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Toxicological information

Endpoint summary

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Administrative data

Description of key information

Calcium dipropionate does not show signs of dermal sensitisation, and the two constituents calcium and propionic acid also have not shown any skin sensitisation potential in experimental testing.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline with acceptable restrictions (no positive contrtol group, lesser animals (test group), lesser application volume during induction)
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
yes
Remarks:
(no positive control group, lesser animals (test group), lesser application volume during induction)
Principles of method if other than guideline:
Method: other: according to the method described by Magnusson and Kligmann "Allergie contact dermatitis in the guinea pig" Ed. Ch.C. Thomas, Springfield, Illinois, USA (1970)
GLP compliance:
no
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
Not applicable.
Species:
guinea pig
Strain:
other: albino SPF guinea pigs
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Central Institute for the Breeding of Laboratory Animals TNO, Zeist, The Netherlands
- Age at study initiation: young
- Sex: male
- Weight at study initiation: 200-300g
- Housing: in suspended stainless steel cages, fitted with wire mesh floors and fronts
- Diet: ad libitum; stock diet enriched with vitamin C
- Water: ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 10
- Humidity (%): 45 ± 5
- Photoperiod (hrs dark / hrs light): 12/12
Route:
intradermal and epicutaneous
Vehicle:
other: Induction: water and vaseline for intradermal and topical induction, respectively. Challenge: vaseline
Concentration / amount:
Induction: 2% (intradermal), 20% (topical)
challenge: 20% (topical)
Route:
epicutaneous, open
Vehicle:
other: Induction: water and vaseline for intradermal and topical induction, respectively. Challenge: vaseline
Concentration / amount:
Induction: 2% (intradermal), 20% (topical)
challenge: 20% (topical)
No. of animals per dose:
Control: 10
treated animals: 6
Details on study design:
MAIN STUDY
A. INDUCTION EXPOSURE
Intradermal Injection:
- Site: shoulder
- Concentration: 2% (0.05 ml/site) (lowest irritating concentration)
- Vehicle: distilled water
- Test group 1: Freund's complete adjuvant (FCA)
- Test group 2: The test article in distilled water
- Test group 3: Freund's complete adjuvant and test article in distilled water (1:1)
- Control group 1: Freund's complete adjuvant (FCA) 1:1 with physiological saline(0.9%).
- Control group 2: Distilled water
- Control group 3: Freund's complete adjuvant and distilled water (1:1)
- Frequency of applications: 1x, 2 injections/dose
- Evaluation (hr after injection): no data

Topical Induction Exposure:
- Time Schedule: about 1 week after intradermal injections
- Concentration: 20% in vaseline
- Route of exposure: epicuteneous, patches of whatman filter paper (2 x 4 cm) saturated with the test substance
- Type of coverage: occlusive
- Duration: 48h.
- Evaluation (hr after injection): no data

B. CHALLENGE EXPOSURE
1st Challenge: Test groups and control group treated identically in the following manner
- Day(s) of challenge: 2 weeks after topical induction exposure
- Route of exposure: epicutaneous, applied to an area of about 2 x 2cm; A small amount of the mixture was applied to the shaved area of each animal and gently massaged in with a glass rod for about 30 seconds
- Exposure period: 24 h
- Concentration: 20%,
- Vehicle: vaseline
- Evaluation (hr after challenge): 24h, scoring of findings using Draize score system for scoring skin irritation

Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
20% in vaseline
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
No clinical signs occured
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 20% in vaseline. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: No clinical signs occurred.
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
20% in vaseline
No. with + reactions:
0
Total no. in group:
6
Clinical observations:
No clinical signs occured
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 20% in vaseline. No with. + reactions: 0.0. Total no. in groups: 6.0. Clinical observations: No clinical signs occurred.
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
Not specified
No. with + reactions:
0
Total no. in group:
0
Clinical observations:
not specified
Remarks on result:
other: not specified

- All animals remained in good health during the experiment and gained weight.

 

INDUCTION

- Intradermal

The intra-dermal injections of each of the three test substances given in the induction phase of the study resulted in the following reactions:

 

1. Freund's Complete Adjuvant: erythema: 2, edema: 2

 

2. 2 % Luprosil in water: greyish discolouration (diameter 6 mm)

 

3. 2% Luprosil in Adjuvant and water (1 :1) : erythema, edema.

