluated.

No substance related effects occurred in treated animals, except for the observation of post dosing salivation and dark material around the nose in the mid and high dose groups in F0 males and the negative ammonium sulfide staining in two high dose and one mid dose F0-female. No treatment related findings were noted in the F1 pups during lactation. No treatment related gross necropsy findings were evident in any of the F1 pups examined (stillborn, dead during lactation, culled or examined at scheduled sacrifice on lactation day 21). As no effects occurred at the highest dose, a NOAEL cannot be identified, and is greater than 500 mg/kg bw/day for reproductive and developmental toxicity. Based on the results of this study it is concluded that the 500 mg/kg/day dose level is the no observed adverse effect level (NOAEL) for parental F0 and F1 pup toxicity (no significant adverse effects occurred at this dose level).

These results can be used to fulfill the information requirements for the chemical substance Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts, due to the high structural similarity of these substances. For the detailed procedure of the read-across principle and justifications, please refer to the separate Read-Across Statement (Chemservice S.A., 2017).

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

500 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

High quality since the key study is GLP compliant and has Klimisch score of 2.

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

In the key one-generation reproduction study, a calcium sulfonate read across substance, (CAS 115733-09-0), was administered in corn oil via oral gavage to 28 Sprague-Dawley rats/sex at dose levels of 0, 50, 167 and 500 mg/kg bw/day (Bjorn, 2004, according to OECD 415). All F0 males were dosed for 70 days prior to mating, mating (maximum 3 weeks) and through the completion of parturition. All F0 females were dosed for up to 70 days (14 days prior to mating, during mating and gestation and through day 20 of lactation. The F1 pups were treated in gestation and through day 20 of lactation (via lactation). The animals were observed twice daily for appearance and behaviour, and a detailed clinical observation was performed weekly and daily for females during gestation. Cage site observations were performed daily approximately 30 to 120 minutes post dosing. In addition, the bodyweights were determined weekly and on the day of euthanasia for males. Females were weighed after evidence of mating on gestational days 0, 7, 14 and 21 and on lactation fays 1, 4, 7, 14 and 21. Food consumption was recorded on the same days as body weights except during the mating period and during lactation. Animals were paired 1:1 for mating, after successful mating each pregnant female was caged individually. Positive evidence of mating was confirmed by the presence of sperm or a vaginal copulatory plug (day 0 of gestation). If evidence of mating was not present after three weeks, mating was discontinued. All of the surviving F0 females were allowed to deliver and rear their pups to lactation day 21. The offsprings were exposed to the test substance in utero and through nursing during lactation days 1-21 until euthanization on post-natal day 21. On lactation day 4 each litter was randomly culled to a maximum of eight pups, 4/sex/litter, when possible. Detailed pup examinations were performed on lactation days 0, 4, 7, 14 and 21. Pup sex was determined on lactation day 0 and verified on lactation days 4, 7, 14 and 21. Individual pup weights were determined on lactation days 1, 4, 7 14 and 21. Pups that were stillborn, cannibalized or found dead were subjected to a gross necropsy with emphasis on developmental morphology. Pups culled on day 4 were subjected to an abbreviated gross necropsy with emphasis on the reproductive system. All surviving pups were euthanized on lactation day 21 and examined macroscopically. All internal gross lesions were preserved for possible future microscopic examination. Gross necropsies (consisting of external and internal examinations including the cervical, thoracic and abdominal viscera) were performed on death, organ weights and microscopic examinations were performed on termination. The surviving F0 dams were necropsied on lactation day 21, following a minimum of 60 days of dosing. The surviving F0 males were necropsied at the conclusion of parturition following a minimum of 96 days of dosing. F0 females that failed to deliver were necropsied on post-mating day 25 (with evidence of mating) or 25 days following the termination of the mating period (with no evidence of mating). Organ weights were determined and microscopic examinations were conducted for all surviving control and high dose F0 animals. Tissues examined microscopically included the liver, kidney, brain, right epididymides, cervix, coagulation gland, ovaries, pituitary, prostrate, seminal vesicles, testes, uterus, vagina and gross lesions. F0 animals from all groups found dead or sacrificed early were subjected to a gross necropsy and the microscopic evaluation of all tissues. Sperm was collected from all surviving F0 males and evaluated for sperm count, concentration, motility and morphology assessment. The parameters examined in P males included: testis weight, epididymis weight, sperm count in epididymides, enumeration of cauda epididymal sperm reserve, sperm motility and sperm morphology. The F1 offsprings were examined for number and sex of pups, stillbirths, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities. Moreover a gross examination of dead pups was conducted for external and internal abnormalities. So the possible cause of death of pups born or found dead was evaluated. No substance related effects occurred in treated animals, except for the observation of post dosing salivation and dark material around the nose in the mid and high dose groups in F0 males and the negative ammonium sulfide staining in two high dose and one mid dose F0-female. No treatment related findings were noted in the F1 pups during lactation. No treatment related gross necropsy findings were evident in any of the F1 pups examined (stillborn, dead during lactation, culled or examined at scheduled sacrifice on lactation day 21). Based on the results of this study it is concluded that the 500 mg/kg/day dose level, the highest dose tested, is the no observed adverse effect level (NOAEL) for parental F0 and F1 pup toxicity for CAS 115733 -09 -0 and also for the read across target substance Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts.

