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Diss Factsheets

Administrative data

Description of key information

Read-across with Li2CO3:

Lithium carbonate was found non-sensitizing when topically applied to guinea pigs in a study according to OECD 406 and EU method B.6.

Read-across with citric acid:

Citric acid has been shown to be safe when ingested or applied to skin in cosmetics.

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:
key study
Study period:
1993-10-18 to 1993-11-11
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
1981
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Version / remarks:
1987
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPP 81-6 (Skin Sensitisation)
Version / remarks:
1984
Deviations:
no
Principles of method if other than guideline:
NA
GLP compliance:
yes
Type of study:
Buehler test
Justification for non-LLNA method:
A valid skin sensitisation study according to OECD guideline 406 with lithium carbonate is available and additionally an LLNA study with the read-across substance Sodium dihydrogenorthophosphate.
Species:
guinea pig
Strain:
Hartley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: HRP, Inc., Denver, PA
- Age at study initiation: Young adult
- Weight at study initiation: 301 g - 379 g
- Housing: individually housed in suspended polycarbonate cages
- Diet (e.g. ad libitum): ad libitum, Purina Guinea Pig Chow 5025
- Water (e.g. ad libitum): ad libitum, fresh tap water


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18.9°C - 23.3 °C
- Humidity (%): 37 % - 89 %
- Photoperiod (hrs dark / hrs light): 12 hours fluorescent light/ 12 hours dark
Route:
epicutaneous, occlusive
Vehicle:
other: ethanol, acetone
Concentration / amount:
0.3 g undiluted test material
Day(s)/duration:
Once weekly until a total of three applications/ 6 h
Route:
epicutaneous, occlusive
Vehicle:
other: ethanol, acetone
Concentration / amount:
0.3 g undiluted test material
No. of animals per dose:
Test group: 20 (10 male, 10 female)
Positive control group: 10 (5 male, 5 female)
Challenge group: 10 (5 male, 5 female)
Details on study design:
The test material (0.3 g) was applied undiluted to each of 20 Hill Top Chambers®. In addition, 0.3 g test material plus 0.3 mL of 0.15 % DNCB in 80 % ethanol was applied to the test sites (left shoulder), and secured with hypoallergenic tape. Each animal was then wrapped with an elastic, plastic-lined bandage.
Six hours later, the bandage and chambers were removed and the test sites were wiped with clean gauze moistened with methanol. The test sites were then rinsed with tap water. The guinea pigs were dosed in this manner once weekly until a total of three applications had been administered. Following a 14 day rest period, the guinea pigs were challenged on a virgin site on the right shoulder in the manner described above.
Challenge controls:
An additional 10 naive animals each received 0.3 g of the test material for comparison.
Positive control substance(s):
yes
Remarks:
1-chloro-2,4-dinitrobenzene (DNCB)
Positive control results:
Animals in the positive control group had slight erythema and edema following the initial induction application and all but one had well defined to moderate erythema and slight to mild edema following challenge.
No irritation was noted on any of the test or challenge control animals at any time during the study.
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
0.3 g test substance
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
None
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
other: challenge group
Dose level:
0.3 g test substance
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
None
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
0.3 g test substance
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
None
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
other: challenge group
Dose level:
0.3 g test substance
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
None
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
0.3 g test substance and 0.3 mL of 0.15 % DNCB in 80 % ethanol
No. with + reactions:
10
Total no. in group:
10
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
0.3 g test substance and 0.3 mL of 0.15 % DNCB in 80 % ethanol
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
None
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
other: positive control challenge
Dose level:
0.3 g test substance and 0.3 mL of 0.15 % DNCB in 80 % ethanol
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
None
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
other: positive control challenge
Dose level:
0.3 g test substance and 0.3 mL of 0.15 % DNCB in 80 % ethanol
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
None

The challenge results for erythema are summarized below:

Erythema Scoresa

Group

 

0

1

2

3

4

Incidenceb

Severityc

Test Material

(24hr)

0

0

0

0

0

0/20

0

 

(48hr)

0

0

0

0

0

0/20

0

Challenge Control

(24hr)

0

0

0

0

0

0/10

0

 

(48hr)

0

0

0

0

0

0/10

0

Positive Control

(24hr)

0

1

1

8

0

9/10

2.7

 

(48hr)

0

1

5

4

0

9/10

2.3

a: Number animals exhibiting each score.

b: Number animals having scores greater than 1/ Total number animals challenged

c: Sum of (Number animals exhibiting each score x score)/ Total number animals challenged

Interpretation of results:
not sensitising
Conclusions:
Under the conditions of this study, the test material is non-sensitising when topically applied to Hartley guinea pigs. Based on this result, it can be assumed that lithium carbonate is not a sensitiser.
Executive summary:

A skin sensitisation test in Hartley guinea pigs was performed according to OECD 406 and EU method B.6. Lithium carbonate Pharmaceutical Grade (0.30 g) was applied undiluted topically to the left shoulders (previously clipped free of hair) of 10 male and 10 female Hartley guinea pigs. The test material was left in contact with the skin for approximately six hours. The animals received three induction treatments one week apart. A concurrent positive control group of 10 animals was treated in a similar manner with DNCB (0.15 % weight/volume). 14 days after the third induction treatment, the animals were challenged with the test material at a virgin skin site. An additional 5 male and 5 female naive animals received 0.30 g of the undiluted test material (challenge control group). The positive control group was challenged with DNCB. Observations for skin reactions were recorded at initiation and termination. All animals remained healthy and gained weight during the study. No skin reactions were noted on any of the test or challenge control animals at any time during the study. Animals in the positive control group had slight erythema and edema following the initial induction application and all but one had well defined to moderate erythema and slight to mild edema following challenge. Under the conditions of this study, the test material is non-sensitising when topically applied to Hartley guinea pigs.

