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

Exposure related observations in humans: other data

Administrative data

Endpoint:

exposure-related observations in humans: other data

Type of information:

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

Adequacy of study:

supporting 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 Sulfonic acids, petroleum, calcium salts (CAS 61789-86-4) 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 skin irritation / corrosion, 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: Sulfonic acids, petroleum, calcium salts (CAS 61789-86-4, EC 263-093-9)
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 Sulfonic acids, petroleum, calcium salts (CAS 61789-86-4) 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 only similar to a certain extent. However, a certain difference can be expected due to the presence of additional benzene rings and a signficantly increased amount of secondary alkylations. They still 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 is classified as Skin Sens Cat. 1A and Sulfonic acids, petroleum, calcium salts (CAS 61789-86-4) is not classified.
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 serve in a worst case approach as a read-across substance for the C20-24 calcium sulfonate. So, based on the WOE of these data, the available data on CAS 61789-86-4 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. 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 separate Read-Across Statement (Chemservice S.A., 2017) and/or the robust study summaries of the respective studies in this IUCLID file.

Cross-reference

Reason / purpose for cross-reference:

read-across source

Reference

Endpoint:

exposure-related observations in humans: other data

Adequacy of study:

supporting study

Study period:

Between 04 March 1993 and 26 March 1993

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Study conducted in accordance with generally accepted scientific principles but criteria for subject selection was not described.

Type of study / information:

study with volunteers

Endpoint addressed:

skin irritation / corrosion

Qualifier:

no guideline available

GLP compliance:

not specified

Ethical approval:

confirmed and informed consent free of coercion received

Details on study design:

The 48-Hour Patch Test was conducted to determine comparative dermal irritation to determine tolerability for subsequent human patch testing as follows:
Panel No: 93030
The study was initiated on March 4,1993 and observations (skin reactivity) were made on March 6, 1993 (48-hours) and March 8, 1993 (96-hours).
Panel No: 93037
The study was initiated on March 22,1993 and observations (skin reactivity) were made on March 24, 1993 (48-hours) and March 26, 1993 (96-hours).
Approximately 0.2 mL of each test article was placed onto Parke-Davis Readi-Bandage occlusive patches. The patch test units were applied to the back of each subject for a period of 48-hours.
At the end of the 48-hour contact period, the patch test units were removed at the Clinic and scored for dermal reactivity. A second reading was taken 48-hours later (96-hour post-application).

Dermal responses were recorded using the following 6-point scale:
0 = No evidence of any effect
+ = Barely Perceptible (Minimal, faint, uniform or spotty erythema)
1 = Mild (Pink, uniform erythema covering most of the contact site)
2 = Moderate (Pink-red erythema uniform in the entire contact site)
3 = Marked (Bright-red erythema with/without petechiae or papules)
4 = Severe (Deep-red erythema with/without vesiculation or weeping)
All other observed dermal sequelae (Le. oedema, dryness, hypo- or hyperpigmentation, etc.) were appropriately recorded and described as mild, moderate or severe.

Exposure assessment:

measured

Details on exposure:

Panel No: 93030
Twenty-seven (27) subjects, 8 males and 19 females, ranging in age from 18 to 67 years, were empaneled to test 1%, 3%, and 10% concentrations of the test articles, including 2 controls.
Panel No: 93037
Twenty-eight (28) subjects, 7 males and 21 females, ranging in age from 18 to 58 years, were empaneled to test 30% and 100% (Neat) concentrations of the test articles, without the controls.
The subjects were informed of the nature of the tests, including possible adverse reactions.
Written informed consent was obtained.
Additionally, the subjects were considered dependable and able to read and understand instructions. The subjects did not exhibit any physical or dermatological conditions which would have precluded application of the test articles.

The subjects did not exhibit any physical or dermatological conditions which would have precluded application of the test articles.

Results:

A total of 27/27 subjects satisfactorily completed the test procedure for Panel no. 93030. A total of 28/28 subjects satisfactorily completed the test procedure for Panel no. 93037. There were no discontinued panellists at any time during the come of the studies.

None of the patch test reactivity observed was considered to be evidence of allergic contact sensitization. All were considered indicative of irritation.
Peak levels of dermal irritation were observed at the 48-hour reading (i.e., following removal of the patch). By the 96-hour reading, overall levels and seventy of reactivity were generally diminished.
Student-Newman-Keuls post-hoc analyses showed the following significant (P 5.05) differences in mean irritation scores observed among all the concentrations tested.
Under the conditions of a 48-hour (occlusive) patch test, the following overall (general) ranking of the test articles based on comparative mean irritation scores was observed: Calcium sulfonate C15-36 TBN=13 >= Calcium sulfonate TBN=13 >=Calcium sulfonate TBN=30 > Non-sulfonate substance >= Calcium sulfonate TBN=300 (EC# 263-093-9) = Calcium sulfonate TBN=300 = mineral oil = mineral oil.
Based on these data, test concentrations of 10% or less are considered to be appropriate and probably tolerable for subsequent repeated insult (occlusive) patch testing (RIFT) for the estimation of potential induced allergic contact sensitization in human subjects.