Justification for selection of Effect on fertility via oral route:
best study available

Effects on developmental toxicity

Description of key information

Read Across: One Generation reproduction toxicity study, a calcium sulfonate read across substance (CAS 115733-09-0), NOAEL (for p) and f1 > 500 mg/kg bw/day.

Link to relevant study records

Reference

Endpoint:

developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
In this justification, the read-across (bridging) concept is applied, based on the chemical structure of the potential analogues, their toxicokinetic behaviour and other available (eco-)toxicological data.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
C20-24 calcium sulfonate and Benzenesulfonic acid, C14-24-branched and linear alkyl derivs., calcium salts (CAS 115733-09-0) are members of a category of chemicals described as alkaryl sulfonates, which was established as part of the U.S. Environmental Protection Agency High Production Volume (HPV) Challenge Program. The substances of this category have a common functional group - the salt of aryl sulfonic acid. Furthermore, they all have a divalent alkaline earth metal, one or more linear and/or branched alkyl groups of variable chain length and branching characteristics or extended heterocyclic carbon system from the sulfonated benzene ring. Finally, they have common precursors and/or the likelihood of common breakdown products via physical and biological processes, resulting in structurally similar chemicals, and similar physicochemical properties, environmental fate, ecotoxicity and mammalian toxicity.
Concerning their developmental toxicity, it is believed that both substance will be metabolised by the same mechanisms by mammalian organisms. Therefore they are expected to follow the same pattern. For the detailed procedure of the read-across principle and justifications, please refer to the analogue approach justification depicted below and the separate Read-Across Statement (Chemservice S.A., 2017).

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Source chemical: Benzenesulfonic acid, C14-24-branched and linear alkyl derivs., calcium salts (CAS 115733-09-0, EC No none)
Target chemical: Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts (C20-24 calcium sulfonate, CAS No none, EC No none)

3. ANALOGUE APPROACH JUSTIFICATION
C20-24 calcium sulfonate and Benzenesulfonic acid, C14-24-branched and linear alkyl derivs., calcium salts (CAS 115733-09-0) are UVCB substances that are produced using similar manufacturing process and raw materials and are manufactured in mineral oil. They are members of a category of chemicals described as alkaryl sulfonates, which was established as part of the U.S. Environmental Protection Agency High Production Volume (HPV) Challenge Program. These substances are similar in that they have a common functional group, the salt of aryl sulfonic acid. TOXMATCH and OECD Toolbox QSAR structure similarity assessments using Tanimoto distance fingerprint, Hellinger distance atom environment, Euclidian distance and Dice calculations indicate that these substances are very similar. Likewise, they have similar physicochemical properties, similar environmental fate characteristics, and similar ecotoxicity and mammalian toxicity profiles. For example, these substances can dissociate only in the presence of strong acids such as in the stomach but are not expected to dissociate under environmental conditions. For further details on this, please refer to the separate Read-Across Statement (Chemservice S.A., 2017). The similar toxicity profiles indicate that they have a similar MOA. C20-24 calcium sulfonate and Benzenesulfonic acid, C14-24-branched and linear alkyl derivs., calcium salts (CAS 115733-09-0) are classified as Skin Sens Cat. 1B and Skin Irrit 2, respectively.
The similar findings (refer to data matrix outlined below and the separate Read-Across Statement) for both substances support the conclusion that similar molecules are expected to be formed from both substances, and in consequence, similar effects can be reasonably expected. Hence, the analogue may perfectly serve as a read-across substance for the C20-24 calcium sulfonate and vice versa. So, based on the WOE of these data, the available data on CAS 115733-09-0 can be used to cover the systemic endpoints currently lacking for C20-24 calcium sulfonate and read across is scientifically justified, making further testing obsolete.

