Registration Dossier

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

Based on the available animal that all show positive results and the human data that demonstrate positive results at and above 10%w/w concentration it is considered that the low TBN substance is classified as a skin sensitiser. These results also show that the high TBN substance is not a skin sensitizer. 

Classification and Labeling is proposed and explained for Sulfonic acids, petroleum, barium salts using data from skin sensitization studies on natural and synthetic calcium sulfonates. For Registration, Evaluation, Authorization and Restriction of Chemicals (REACH) classification and labeling, EU Classification, Labeling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 applies. 

 

In the lubricant additive industry, calcium sulfonate is a common name for natural and synthetic long-chain alkylbenzenesulfonic acids, calcium salts. Calcium sulfonates, which have surfactant properties, are used as detergents in a broad variety of lubricant applications. In some cases, excess calcium carbonate is added to calcium sulfonates to add acid buffering capacity (commonly known as “overbasing”). Calcium sulfonates with a large excess of calcium carbonate are referred to as high overbased or high total base number (TBN) calcium sulfonates, whereas calcium sulfonates with small amounts of added calcium carbonate are called low overbased or low TBN calcium sulfonates. Animal studies show that calcium sulfonates with a TBN greater than 300 are not skin sensitizers while the results in animals at a TBN of 300 exhibit a mixed skin sensitization response. However, human repeat insult patch tests clearly show that high TBN overbased calcium sulfonates (TBN ≥ 300) are not sensitizers and that low TBN calcium sulfonates do not cause sensitization in a substantial number of persons at concentrations of 10% or lower within the definition of sensitization under EU Regulation (EC) No. 1272/2008.

 

Sensitization:

 

Low TBN Calcium Sulfonates

 

In a key study the dermal sensitization of an analog of this substance (Benzene, polypropene derivs., sulfonated, calcium salts; EC 616-278-7; TBN = 13) was evaluated in the local lymph node assay (LLNA) (Lees D, 1996). Groups of male mice (4/group) were dose with approximately 25 µl of 0.1, 1, 10 or 30% concentrations of the test material in DMF on the dorsal surface of each ear for three consecutive days. The animals were then injected with 3H-methylthymidine, and the auricular lymph nodes were then collected and prepared for scintillation counting. A three-fold or greater increase in isotope incorporation was observed at all test concentrations. Although investigators have reported that LLNA over predicts the sensitization potential of surfactants (Basketer DA & Kimber I, 2011; Ball et al, 2011), the positive response in this study is supportive of the sensitization response for low TBN calcium sulfonates noted in other sensitization studies.

 

In another key supporting study the dermal sensitization of an analog of this substance (Benzene, polypropene derivs., sulfonated, calcium salts;EC 616-278-7; TBN = 13) was evaluated in guinea pigs (Bonnette KL, 1993a; Table 1). The animals were treated topically with a 100% concentration of the test substance once per week during the three week induction phase. Following a two week rest period, the animals were topically challenged with a 50% concentration of the test substance. After approximately one week the animals were rechallenged with a 25% concentration of the test substance. Following the first rechallenge, the animals then were rechallenged with a 10% concentration of the test substance. The number of animals exhibiting positive sensitization responses for the test substance at 50%, 25%, and 10% were 9/10, 10/10, and 9/10, respectively, and the mean 24/48 hour Draize scores were 1.9/2.1, 1.6/2.0, and 1.5/1.5, respectively. The mean 24/48 hour Draize scores for the naïve controls at 50%, 25%, and 10% were 0.2/0.2, 0.7/0.6, and 0.5/0.5, respectively. Based on these results the test substance was determined to be a sensitizer.

 

 

TABLE 1. Dermal Sensitization Study (Modified Buehler Design) in Guinea Pigs with a 100% Low TBN Calcium Sulfonate (Benzene, Polypropene Derivs., Sulfonated, Calcium Salts; EC 616-278-7; TBN = 13) Induction: Challenge Results (Bonnette KL, 1993a)

Group

Concentration

Mean Draize Score

# Positive

Conclusion

24 hours

48 hours

Test

50%

1.9

2.1

9/10

Sensitizer

Control

50%

0.2

0.2

 

 

 

 

 

 

 

 

Test

25%

1.6

2.0

10/10

Sensitizer

Control

25%

0.7

0.6

 

 

 

 

 

 

 

 

Test

10%

1.5

1.5

9/10

Sensitizer

Control

10%

0.5

0.5

 

 

Control = Topical application of test article to naïve animals to account for primary irritation reactions

 

 

In another key study the dermal sensitization of an analog of this substance (Benzene, polypropene derivs., sulfonated, calcium salts; EC 616-278-7; TBN = 13) was evaluated in guinea pigs (Shults SK, 1993). The animals were treated topically with a 100% concentration of the test substance once per week during the three week induction phase. Following a two week rest period, the animals were topically challenged with a 25% concentration of the test substance. After approximately one week the animals were rechallenged with a 10% concentration of the test substance. Following the first rechallenge, the animals then were rechallenged with a 10% concentration of the test substance. The number of animals exhibiting positive sensitization responses for the test substance at 25%, 10% rechallenge, and 10% second rechallenge were 10/10, 9/10, and 7/10, respectively, and the mean 24/48 hour Draize scores were 1.4/1.15, 0.8/0.95, and 0.8/0.85, respectively. The mean 24/48 hour Draize scores for the naïve controls at 25%, 10% rechallenge, and 10% second rechallenge were 0.8/0.06, 0.55/0.6, and 0.3/0.65, respectively. Based on these results the test substance was determined to be a sensitizer.