See attached background material Table 1 - 8 for individual test subject irritation scores.

Conclusions:

Under the conditions of a 48-hour (occlusive) patch test, the following overall (general) ranking of the test articles based on comparative mean irritation scores was observed: Calcium sulfonate C15-36 TBN=13 >= Calcium sulfonate TBN=13 >= Calcium sulfonate TBN=30 > Non-sulfonate substance >= Calcium sulfonate TBN=300 (EC 263-093-9) = Calcium sulfonate TBN=300 = Mineral oil = Mineral oil.

Based on these data, test concentrations of 10% or less are considered to be appropriate and probably tolerable for subsequent repeated insult (occlusive) patch testing (RIFT) for the estimation of potential induced allergic contact sensitization in human subjects.

Executive summary:

To determine and compare the relative primary irritation potential and estimate tolerability for subsequent occlusive RIPT studies of eight (8) test articles when applied to the skin of human subjects for 48-hours under occlusive patches.

Under the conditions of a 48-hour (occlusive) patch test, the following overall (general) ranking of the test articles based on mean irritation scores was observed: Calcium sulfonate C15-36 TBN=13 >= Calcium sulfonate TBN=13 >= Calcium sulfonate TBN=30 > Non-sulfonate substance >= Calcium sulfonate TBN=300 (EC 263-093-9) = Calcium sulfonate TBN=300 = Mineral oil = Mineral oil.

Based on these data, test concentrations of 10% or less are considered to be appropriate and probably tolerable for subsequent repeated insult (occlusive) patch testing (RIFT) for the estimation of potential induced allergic contact sensitization in human subjects.

Materials and methods

Test material

Test material information

Constituent 1

Reference substance name:

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

EC Number:

947-519-7

Molecular formula:

Too complex

IUPAC Name:

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

Test material form:

semi-solid (amorphous): gel

Details on test material:

dark brown paste

Results and discussion

Results:

A total of 27/27 subjects satisfactorily completed the test procedure for Panel no. 93030. A total of 28/28 subjects satisfactorily completed the test procedure for Panel no. 93037. There were no discontinued panellists at any time during the come of the studies.

None of the patch test reactivity observed was considered to be evidence of allergic contact sensitization. All were considered indicative of irritation.
Peak levels of dermal irritation were observed at the 48-hour reading (i.e., following removal of the patch). By the 96-hour reading, overall levels and seventy of reactivity were generally diminished.
Student-Newman-Keuls post-hoc analyses showed the following significant (P 5.05) differences in mean irritation scores observed among all the concentrations tested.
Under the conditions of a 48-hour (occlusive) patch test, the following overall (general) ranking of the test articles based on comparative mean irritation scores was observed: Calcium sulfonate C15-36 TBN=13 >= Calcium sulfonate TBN=13 >=Calcium sulfonate TBN=30 > Non-sulfonate substance >= Calcium sulfonate TBN=300 (EC# 263-093-9) = Calcium sulfonate TBN=300 = mineral oil = mineral oil.
Based on these data, test concentrations of 10% or less are considered to be appropriate and probably tolerable for subsequent repeated insult (occlusive) patch testing (RIFT) for the estimation of potential induced allergic contact sensitization in human subjects.

Any other information on results incl. tables

See attached background material table 1 -8 for individual test subject irritation scores on source substance.

Applicant's summary and conclusion

Conclusions:

Under the conditions of a 48-hour (occlusive) patch test, the following overall (general) ranking of the test articles based on comparative mean irritation scores was observed: Calcium sulfonate C15-36 TBN=13 >= Calcium sulfonate TBN=13 >= Calcium sulfonate TBN=30 > Non-sulfonate substance >= Calcium sulfonate TBN=300 (EC 263-093-9) = Calcium sulfonate TBN=300 = Mineral oil = Mineral oil.
Based on these data, test concentrations of 10% or less are considered to be appropriate and probably tolerable for subsequent repeated insult (occlusive) patch testing (RIFT) for the estimation of potential induced allergic contact sensitization in human subjects. 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:

To determine and compare the relative primary irritation potential and estimate tolerability for subsequent occlusive RIPT studies of eight (8) test articles when applied to the skin of human subjects for 48-hours under occlusive patches.

Under the conditions of a 48-hour (occlusive) patch test, the following overall (general) ranking of the test articles based on mean irritation scores was observed: Calcium sulfonate C15-36 TBN=13 >= Calcium sulfonate TBN=13 >= Calcium sulfonate TBN=30 > Non-sulfonate substance >= Calcium sulfonate TBN=300 (EC 263-093-9) = Calcium sulfonate TBN=300 = Mineral oil = Mineral oil.

Based on these data, test concentrations of 10% or less are considered to be appropriate and probably tolerable for subsequent repeated insult (occlusive) patch testing (RIFT) for the estimation of potential induced allergic contact sensitization in human subjects.

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).