4. DATA MATRIX
There is mainly data available on the toxicological properties of the analogues CAS 61789-86-4 / its overbased version CAS 68783-96-0 and for CAS 70024-69-0 / its overbased version CAS 70024-71-4. Data on Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts covers merely the physico chemical properties. Hence, the identification and discussion of common properties of the analogues and the C20-24 calcium sulfonate will be mainly based on this physicochemical data.
The available data for the following physico-chemical properties, which are relevant for absorption into living organisms, are very similar. The substances are rather huge molecules and have a similar molecular weight range, which triggers already similarities in their absorption behaviour. Furthermore, the physico-chemical properties like their partition coefficient, water solubility and vapour pressure are similar. Regarding the application of these substances, the substances are usually solved in an inert mineral oil to enable handling. The C20-24 calcium sulfonate and all analogous substances are hydrolytically stable in the natural environment and at least CAS 70024-69-0 and CAS 61789-86-4 are not readily biodegradable, and the available data suggests this to apply also for C20-24 calcium sulfonate. Taking into account the vast amount of data available for partition coefficient data on various calcium sulfonates it can be concluded that they do not have a significant potential for bioaccumulation in aquatic and terrestrial organisms. However, they are expected to be adsorbed to a significant extent to the sediment and soil and to be thereby not bioavailable, which was confirmed by the results of short-term toxicity tests to fish, daphnia and algae for CAS 70024-71-4; CAS 115733-09-0 and CAS 61789-64-4, in which the lowest LL50 was already > 100 mg/L WAF.
For the following toxicological endpoints there is data available derived from CAS 70024-69-0/ CAS 70024-71-4, Analogue of CAS 70024-69-0, CAS 115733-09-0, CAS 61789-86-4/ CAS 68783-96-0 and CAS 75975-85-8: Acute toxicity, Skin irritation / corrosion, Eye irritation /corrosion, Skin sensitization, Repeated dose toxicity, Genetic toxicity in vitro and in vivo and Toxicity to reproduction (fertility / developmental toxicity). Furthermore a rather extensive data package is available concerning the human sensitization potential of numerous analogous substances. For the acute oral toxicity, the values for all read across substances are very high, all LD50 values being above 2000 mg/kg (reaching in older tests up to greater than 20,000 mg/kg) and the values for the substances can be considered as similar within normal biological variations. The substances are also not toxic via the inhalation or the dermal route of exposure. Regarding Skin/Eye Irritation, the available data on CAS 70024-69-0 and CAS 61789-86-4 shows both substances to be not irritating to the skin or the eyes. The skin sensitization data in animals and humans (for CAS 75975-85-8; CAS 61789-86-4 and EC 939-141-6) evaluated in a weight-of-evidence approach indicates that low TBN calcium sulfonates (TBN < 300) are skin sensitizers with a specific concentration limit (SCL) of 10% and that high TBN calcium sulfonates (TBN ≥ 300) are not skin sensitizers. Last but not least, the available genetic toxicity data for Analogue of CAS 70024-69-0, CAS 61789-86-4 and its overbased version CAS 68783-96-0 prove all of these substances to be not mutagenic. The NOAELs derived for the endpoints Repeated dose toxicity (Analogue of CAS 70024-69-0 and CAS 61789-86-4) and Toxicity to reproduction (fertility / developmental toxicity for CAS 115733-09-0)) have been also found to be in a similar range.
For further details please refer to the seperate Read-Across Statement (Chemservice S.A., 2017) and/or the robust study summaries of the respective studies in this IUCLID file.