 

In another key study the dermal sensitization of an analog of this substance (Benzene, polypropene derivs., sulfonated, calcium salts; EC 616-278-7; TBN =13) was evaluated in a human repeat insult patch test (Shanahan RW & Erianne JA, 1993a; Table 2). A panel of 53 subjects was identified for this test. In the induction phase the undiluted (100% concentration) test substance was administered directly to the skin and covered with a semi-occlusive patch three times per week for a total of nine applications. Following a two week rest period, each of the 44 subjects that completed the induction phase was topically challenged with the undiluted (100% concentration) test substance. Positive responses (scores ≥ 1) were observed in 9/44 and 6/44 at the 24 and 72 hour readings, respectively. Rechallenge of the of the six subjects suspective of exhibiting allergic reactions confirmed allergic contact dermatitis in four (4/44 or 9%). Based on these results the test substance was determined to be a sensitizer.

 

In another key study the dermal sensitization of an analog of this substance (Benzene, polypropene derivs., sulfonated, calcium salts; EC 616-278-7; TBN = 13) was evaluated in a human repeat insult patch test (Shanahan RW & Erianne JA, 1994a; Table 2). A panel of 55 subjects was identified for this test. In the induction phase a 20% concentration of the test substance in mineral oil was administered directly to the skin and covered with a semi-occlusive patch three times per week for a total of nine applications. Following a two week rest period, each of the 45 subjects that completed the induction phase was topically challenged with a 20% concentration of the test substance in mineral oil. Positive responses (scores ≥ 1) were observed in 16/45 and 16/45 at the 24 and 72 hour readings (or 48 or 96 hour make-up readings), respectively. Approximately 31 % (14/45) of the test population exhibited skin reactivity patterns that were suggestive or indicative of low-to moderate-grade, induced allergic contact dermatitis. Based on these results the test substance was determined to be a sensitizer.

 

 

Table 2. Human Repeat Insult Patch Tests (HRIPT) with a Low TBN Calcium Sulfonate (Benzene, Polypropene Derivs., Sulfonated, Calcium Salts; EC 616-278-7; TBN = 13): Challenge Results

Test Phase

Concentration

# Positive Responses

Conclusion

Study

24 hours

72 hours

Induction

100%

 

 

Sensitizer

Shanahan RW & Erianne JA, 1993a

Challenge

100%

9/44

6/44

 

 

 

 

 

 

Induction

20%

 

 

Sensitizer

Shanahan RW & Erianne JA, 1994a

Challenge

20%

16/45*

16/45*

*48 or 96 hour make-up readings were required for some subjects

 

Low TBN Specific Concentration Limit (SCL)

 

The weight-of-evidence of all the animal and human studies demonstrates that low TBN calcium sulfonates are skin sensitizers. However, well-conducted, reliable, controlled HRIPT studies show that these substances do not cause sensitization in a substantial number of subjects at 10% and lower.

 

In another key study the dermal sensitization of an analog of this substance (Sulfonic acids, petroleum, calcium salts; EC 263-093-9; TBN = 30) was evaluated in a human repeat insult patch test (Alworth K, Schwartz H & Erianne JA, 1995a; Table 3). Five panels consisting of a total of 166 subjects were identified for this test. In the induction phase a 10% concentration of the test substance in mineral oil was administered directly to the skin and covered with an occlusive patch three times per week for a total of nine applications. Following a two week rest period, each of the 142 subjects that completed the induction phase was topically challenged with a 10% concentration of the test substance in mineral oil. A total of 8/142 (5.6%) of the subjects exhibited sensitization responses. Based on these results the test substance was determined to cause a low incidence of sensitization characterized by mild to moderate reactions in all but one subject.

 

In another key study the dermal sensitization of an analog of this substance (Sulfonic acids, petroleum, calcium salts; EC 263-093-9; TBN = 30) was evaluated in a human repeat insult patch test (Eisenberg RR,1994a; Table 3). A panel of 220 subjects was identified for this test. In the induction phase a 10% concentration of the test substance in mineral oil was administered directly to the skin and covered with an occlusive patch three times per week for a total of ten applications. Following a two week rest period, each of the 205 subjects that completed the induction phase was topically challenged with a 10% concentration of the test substance in mineral oil. A total of 12/205 (5.8%) of the subjects exhibited sensitization responses following the 10% challenge.  Based on these results the test substance was determined to cause a low incidence of sensitization characterized by mild to moderate reactions at 10%.

 

In another key study the dermal sensitization of an analog of this substance (Benzene, polypropene derivs., sulfonated, calcium salts; EC 616-278-7; TBN = 13) was evaluated in a human repeat insult patch test (Alworth K, Schwartz H & Erianne JA, 1995b; Table 3). Five panels consisting of a total of 159 subjects were identified for this test. In the induction phase a 10% concentration of the test substance in mineral oil was administered directly to the skin and covered with an occlusive patch three times per week for a total of nine applications. Following a two week rest period, each of the 154 subjects that completed the induction phase was topically challenged with a 10% concentration of the test substance in mineral oil. A total of 4/154 (2.6%) of the subjects exhibited sensitization responses. Based on these results the test substance was determined to cause a low incidence of sensitization characterized by mild to moderate reactions.

 

In another key study the dermal sensitization of an analog of this substance (Benzene, polypropene derivs., sulfonated, calcium salts; EC 616-278-7; TBN = 13) was evaluated in a human repeat insult patch test (Eisenberg RR,1994b; Table 3). A panel of 223 subjects was identified for this test. In the induction phase a 10% concentration of the test substance in mineral oil was administered directly to the skin and covered with an occlusive patch three times per week for a total of ten applications. Following a two week rest period, each of the 199 subjects that completed the induction phase was topically challenged with a 10% concentration of the test substance in mineral oil.  A total of 12/199 (6.0%) of the subjects exhibited sensitization responses following the 10% challenge.  Based on these results the test substance was determined to cause a low incidence of sensitization characterized by mild to moderate reactions at 10%.