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
Please refer to attached "Read-across justification" in section 13.
Reason / purpose for cross-reference:
read-across source
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
0.3 g test substance
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
None
Remarks on result:
other: Based on Li2CO3 (FMC, Albemarle 1994)
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
other: challenge group
Dose level:
0.3 g test substance
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
None
Remarks on result:
other: Based on Li2CO3 (FMC, Albemarle 1994)
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
0.3 g test substance
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
None
Remarks on result:
other: Based on Li2CO3 (FMC, Albemarle 1994)
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
other: challenge group
Dose level:
0.3 g test substance
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
None
Remarks on result:
other: Based on Li2CO3 (FMC, Albemarle 1994)
Endpoint:
skin sensitisation: in vitro
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
other:
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

A skin sensitisation study with lithium citrate tetrahydrate is not available. Thus, read-across with lihtium carbonate was performed to cover this endpoint.

Read-across with Lithium carbonate (FMC, Albemarle, I93-1801 1993)

A skin sensitisation test in Hartley guinea pigs was performed according to OECD 406 and EU method B.6 (Buehler test). Lithium carbonate Pharmaceutical Grade (0.30 g) was applied undiluted topically to the left shoulders (previously clipped free of hair) of 10 male and 10 female Hartley guinea pigs. The test material was left in contact with the skin for approximately six hours. The animals received three induction treatments one week apart. A concurrent positive control group of 10 animals was treated in a similar manner with DNCB (0.15 % weight/volume). 14 days after the third induction treatment, the animals were challenged with the test material at a virgin skin site. An additional 5 male and 5 female naive animals received 0.30 g of the undiluted test material (challenge control group). The positive control group was challenged with DNCB. Observations for skin reactions were recorded at initiation and termination. All animals remained healthy and gained weight during the study. No skin reactions were noted on any of the test or challenge control animals at any time during the study. Animals in the positive control group had slight erythema and edema following the initial induction application and all but one had well defined to moderate erythema and slight to mild edema following challenge. Under the conditions of this study, the test material is non-sensitizing when topically applied to Hartley guinea pigs.

Thus, based on the results obtained with lithium carbonate, the target substance is not considered to be classified and labelled with respect to skin sensitisation according to Regulation (EC) No 1272/2008 (CLP).

Skin sensitisation potential of citric acid

It is expected that the chemical species of interest by assessing the skin sensitisation potential of the target substance, lithium citrate tetrahydrate, is the lithium moiety and therefore read-across with citric acid was not considered necessary based on the reasons described below.

Citric acid is a naturally occurring constituent of plants and animal tissue and appears as an intermediate in the krebs cycle in every eukaryote cell. Approximately 2 kg of citric acid are formed and metabolized every day in humans (OECD SIDS, 2001).

Furthermore, citric acid has a wide dispersive use, as it is reported to be added to processed food and beverages, used in pharmaceutical industries and in household cleaners as well as in special technical applications. Citric acid is listed as generally recognized safe (GRAS) direct food additive by the Food and Drug Administration (FDA) and citrate-containing ingredients are allowed as active ingredients, at a maximum daily dosage of 8 g, inantacid over-the-counter (OTC) products (21CFR331.11).

Additionally, citric acid is used in the cosmetic industry as chelating agent, pH adjuster, or fragrance ingredient. According to the Tentative Safety Assessment of the Cosmetic Ingredient Review Expert Panel (2011) citric acid is used in almost every category of cosmetic products. 6795 uses are reported in the Tentative Safety Assessment Report at concentrations up to 4% in leave-on formulations, 10% in rinse-off formulations, and 39% in products diluted for (bath) use.

Thus, based on these uses, consumers are directly exposed to citric acid. Citric acid has been shown to be safe for ingestion and the substance is widely used in cosmetic products, which includes a skin application, the sensitisation potential of the substance is seen as low. The OECD SIDS Initial Assessment Report for citric acid also concluded that ‘genuine sensitisation to citric acid seems to be a rare phenomenon’.

References:

OECD SIDS (2001): Citric acid CAS 77-92-9, SIDS Initial Assessment Report for 11th SIAM (Orlando, Fla., January 2001)

Cosmetic Ingredient Review Expert Panel (2011):Tentative Safety Assessment.Citric Acid, Inorganic Citrate Salts and Alkyl Citrate Esters As Used in Cosmetics

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available (further information necessary)

Justification for classification or non-classification

Classification, Labelling, and Packaging Regulation (EC) No 1272/2008:
The available experimental test data are reliable and suitable for classification purposes under Regulation (EC) No 1272/2008. Based on available data on skin sensitisation, the test item is not classified according to Regulation (EC) No 1272/2008 (CLP), as amended for the tenth time in Regulation (EU) No 2017/776.