Reason / purpose for cross-reference:

read-across source

Analytical verification of doses or concentrations:

yes

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
Clinical signs (parental animals): no effects
Body weight and food consumption (parental animals): no effects
Test substance intake (parental animals): no data
Reproductive function: estrous cycle (parental animals): not examined
Reproductive function: sperm measures (parental animals): no effects
Reproductive performance (parental animals): no effects
Organ weights (parental animals): no effects
Gross pathology (parental animals): no effects
Histopathology (parental animals): yes
Details on results (parental animals): There were no remarkable findings in F0 males, with the exception of post dosing salivation.
In F0 females there were no remarkable findings with the exception of negative ammonium sulphide staining in two high dose and one mid dose animal.

Dose descriptor:

NOAEL

Effect level:

> 500 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Basis for effect level:

other: maternal toxicity

Dose descriptor:

NOAEL

Effect level:

> 500 mg/kg bw/day (actual dose received)

Based on:

act. ingr.

Basis for effect level:

other: developmental toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Viability (offspring): no effects
Clinical signs (offspring): no effects
Body weight (offspring): no effects
Sexual maturation (offspring): not examined
Organ weights (offspring): no effects
Gross pathology (offspring): no effects
Histopathology (offspring): no effects
Details on results (offspring): There were no remarkable observations in F1 animals.

Dose descriptor:

NOAEL

Remarks on result:

other: not determinable due to study type

Abnormalities:

not specified

Developmental effects observed:

not specified

Results of the homogeneity analysis indicate that the test article was homogeneous in the vehicle and stable for ten days when stored under ambient conditions. Concentration analysis confirmed that the test article was at the appropriate concentration in the dosing solutions.

Results

F0 Generation:

F0 males exhibited a dose related increase in post dosing salivation and dark material around the nose in the mid and high dose groups The remaining F0 male parameters were unremarkable including: mean body weight and food consumption, mating and fertility indicies, absolute and relative organ weights, sperm evaluation parameters and macro and microscopic pathology.

The clinical signs of the F0 females were generally unremarkable. There were no toxicologically meaningful differences between the control low, mid and high dose groups with respect to F0 female mean body weights, body weight change, food consumption, mating and fertility indicies, precoital intervals or gestation length. A macroscopic finding observed in two high dose and one mid female sacrificed on post mating day 25 was a finding of negative ammonium sulfide staining in animals that failed to deliver and were euthanized on gestation day 25.

No other remarkable findings were noted in the F0 females at necropsy and no meaningful microscopic lesions were observed in any of the treated F0 females.

F1 Generation:

No treatment related findings were noted in the F1 pups during lactation. No treatment related gross necropsy findings were evident in any of the F1 pups examined (stillborn, dead during lactation, culled or examined at scheduled sacrifice on lactation day 21.)

Conclusions:

Adverse effects did not occur in parental animals or offsprings at doses up to 500 mg/kg bw/day, therefore a NOAEL of > 500 mg/kg bw was identified in this study. These results can be used to fulfill the information requirements for the chemical substance Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts, due to the high structural similarity of these substances. For the detailed procedure of the read-across principle and justifications, please refer to the separate Read-Across Statement (Chemservice S.A., 2017).

Executive summary:

In a 1-generation reproduction study, benzenesulfonic acid, C14-C24 branched and linear alkyl derivatives (CAS 115733 -09 -0) was administered in corn oil via oral gavage to 28 Sprague-Dawley rats/sex at dose levels of 0, 50, 167 and 500 mg/kg bw/day (Bjorn, 2004, according to OECD 415). All F0 males were dosed for 70 days prior to mating, mating (maximum 3 weeks) and through the completion of parturition. All F0 females were dosed for 14 days prior to mating, mating (maximum 3 weeks), 25 days of gestation and through day 20 of lactation. The offspring (F1) were potentially exposed to the test substance in utero (during gestation) and through nursing during lactation days 1-21 until euthanization on post-natal day 21. On lactation day 4 each litter was randomly culled to a maximum of eight pups, 4/sex/litter, when possible. Detailed pup examinations were performed on lactation days 0, 4, 7, 14 and 21. Pup sex was determined on lactation day 0 and verified on lactation days 4, 7, 14 and 21. Individual pup weights were determined on lactation days 1, 4, 7 14 and 21. Pups that were stillborn, cannibalized or found dead were subjected to a gross necropsy with emphasis on developmental morphology. Pups culled on day 4 were subjected to an abbreviated gross necropsy with emphasis on the reproductive system. All surviving pups were euthanized on lactation day 21 and examined macroscopically. All internal gross lesions were preserved for possible future microscopic examination.