 

In another key study the dermal sensitization of an analog of this substance (Benzene, polypropene derivs., sulfonated, calcium salts; EC 616-278-7; TBN = 13) was evaluated in a human repeat insult patch test (Alworth K, Schwartz H & Erianne JA, 1995c; Table 3). Four panels consisting of a total of 157 subjects were identified for this test. In the induction phase a 10% concentration of the test substance in mineral oil was administered directly to the skin and covered with an occlusive patch three times per week for a total of nine applications. Following a two week rest period, each of the 140 subjects that completed the induction phase was topically challenged with a 10% concentration of the test substance in mineral oil. A total of 4/140 (2.9%) of the subjects exhibited sensitization responses. Based on these results the test substance was determined to cause a low incidence of sensitization characterized by mild to moderate reactions in all but one subject.

 

In another key study the dermal sensitization of an analog of this substance (Benzene, polypropene derivs., sulfonated, calcium salts; EC 616-278-7; TBN = 13) was evaluated in a human repeat insult patch test (Eisenberg RR,1994c; Table 3). A panel of 227 subjects was identified for this test. In the induction phase a 10% concentration of the test substance in mineral oil was administered directly to the skin and covered with an occlusive patch three times per week for a total of ten applications. Following a two week rest period, each of the 199 subjects that completed the induction phase was topically challenged with a 10% concentration of the test substance in mineral oil.  A total of 12/199 (6.0%) of the subjects exhibited sensitization responses following the 10% challenge.  Based on these results the test substance was determined to cause a low incidence of sensitization characterized by mild to moderate reactions at 10%

 

In another key study the dermal sensitization of an analog of this substance(Benzene, polypropene derivs., sulfonated, calcium salts; EC 616-278-7; TBN = 85), was evaluated in a human repeat insult patch test (Shanahan RW & Erianne JA, 1994b; Table 3). A panel of 53 subjects was identified for this test. In the induction phase a 10% concentration of the test substance in mineral oil was administered directly to the skin and covered with a semi-occlusive patch three times per week for a total of nine applications. Following a two week rest period, each of the 48 subjects that completed the induction phase was topically challenged with a 10% concentration of the test substance in mineral oil. A total of 3/43 (6.3%) of the subjects exhibited sensitization responses. Based on these results the test substance was determined to cause a low incidence of sensitization characterized by mild to moderate reactions in all but one subject.

 

In another key study the dermal sensitization of an analog of this substance (Sulfonic acids, petroleum, calcium salts; EC 263-093-9; TBN = 82), was evaluated in a human repeat insult patch test (Shanahan RW & Erianne JA, 1994c; Table 3). A panel of 60 subjects was identified for this test. In the induction phase a 10% concentration of the test substance in mineral oil was administered directly to the skin and covered with a semi-occlusive patch three times per week for a total of nine applications. Following a two week rest period, each of the 56 subjects that completed the induction phase was topically challenged with a 10% concentration of the test substance in mineral oil. A total of 0/56 (0.0%) of the subjects exhibited sensitization responses.   Seven of the subjects that had positive responses during the challenge phase reported for rechallenge with a 1% concentration of the test substance. All except one subject had negative responses. The one subject exhibited a mild response (1+) only at the virgin site at the 24 hour observation. However, this site was noted as negative in the final (48 hour) evaluation. Based on these results the test substance was determined to not cause a sensitization response.

 

In another key study the dermal sensitization of an analog of this substance (Sulfonic acids, petroleum, calcium salts; EC 263-093-9; TBN = 100) was evaluated in a human repeat insult patch test (Shanahan RW & Erianne JA, 1994d; Table 3). A panel of 52 subjects was identified for this test. In the induction phase a 10% concentration of the test substance in mineral oil was administered directly to the skin and covered with a semi-occlusive patch three times per week for a total of nine applications. Following a two week rest period, each of the 51 subjects that completed the induction phase was topically challenged with a 10% concentration of the test substance in mineral oil. A total of 0/51 (0.0%) of the subjects exhibited sensitization responses. Based on these results the test substance was determined to not cause a sensitization response.

 

In another key study the dermal sensitization of an analog of this substance substance (Benzene, polypropene derivs., sulfonated, calcium salts; EC 616-278-7; TBN = 13) was evaluated in a human repeat insult patch test (DiFiglia CJ, Shanahan RW & Erianne JA, 1993d). A panel of 53 subjects was identified for this test. In the induction phase a 1% concentration of the test substance in mineral oil was administered directly to the skin and covered with an occlusive patch three times per week for a total of nine applications. Following a two week rest period, each of the 48 subjects that completed the induction phase was topically challenged with a 1% concentration of the test substance in mineral oil. A total of 0/48 (0%) of the subjects exhibited sensitization responses following the 1% challenge.  Based on these results the test substance was determined not to induce irritation or sensitization at 1%.