 

- Topical

The topical application of the test substances in a 20% mixture with vaseline during the induction period did not result in erythema or edema or produced only very slight erythema

 

CHALLENGE

The challenge dose of the test substances provoked neither erythema nor edema in the test animals and in the controls.

 

From these results it is concluded that under the conditions of' this experiment the Luprosil salt (78/28) did not induce sensitization

Interpretation of results:
not sensitising
Remarks:
Migrated information
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline with acceptable restrictions (no positive control group, lesser animals(test group), lesser application volume during induction)
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
yes
Remarks:
(no positive control group, lesser animals (test group), lesser application volume during induction)
Principles of method if other than guideline:
Method: other: according to the method described by Magnusson and Kligmann "Allergie contact dermatitis in the guinea pig" Ed. Ch.C. Thomas, Springfield, Illinois, USA (1970)
GLP compliance:
no
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
Not applicable.
Species:
guinea pig
Strain:
other: albino SPF guinea pigs
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Central Institute for the Breeding of Laboratory Animals TNO, Zeist, The Netherlands
- Age at study initiation: young
- Sex: male
- Weight at study initiation: 200-300g
- Housing: in suspended stainless steel cages, fitted with wire mesh floors and fronts
- Diet: ad libitum; stock diet enriched with vitamin C
- Water: ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 10
- Humidity (%): 45 ± 5
- Photoperiod (hrs dark / hrs light): 12/12
Route:
intradermal and epicutaneous
Vehicle:
other: Induction: water and vaseline for intradermal and topical induction, respectively. Challenge: vaseline
Concentration / amount:
Induction: 2% (intradermal), 20% (topical)
challenge: 20% (topical)
Route:
epicutaneous, open
Vehicle:
other: Induction: water and vaseline for intradermal and topical induction, respectively. Challenge: vaseline
Concentration / amount:
Induction: 2% (intradermal), 20% (topical)
challenge: 20% (topical)
No. of animals per dose:
Control: 10
treated animals: 6
Details on study design:
MAIN STUDY
A. INDUCTION EXPOSURE
Intradermal Injection:
- Site: shoulder
- Concentration: 2% (0.05 ml/site) (lowest irritating concentration)
- Vehicle: distilled water
- Test group 1: Freund's complete adjuvant (FCA)
- Test group 2: The test article in distilled water
- Test group 3: Freund's complete adjuvant and test article in distilled water (1:1)
- Control group 1: Freund's complete adjuvant (FCA) 1:1 with physiological saline (0.9%).
- Control group 2: Distilled water
- Control group 3: Freund's complete adjuvant and distilled water (1:1)
- Frequency of applications: 1x, 2 injections/ dose
- Evaluation (hr after injection): no data

Topical Induction Exposure:
- Time Schedule: about 1 week after intradermal injections
- Concentration: 20% in vaseline
- Route of exposure: epicuteneous, patches of whatman filter paper (2 x 4 cm) saturated with the test substance
- Type of coverage: occlusive
- Duration: 48h.
- Evaluation (hr after injection): no data

B. CHALLENGE EXPOSURE
1st Challenge: Test groups and control group treated identically in the following manner
- Day(s) of challenge: 2 weeks after topical induction exposure
- Route of exposure: epicutaneous, applied to an area of about 2 x 2cm; A small amount of the mixture was applied to the shaved area of each animal and gently massaged in with a glass rod for about 30 seconds
- Exposure period: 24 h
- Concentration: 20%,
- Vehicle: vaseline
- Evaluation (hr after challenge): 24h, scoring of findings using Draize score system for scoring skin irritation

Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
20% in vaseline
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
No clinical signs occurred
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: 20% in vaseline. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: No clinical signs occurred.
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
20% in vaseline
No. with + reactions:
0
Total no. in group:
6
Clinical observations:
No clinical signs occurred
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 20% in vaseline. No with. + reactions: 0.0. Total no. in groups: 6.0. Clinical observations: No clinical signs occurred.
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
Not specified.
No. with + reactions:
0
Total no. in group:
0
Clinical observations:
not specified
Remarks on result:
other: not specified

- All animals remained in good health during the experiment and gained weight.