The F1 offsprings were examined for number and sex of pups, stillbirths, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities. Moreover a gross examination of dead pups was conducted for external and internal abnormalities. So the possible cause of death fro pups born or found dead was evaluated.

No treatment related findings were noted in the F1 pups during lactation. No treatment related gross necropsy findings were evident in any of the F1 pups examined (stillborn, dead during lactation, culled or examined at scheduled sacrifice on lactation day 21). As no effects occurred at the highest dose, the NOAEL for developmental toxicity is greater than 500 mg/kg bw/day.

These results can be used to fulfill the information requirements for the chemical substance Reaction products of benzenesulfonic acid, mono-C20-24 (even)-sec-alkyl derivs. para-, calcium salts, due to the high structural similarity of these substances. For the detailed procedure of the read-across principle and justifications, please refer to the separate Read-Across Statement (Chemservice S.A., 2017).

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

In the key study, a one-generation reproduction study, the calcium sulfonate read across substance (CAS 115733-09-0) was administered in corn oil via oral gavage to 28 Sprague-Dawley rats/sex at dose levels of 0, 50, 167 and 500 mg/kg bw/day (Bjorn, 2004, according to OECD 415). All F0 males were dosed for 70 days prior to mating, mating (maximum 3 weeks) and through the completion of parturition. All F0 females were dosed for up to 70 days (14 days prior to mating, during mating and gestation and through day 20 of lactation. The offsprings (F1) were exposed to the test substance in utero (during gestation) and through nursing during lactation day 1 until euthanization on post-natal day 21. On lactation day 4 each litter was randomly culled to a maximum of eight pups, 4/sex/litter, when possible. Detailed pup examinations were performed on lactation days 0, 4, 7, 14 and 21. Pup sex was determined on lactation day 0 and verified on lactation days 4, 7, 14 and 21. Individual pup weights were determined on lactation days 1, 4, 7 14 and 21. Pups that were stillborn, cannibalized or found dead were subjected to a gross necropsy with emphasis on developmental morphology. Pups culled on day 4 were subjected to an abbreviated gross necropsy with emphasis on the reproductive system. All surviving pups were euthanized on lactation day 21 and examined macroscopically. All internal gross lesions were preserved for possible future microscopic examination.

The F1 offsprings were examined for number and sex of pups, stillbirths, postnatal mortality, presence of gross anomalies, weight gain, physical or behavioural abnormalities. Moreover a gross examination of dead pups was conducted for external and internal abnormalities. So the possible cause of death for pups born or found dead was evaluated.

No treatment related findings were noted in the F1 pups during lactation. No treatment related gross necropsy findings were evident in any of the F1 pups examined (stillborn, dead during lactation, culled or examined at scheduled sacrifice on lactation day 21). As no effects occurred at the highest dose, the NOAEL for CAS 115733 -09 -0 for developmental toxicity is greater than 500 mg/kg bw/day.

Justification for selection of Effect on developmental toxicity: via oral route:
best study available

Justification for classification or non-classification

In the one-generation study with the calcium sulfonate read across substance (CAS 115733 -09 -0) no substance related effects occurred in treated animals, except for the observation of post dosing salivation and dark material around the nose in the mid and high dose groups in F0 males and the negative ammonium sulfide staining in two high dose and one mid dose F0-female. No treatment related findings were noted in the F1 pups during lactation. No treatment related gross necropsy findings were evident in any of the F1 pups examined (stillborn, dead during lactation, culled or examined at scheduled sacrifice on lactation day 21). Based on the results of this study it is concluded that the 500 mg/kg/day dose level is the no observed adverse effect level (NOAEL) for parental F0 and F1 pup toxicity (no significant adverse effects occurred at this dose level) for CAS 115733-09-0. Consequently, as neither reproductive effects nor toxicologically significant systemic effects were found in maternal organisms and in pups at the highest dose level test, the calcium sulfonate target substance (mono-C20-24 (even)) is not expected to be a reproductive or developmental toxicant. The substance does not meet the criteria for classification and labelling in accordance with Regulation (EC) No 1272/2008.