 

 

Table 3. Calcium Sulfonate Human Repeat Insult Patch Tests (HRIPT) with a 10% Induction Phase Concentration                                                                                    

Substance

Challenge %

Challenge Response

Sensitization Response      (%)

Conclusion

Study

EC 263-093-9 (TBN = 30)

10%

7/142 with mild to moderate erythema/edema including mild to moderate papular reactions; 1/142 with moderate erythema @ 24 hours and severe erythema @ 72 hours

8/142 (5.6)

Sensitizer: low incidence with mild to moderate reactions in all but one of 8 subjects

Alworth K, Schwartz H & Erianne JA, 1995a

EC 263-093-9 (TBN = 30)

10%

3/205 with mild erythema @ original & virgin sites; 1/205 with moderate erythema @ both areas; 7/205 with mild erythema original site; 1/205 with mild erythema virgin site (Note: 6/7 rechallenged at 1% did not exhibit reactions)

12/205 (5.8)

Sensitizer: low incidence with mild to moderate reactions

Eisenberg RR, 1994a

 

EC 616-278-7 (TBN = 13)

10%

2/154 with mild to moderate erythema with moderate papular reactions; 2/154 with mild to marked erythema and with moderate edema and moderate papular reactions in the induction phase that were considered sensitized and, therefore were not challenged

4/154 (2.6)

Sensitizer: low incidence with mild to moderate reactions

Alworth K, Schwartz H & Erianne JA, 1995b

EC 616-278-7 (TBN = 13)

10%

6/199 with mild erythema @ original sites; 5/199 with moderate erythema original site; 1/199 with moderate erythema virgin site

12/199 (6.0)

Sensitizer: low incidence with mild to moderate reactions

Eisenberg RR, 1994b

 

EC 616-278-7 (TBN = 13)

10%

3/140 with mild to moderate erythema with mild to moderate edema and/or mild to severe papular reactions in some; 1/140 with moderate erythema with mild to severe papular reaction including an adverse reaction report of reaction spreading to back/neck @ 96 hrs with erythema deminishing @ 192 hours but papular reaction spreading to the eyes

4/140 (2.9)

Sensitizer: low incidence with mild to moderate reactions in all but one of 4 subjects

Alworth K, Schwartz H & Erianne JA, 1995c

EC 616-278-7 (TBN = 13)

10%

1/210 with mild erythema original and virgin site; 6/210 with BP to mild erythema original site; 5/210 moderate erythema original site; 1/210 with marked erythema original site; 1/210 with mild erythema virgin site; 1/210 with marked erythema original site

15/210 (7.1)

Sensitizer: low incidence with mild to moderate reactions

Eisenberg RR, 1994c

 

EC 616-278-7 (TBN = 85)

10%

2/48 with mild to moderate erythema and 1/48 with moderate edema and papular that spread beyond contact site during induction were not challenged

3/48 (6.3)

Sensitizer: low incidence with mild to moderate reactions

Shanahan RW & Erianne JA, 1994b

EC 263-093-9 (TBN = 82)

10%

56/56 no reaction

0/56 (0)

Not a sensitizer

Shanahan RW & Erianne JA, 1994c

EC 263-093-9 (TBN = 100)

10%

51/51 no reaction

0/51 (0)

Not a sensitizer

Shanahan RW & Erianne JA, 1994d

EC 263-093-9 = Sulfonic acids, petroleum, calcium salts

EC 616-278-7 = Benzene, polypropene derivs., sulfonated, calcium salts

 

 

In accordance with EU CLP Regulation (EC) No. 1272/2008, classification of low TBN calcium sulfonates is required for sensitization with a specific concentration limit of 10%.

 

High TBN Calcium Sulfonates

 

In another key study the dermal sensitization of this substance (Sulfonic acids, petroleum, calcium salts; EC 263-093-9; TBN = 375) was evaluated in guinea pigs (Kiplinger GR, 1992a; Table 4). The animals were treated topically with a 100% concentration of the test substance once per week during the three week induction phase. Following a two week rest period, the animals were topically challenged with a 25% concentration of the test substance. After approximately one week the animals were rechallenged with a 25% concentration of the test substance. The number of animals exhibiting positive sensitization responses for the test substance at 25% challenge and 25% rechallenge were 0/12 and 0/12, respectively, and the mean 24/48 hour Draize scores were 0.4/0.4 and 0.4/0.4, respectively. The mean 24/48 hour Draize scores for the naïve controls at 25% challenge and 25% rechallenge were 0.1/0.1 and 0.4/0.3, respectively. Based on these results the test substance was determined not to be a sensitizer.

 

 

 

Table 4. Dermal Sensitization Study (Modified Buehler Design) in Guinea Pigs with a 100% High TBN Calcium Sulfonate (Sulfonic acids, petroleum, calcium salts; EC 263-093-9; TBN = 375) Induction: Challenge Results (Kiplinger GR, 1992a)

Group

Concentration

Mean Draize Score

# Positive

Conclusion

24 hours

48 hours

Test

25%

0.4

0.4

0/12

Not a sensitizer

Control

25%

0.1

0.1

 

 

 

 

 

 

 

 

Test

25%

0.4

0.4

0/12

Sensitizer

Control

25%

0.4

0.3

 

 

 

In another key study the dermal sensitization of this substance (Sulfonic acids, petroleum, calcium salts; EC 263-093-9; TBN = 400) was evaluated in guinea pigs (Reagan EL, 1988). The animals were treated topically with a 100% concentration of the test substance once per week during the three week induction phase. Following a two week rest period, the animals were topically challenged with a 60% concentration of the test substance. After approximately one week the animals were rechallenged with a 60% concentration of the test substance. The number of animals exhibiting positive sensitization responses for the test substance at 60% challenge and 60% rechallenge were 4/10 and 0/10, respectively, and the mean 26/48 hour Draize score severity idices were 0.7/0.5 and 0.0/0.2, respectively. The mean 26/48 hour Draize score severity indices for the naïve controls at 60% challenge and 60% rechallenge were 0.5/0.3 and 0.0/0.0, respectively. Based on these results the test substance was determined not to be a sensitizer.