 

INDUCTION

- Intradermal

The intra-dermal injections of each of the three test substances given in the induction phase of the study resulted in the following reactions:

 

1. Freund's Complete Adjuvant: erythema: 2, edema: 2

 

2. 2 % Luprosil in water: greyish discolouration (diameter 6 mm)

 

3. 2% Luprosil in Adjuvant and water (1 :1) : erythema, edema.

 

- Topical

The topical application of the test substances in a 20% mixture with vaseline during the induction period did not result in erythema or oedema or produced only very slight erythema

 

CHALLENGE

The challenge dose of the test substances provoked neither erythema nor oedema in the test animals and in the controls.

 

From these results it is concluded that under the conditions of' this experiment the Luprosil salt (78/28) did not induce sensitization

Interpretation of results:
not sensitising
Remarks:
Migrated information
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Read-across approach


Selected endpoints for the human health hazard assessment are addressed by read-across, using a combination of data on the metal cation and the organic acid anion. This way forward is acceptable, since metal carboxylates are shown to dissociate to the organic anion and the metal cation upon dissolution in aqueous media. No indications of complexation or masking of the metal ion through the organic acid were apparent during the water solubility and dissociation tests (please refer to the water solubility and dissociation in sections 4.8 and 4.21 of IUCLID). Once the individual transformation products of the metal carboxylate become bioavailable (i.e. in the acidic environment in the gastric passage or after phagocytosis by pulmonary macrophages), the “overall” toxicity of the dissociated metal carboxylate can be described by a combination of the toxicity of these transformation products, i.e. the metal cation and carboxylate anion according to an additivity approach.


 


Calcium dipropionate is the calcium salt of propionic acid, which readily dissociates to the corresponding divalent calcium cation and monovalent propionate anions. The calcium cation and the propionate anion are considered to represent the overall toxicity of calcium dipropionate in a manner proportionate to the free acid and the metal (represented by one of its readily soluble salts). 


 


A detailed justification for the read-across approach is added as a separate document in section 13 of IUCLID.


 


Sensitisation


Information on skin sensitisation with calcium dipropionate is available. In addition, the skin sensitisation potential will be addressed with existing data on the dissociation products as detailed in the table below. Further details on the skin sensitisation potential of the individual constituents within the framework of regulation (EC) 1907/2006 are given below.


 


Table: Summary of skin sensitisation data of calcium dipropionate and the individual constituents.


















 



calcium substances



propionic acid


(CAS# 79-09-4)



Calcium dipropionate


(CAS# 4075-81-4)



Skin sensitisation



not sensitising



not sensitising


not sensitising

 


Calcium dipropionate did not show signs of dermal sensitisation, and the two constituents calcium and propionic acid also have not shown any skin sensitisation potential in experimental testing. Thus, Calcium dipropionate is not to be classified according to regulation (EC) 1272/2008 as skin sensitising. Further testing is not required. For further information on the toxicity of the individual constituents, please refer to the relevant sections in the IUCLID and CSR.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

According to the CLP regulation the hazard identification and subsequently a proposal for classification as “Respiratory sensitiser” will normally be based on human experience. In this context, hypersensitivity is normally seen as asthma, but other hypersensitivity reactions such as rhinitis/conjunctivitis and alveolitis are also considered. The condition will have the clinical character of an allergic reaction. However, immunological mechanisms do not have to be demonstrated.


The evidence could be:



  1. clinical history and data from appropriate lung function tests related to exposure to the substance, confirmed by other supportive evidence which may include:

    • in vivo immunological test (e.g. skin prick test);

    • in vitro immunological test (e.g. serological analysis);

    • studies that indicate other specific hypersensitivity reactions where immunological mechanisms of action have not been proven, e.g. repeated low-level irritation, pharmacologically mediated effects;

    • a chemical structure related to substances known to cause respiratory hypersensitivity



  2. data from one or more positive bronchial challenge tests with the substance conducted according to accepted guidelines for the determination of a specific hypersensitivity reaction.


Calcium dipropionate is not expected to show a respiratory sensitising potential.

Justification for classification or non-classification

Calcium dipropionate does not show signs of dermal sensitisation, and the two constituents calcium and propionic acid also have not shown any skin sensitisation potential in experimental testing. Thus, Calcium dipropionate is not to be classified according to regulation (EC) 1272/2008 as skin sensitising.


In long-time industrial experience in the production and handling of substance calcium dipropionate, no cases of respiratory hypersensitivity have been observed. Classification as respiratory sensitiser is not applicable.