 

In another key study the dermal sensitization of this substance (Sulfonic acids, petroleum, calcium salts; EC 263-093-9; TBN = 375) was evaluated in guinea pigs (Kiplinger GR, 1992b). The animals were treated topically with a 30% concentration of the test substance once per week during the three week induction phase. Following a two week rest period, the animals were topically challenged with a 25% concentration of the test substance. After approximately one week the animals were rechallenged with a 25% concentration of the test substance. The number of animals exhibiting positive sensitization responses for the test substance at 25% challenge and 25% rechallenge were 0/12 and 0/11, respectively, and the mean 24/48 hour Draize scores were 0.4/0.3 and 0.4/0.3, respectively. The mean 24/48 hour Draize scores for the naïve controls at 25% challenge and 25% rechallenge were 0.5/0.4 and 0.2/0.2, respectively. Based on these results the test substance was determined not to be a sensitizer.

 

In another key study the dermal sensitization of this substance (Sulfonic acids, petroleum, calcium salts; EC 263-093-9; TBN = 300) was evaluated in guinea pigs (Blaszcak DL, 1992). The animals were treated topically with a 100% concentration of the test substance once per week during the three week induction phase. Following a two week rest period, the animals were topically challenged with a 25% concentration of the test substance. After approximately one week the animals were rechallenged with a 25% concentration of the test substance. The number of animals exhibiting positive sensitization responses for the test substance at 25% challenge and 25% rechallenge were 1/20 and 7/20, respectively, and the mean 24/48 hour Draize scores were 0.0/0.2 and 0.4/0.4, respectively. In the naïve controls 0/10 and 4/10 animals, respectively, exhibited positive irritation responses; the mean 24/48 hour Draize scores for the naïve controls at 25% challenge and 25% rechallenge were 0.0/0.0 and 0.5/0.4, respectively. Dermal responses to the corn oil vehicle alone were similar to the treated animals and naïve control. Based on these results the test substance was determined not to be a sensitizer.

 

In another key study the dermal sensitization of this substance (Sulfonic acids, petroleum, calcium salts; EC 263-093-9; TBN = 300) was evaluated in guinea pigs (Kiplinger GR, 1992c). The animals were treated topically with a 100% concentration of the test substance once per week during the three week induction phase. Following a two week rest period, the animals were topically challenged with a 25% concentration of the test substance. After approximately one week the animals were rechallenged with a 25% concentration of the test substance. The number of animals exhibiting positive sensitization responses for the test substance at 25% challenge and 25% rechallenge were 4/12 and 5/12, respectively, and the mean 24/48 hour Draize scores were 0.7/0.6 and 0.6/0.5, respectively. The mean 24/48 hour Draize scores for the naïve controls at 25% challenge and 25% rechallenge were 0.3/0.4 and 0.3/0.5, respectively. Based on these results the test substance was determined to be a sensitizer.

 

In another key study the dermal sensitization of an analog of this substance (Benzene, polypropene derivs., sulfonated, calcium salts; EC 616-278-7; TBN = 300) was evaluated in guinea pigs (Bonnette KL, 1993b). The animals were treated topically with a 100% concentration of the test substance once per week during the three week induction phase. Following a two week rest period, the animals were topically challenged with a 50% concentration of the test substance. After approximately one week the animals were rechallenged with a 25% concentration of the test substance. Following the first rechallenge, the animals then were rechallenged with a 10% concentration of the test substance. The number of animals exhibiting positive sensitization responses for the test substance at 50%, 25%, and 10% were 8/10, 10/10, and 7/10, respectively, and the mean 24/48 hour Draize scores were 1.1/2.1, 1.6/1.7, and 1.2/1.2, respectively. The mean 24/48 hour Draize scores for the naïve controls at 50%, 25%, and 10% were 0.5/0.5, 0.7/0.8, and 0.3/0.5, respectively. Based on these results the test substance was determined to be a sensitizer.

 

In another key study the dermal sensitization of an analog of this substance (Sulfonic acids, petroleum, calcium salts; EC 263-093-9; TBN = 300) was evaluated in a human repeat insult patch test (Shanahan RW & Erianne JA, 1994f; Table 5). A panel of 213 subjects was identified for this test. In the induction phase a 100% concentration of the test substance was administered directly to the skin and covered with an occlusive patch three times per week for a total of nine applications. Following a two week rest period, each of the 200 subjects that completed the induction phase was topically challenged with a 100% concentration of the test substance. A total of 0/200 (0%) of the subjects exhibited sensitization responses following the 100% challenge.  Based on these results the test substance was determined not to induce irritation or sensitization at 100%.

 

In another key study the dermal sensitization of an analog of this substance (Sulfonic acids, petroleum, calcium salts; EC 263-093-9; TBN = 300) was evaluated in a human repeat insult patch test (DiFiglia CJ, Shanahan RW & Erianne JA, 1993a; Table 5). A panel of 53 subjects was identified for this test. In the induction phase a 10% concentration of the test substance in mineral oil was administered directly to the skin and covered with an occlusive patch three times per week for a total of nine applications. Following a two week rest period, each of the 51 subjects that completed the induction phase was topically challenged with a 10% concentration of the test substance in mineral oil. A total of 0/51 (0%) of the subjects exhibited sensitization responses following the 10% challenge.  Based on these results the test substance was determined not to induce irritation or sensitization at 10%.

 

In another key study the dermal sensitization of an analog of this substance (Sulfonic acids, petroleum, calcium salts; EC 263-093-9; TBN = 300) was evaluated in a human repeat insult patch test (DiFiglia CJ, Shanahan RW & Erianne JA, 1993c; Table 5). A panel of 53 subjects was identified for this test. In the induction phase a 1% concentration of the test substance in mineral oil was administered directly to the skin and covered with an occlusive patch three times per week for a total of nine applications. Following a two week rest period, each of the 50 subjects that completed the induction phase was topically challenged with a 1% concentration of the test substance in mineral oil. A total of 0/50 (0%) of the subjects exhibited sensitization responses following the 1% challenge.  Based on these results the test substance was determined not to induce irritation or sensitization at 1%.

 

 

 

Table 5. Human Repeat Insult Patch Tests (HRIPT) with a High TBN Sulfonic acids, petroleum, calcium salts; EC 263-093-9; TBN = 300): Challenge Results

Test Phase

Concentration

# Positive Responses

Conclusion

Study

24 hours

72 hours

Induction

100%

 

 

Not a sensitizer

Shanahan RW & Erianne JA, 1994f

Challenge

100%

0/200

0/200

 

 

 

 

 

 

Induction

10%

 

 

Not a sensitizer

DiFiglia CJ, Shanahan RW & Erianne JA, 1993a

Challenge

10%

0/51

0/51

 

 

 

 

 

 

Induction

1%

 

 

Not a sensitizer

DiFiglia, Shanahan RW & Erianne JA, 1993c

Challenge

1%

0/50

0/50

 

 

In another key study the dermal sensitization of a high TBN analog of this substance (Benzene, polypropene derivs., sulfonated, calcium salts; EC 616-278-7; TBN = 300) was evaluated in a human repeat insult patch test (Shanahan RW & Erianne JA, 1993b; Table 6). Five panels consisting of a total of 241 subjects were identified for this test. In the induction phase a 100% concentration of the test substance was administered directly to the skin and covered with an occlusive patch three times per week for a total of nine applications. Following a two week rest period, each of the 222 subjects that completed the induction phase was topically challenged with a 100% concentration of the test substance in mineral oil. The test substance did not induce any clinically significant irritation contact dermatitis. Only 1/222 (0.0%) of the subjects exhibited a reaction which was of questionable substance-related clinical significance. Based on these results the test substance was determined to not cause sensitization.

 

In another key study the dermal sensitization of a high TBN analog of this substance (Benzene, polypropene derivs., sulfonated, calcium salts; EC 616-278-7; TBN = 300) was evaluated in a human repeat insult patch test (Wachs GN, 1993; Table 6). A panel of 57 subjects was identified for this test. In the induction phase a 10% concentration of the test substance in mineral oil was administered directly to the skin and covered with an occlusive patch three times per week for a total of ten applications. Following a two week rest period, each of the 51 subjects that completed the induction phase was topically challenged with a 10% concentration of the test substance in mineral oil. A total of 0/51 (0.0%) of the subjects exhibited sensitization responses. Based on these results the test substance was determined to not cause a sensitization response.

 

 

In another key study the dermal sensitization of a high TBN analog of this substance (Benzene, polypropene derivs., sulfonated, calcium salts; EC 616-278-7; TBN = 300) was evaluated in a human repeat insult patch test (DiFiglia CJ, Shanahan RW & Erianne JA, 1993b; Table 6). A panel of 53 subjects was identified for this test. In the induction phase a 1% concentration of the test substance in mineral oil was administered directly to the skin and covered with an occlusive patch three times per week for a total of nine applications. Following a two week rest period, each of the 49 subjects that completed the induction phase was topically challenged with a 1% concentration of the test substance in mineral oil. A total of 0/49 (0.0%) of the subjects exhibited sensitization responses. Based on these results the test substance was determined to not cause a sensitization response.

 

In another key study the dermal sensitization of a high TBN analog of this substance (Benzene, polypropene derivs., sulfonated, calcium salts; EC 616-278-7; TBN = 300) was evaluated in a human repeat insult patch test (Shanahan RW & Erianne JA, 1994e; Table 6). A panel of 53 subjects was identified for this test. In the induction phase a 1% concentration of the test substance in mineral oil was administered directly to the skin and covered with an occlusive patch three times per week for a total of nine applications. Following a two week rest period, each of the 49 subjects that completed the induction phase was topically challenged with a 1% concentration of the test substance in mineral oil. A total of 0/49 (0.0%) of the subjects exhibited sensitization responses. Based on these results the test substance was determined to not cause a sensitization response.

 

 

 

 

Table 6. Human Repeat Insult Patch Tests (HRIPT) with a High TBN Calcium Sulfonate (Benzene, Polypropene Derivs., Sulfonated, Calcium Salts; EC 616-278-7; TBN = 300): Challenge Results

Test Phase

Concentration

# Positive Responses

Conclusion

Study

24 hours

72 hours

Induction

100%

 

 

Not a sensitizer

Shanahan RW & Erianne JA, 1993b

Challenge

100%

1/222

1/222

 

 

 

 

 

 

Induction

10%

 

 

Not a sensitizer

Wachs GN, 1993

Challenge

10%

0/51

0/511

 

 

 

 

 

 

Induction

1%

 

 

Not a sensitizer

DiFiglia CJ, Shanahan RW & Erianne JA, 1993b

Challenge

1%

0/49

0/49

 

 

 

 

 

 

Induction

1%

 

 

Not a sensitizer

Shanahan RW & Erianne JA, 1994e

Challenge

1%

0/49

0/49

148 hours

 

In accordance with EU CLP Regulation (EC) No. 1272/2008, classification is not required for high TBN calcium sulfonates (TBN ≥ 300).

 

Conclusion

 

The weight-of-evidence 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. Studies in guinea pigs and human volunteers show that low TBN benzene, polypropene derivs., sulfonated, calcium salts (EC 616-278-7; TBN = 13) are skin sensitizers. Numerous well-conducted, reliable, controlled human (HRIPT) studies with benzene, polypropene derivs., sulfonated, calcium salts (EC 616-278-7; TBN values ranging from 13 to 85), and sulfonic acids, petroleum, calcium salts (EC 263-093-9; TBN = 30 to 100) show that low TBN calcium sulfonates do not cause sensitization in a substantial number of subjects at 10% and lower. High TBN calcium sulfonates, sulfonic acids, petroleum, calcium salts (EC 263-093-9; TBN = 375 and 400) do not cause skin sensitization in guinea pigs. Results of guinea pigs studies at TBN = 300 are mixed; two studies of sulfonic acids, petroleum, calcium salts, (EC 263-093-9) report no skin sensitization while one study of sulfonic acids, petroleum, calcium salts (EC 263-093-9) and one study of benzene, polypropene derivs., sulfonated, calcium salts (EC 616-278-7) report skin sensitization, However, numerous well-conducted, reliable, controlled human (HRIPT) studies with benzene, polypropene derivs., sulfonated, calcium salts ( EC 616-278-7; TBN = 300), sulfonic acids, petroleum, calcium salts (EC 263-093-9; TBN = 300), also show that high TBN (TBN ≥ 300) do not cause skin sensitization. In accordance with EU CLP Regulation (EC) No. 1272/2008, classification is required for low TBN calcium sulfonates (TBN < 300) with a specific concentration limit of 10% and classification is not required for high TBN calcium sulfonates (TBN ≥ 300).

 

 

References

 

Alworth KA, Schwartz H & Erianne JA (1995a). Clinical Safety Evaluation OS #18504G @ 10% in Mineral Oil Repeat Insult Patch Test, ETC Entry Nos. 3849.01, 4357.01, 4403.01, Panel Nos. 93081, 95009, 95016, 95032, 95037, 95052, Essex Testing Clinic, Inc., Verona, New Jersey USA.

 

Alworth KA, Schwartz H & Erianne JA (1995b). Clinical Safety Evaluation OS # 87926C (same as OS #87926A) @ 10% in Mineral Oil Repeat Insult Patch Test, ETC Entry Nos. 3848.01, 4357.03, 4403.03, Panel Nos. 93080, 95022, 95045, 95070, 95074, Essex Testing Clinic, Inc., Verona, New Jersey USA.

 

Alworth KA, Schwartz H & Erianne JA (1995c). Clinical Safety Evaluation OS # 65271E @ 10% in Mineral Oil Repeat Insult Patch Test, ETC Entry Nos. 3838.01, 4357.02, 4403.02, Panel Nos. 93072, 95018, 95025, 95062, Essex Testing Clinic, Inc., Verona, New Jersey USA.

 

Ball N, Cagen S, Carrillo J-C, Certa H, Eigler D, Emter D, Emter R, Faulhammer F, Garcia C, Graham C, Haux C, Kolle SN, Kreiling R, Natsch A & Mehling A (2011). Evaluating the Sensitization Potential of Surfactants: Integrating Data from the Local Lymph Node Assay, Guinea Pig Maximization Test, and in vitro Methods in a Weight-of-Evidence Approach. Regulatory Toxicology & Pharmacology 60:389-400.

 

Basketter DA & Kimber I (2011). Skin Irritation, False Positives and the Local Lymph Node Assay: A guideline issue? Regulatory Toxicology & Pharmacology 61(1):137-140.

 

Blaszcak DL (1992). Closed-patch Repeated Insult Dermal Sensitization Study of OS# 18163Q in Guinea Pigs (Buehler Method), Bio/dynamics Project No.: 6153-91, Bio/dynamics Inc., East Millstone,New Jersey USA.

 

Bonnette KL (1993a). Dermal Sensitization Study in Guinea Pigs with OS# 65271E -Modified Buehler Design- (EPA-TSCA, EPA-FIFRA, OECD), SLS Study No. 3263.9, Springborn Laboratories, Inc., Spencerville, Ohio USA.

 

Bonnette KL (1993b). Dermal Sensitization Study in Guinea Pigs with OS# 67708C -Modified Buehler Design- (EPA-TSCA, EPA-FIFRA, OECD), SLS Study No. 3263.10, Springborn Laboratories, Inc., Spencerville, Ohio USA.

 

DiFiglia CJ, Shanahan RW & Erianne JA (1993a). Clinical Safety Evaluation OS #16928AJ (@ 10% in Mineral Oil) Repeated Insult Patch Test, ETC Entry No. 3864.01, Panel No. 93089, Essex Testing Clinic, Inc., Verona, New Jersey USA.

 

DiFiglia CJ, Shanahan RW & Erianne JA (1993b). Clinical Safety Evaluation OS #67708E Repeat Insult Patch Test, ETC Entry No. 3775.01, Panel No. 93027, Essex Testing Clinic, Inc., Verona, New Jersey USA.

 

DiFiglia CJ, Shanahan RW & Erianne JA (1993c). Clinical Safety Evaluation OS #16928AJ (1% in Mineral Oil) Repeat Insult Patch Test, ETC Entry No. 3825.02, Panel No. 93067, Essex Testing Clinic, Inc., Verona, New Jersey USA.

 

DiFiglia CJ, Shanahan RW & Erianne JA (1993d). Clinical Safety Evaluation OS #65271E (1% in Mineral Oil) Repeat Insult Patch Test, ETC Entry No. 3811.01, Panel No. 93059, Essex Testing Clinic, Inc., Verona, New Jersey USA.

 

Eisenberg RR (1994a). Repeat Insult Patch Test 10% w/OS# 18504G In Squibb White Mineral Oil, Experiment Reference No. C94-0115, Consumer Product Testing Co., Fairfield, New Jersey USA.

 

Eisenberg RR (1994b). Repeat Insult Patch Test 10% w/OS# 87926A In Squibb White Mineral Oil, Experiment Reference No. C94-0116, Consumer Product Testing Co., Fairfield, New Jersey USA.

 

Eisenberg RR (1994c). Repeat Insult Patch Test 10% w/OS# 65271E In Squibb White Mineral Oil, Experiment Reference No. C94-0117, Consumer Product Testing Co., Fairfield, New Jersey USA.

Kiplinger GR (1992a). Skin Sensitization Study in Albino Guinea Pigs with OS 47860E, WIL Project Number: WIL-168017, WIL Reasearch Laboratories, Inc., Ashland, Ohio USA.

 

Kiplinger GR (1992b). Skin Sensitization Study in Albino Guinea Pigs with OS 47860E, WIL Project Number: WIL-168018, WIL Reasearch Laboratories, Inc., Ashland, Ohio USA.

 

Kiplinger GR (1992c). Skin Sensitization Study in Albino Guinea Pigs with OS 22969Q, WIL Project Number: WIL-168019, WIL Reasearch Laboratories, Inc., Ashland, Ohio USA.

 

Lees D (1996). OS65271G: Local Lymph Node Assay. Report No. CTL/E/132, Central Toxicology Laboratory, Alderley Park Macclesfield, Cheshire UK.

 

Reagan EL (1988). Dermal Sensitization Study of OS 68022 in Guinea Pigs, FDRL Study No. 9592C, Food & Drug Research Laboratories, Waverly, New York USA.

Shults SK (1993). Dermal Sensitization Study (Closed-Patch Repeated Insult) in Guinea Pigs with OS# 65271E. Document Number: 5577-92-0514-TX-001, Ricerca, Inc., 7528 Auburn Road, Painesville, Ohio USA.

 

Shanahan RW & Erianne JA (1993a). Clinical Safety Evaluation OS #65271E (100%) Repeat Insult Patch Test (Semi-Occulsive) Patch Test, ETC Entry No. 3900.02, Panel No. 93109, Essex Testing Clinic, Inc., Verona, New Jersey USA.

 

Shanahan RW & Erianne JA (1993b). Clinical Safety Evaluation OS #67708E (@ 100%) Repeat Insult Patch Test Patch Test, ETC Entry No. 3870.01, Panel No. 93092, 93123, 93133, 93140, 93147, Essex Testing Clinic, Inc., Verona, New Jersey USA.

 

Shanahan RW & Erianne JA (1994a). Clinical Safety Evaluation OS #65271E @ 20% in Mineral Oil Repeat Insult Patch Test Patch Test, ETC Entry No. 3999.01, Panel No. 93162, Essex Testing Clinic, Inc., Verona, New Jersey USA.

 

Shanahan RW & Erianne JA (1994b). Clinical Safety Evaluation OS #13463M (@ 10% in Mineral Oil) Repeat Insult Patch Test Patch Test, ETC Entry No. 4044.01, Panel No. 94009, Essex Testing Clinic, Inc., Verona, New Jersey USA.  

 

Shanahan RW & Erianne JA (1994c). Clinical Safety Evaluation OS #17759W “Repeat Insult Patch Tests of Varius Sulfonates and Gear Oil Additive Test Articles, ETC Entry No. 4103.02, Panel Nos. 94069, 94071, 94081, 94084, Essex Testing Clinic, Inc., Verona, New Jersey USA.

 

Shanahan RW & Erianne JA (1994d). Clinical Safety Evaluation OS #65841A Repeat Insult Patch Test, ETC Entry No. 4103.01, Panel Nos. 94068, Essex Testing Clinic, Inc., Verona, New Jersey USA.

 

Shanahan RW & Erianne JA (1994e). Clinical Safety Evaluation OS #67708E @ 1% in Mineral Oil Repeat Insult Patch Test, ETC Entry No. 3834.01, Panel No. 93071, Essex Testing Clinic, Inc., Verona, New Jersey USA.

 

Shanahan RW & Erianne JA (1994f). Clinical Safety Evaluation OS #16928AJ Repeat Insult Patch Test, ETC Entry No. 3911.01, Panels Nos. 93117, 93150, 93152, 93157, Essex Testing Clinic, Inc., Verona, New Jersey USA.

 

Wachs GN (1993). Repeat Insult Patch Test OS# 67708E, Experiment Reference No. C-227-93, Consumer Product Testing Co., Fairfield, New Jersey USA.

  


Migrated from Short description of key information:
The sensitisation potential of the substance has been assessed to humans and guinea pigs On the basis of these data the substance is considered sensitising, but the data available on human vounteers suggests that there is a clear threshold at 10%w/w, above which the substance is sensitising whilst at and below which the substance is not sensitising to humans.

Respiratory sensitisation

Endpoint conclusion
Additional information:

As determined by ECHA guidance in Appendix R. 8 -11, and considering that no data from use of the substance are available, it is not possible to assess respiratory sensitisation or estimate a threshold or DNEL. It is known, nonetheless, that some, but not all, skin sensitisers can also cause respiratory sensitisation.


Migrated from Short description of key information:
Respiratory sensitisation has not been assessed. There are currently no validated in vitro or in vivo data and no data available from human exposure (e.g. workers) to demonstrate or deny respiratory senitisation.

Justification for classification or non-classification

Based on the available animal that all show positive results and the human data that demonstrate positive results at and above 10%w/w concentration it is considered that the substance is classified as a skin sensitiser.