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Diss Factsheets

Toxicological information

Skin sensitisation

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Administrative data

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1992
Reference Type:
study report
Title:
Unnamed
Year:
1983
Report date:
1983
Reference Type:
study report
Title:
Unnamed
Year:
1978
Report date:
1978
Reference Type:
grey literature
Title:
No information
Author:
OECD QSAR Application Toolbox v1.1
Year:
2010
Bibliographic source:
ftp: //qsarsext: fetch@ftp. oecd. org/TB_1.1_Install. zip
Reference Type:
grey literature
Title:
No information
Author:
Danish QSAR database
Year:
2010
Bibliographic source:
Available at http: //ecbqsar. jrc. it/

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The study was conducted in 1992. At this time an OECD guideline for a LLNA was not available.

Test material

Constituent 1
Chemical structure
Reference substance name:
Diethyl phosphonate
EC Number:
212-091-6
EC Name:
Diethyl phosphonate
Cas Number:
762-04-9
Molecular formula:
C4H11O3P
IUPAC Name:
diethyl phosphonate
Details on test material:
Read across substance (analogue): diethyl phosphonate
Name of test material (as cited in study report): diethyl phosphonate
- Physical state: liquid
- Analytical purity: 98.86%
- Product number: 002 402 00
- Storage condition of test material: at room temperature at the dark.
- Molecular formula (if other than submission substance): C4H11O3P
- Molecular weight (if other than submission substance): 138.1
- Smiles notation (if other than submission substance): O=P(OCC)OCC
- InChl (if other than submission substance): InChI=1/C4H10O3P/c1-3-6-8(5)7-4-2/h3-4H2,1-2H3/q+1
-Melting point: -27.58 °C
-Boiling point: 175.32 °C
- Vapour pressure: 1.21 mmHG
-LogP oct/water: -0.15
-LogKoc: 0.95

Target substance: dimethyl phosphite
-Physical state: liquid
- Molecular weight: 110.05
- Melting point: -51.64 °C
- Boiling point: 131.51 °C
- Vapour pressure: 9.35 mmHG
- LogP oct/water: -1.13
- LogKoc: 0.419

In vivo test system

Test animals

Species:
guinea pig
Strain:
not specified
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Winkelmann, Borchen/Kreis Paderborn, Germany
- Age at study initiation: 5 to 7 weeks old.
- Weight at study initiation: about 351 g.
- Housing: 5 animals per cage were housed in Makrolon-cages Type IV.
- Diet (e.g. ad libitum): Altromin 3020-Haltungsdiät für Meerschweinchen (Altromin GmbH, Lage, Germany) ad libitum.
- Water (e.g. ad libitum): ad libitum.
- Acclimation period: 7days.


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22±2
- Humidity (%): about 50
- Air changes (per hr): about 10 times per hour
- Photoperiod (hrs dark / hrs light): 12 / 12 (6 am-6 pm)

Study design: in vivo (non-LLNA)

Inductionopen allclose all
Route:
intradermal and epicutaneous
Vehicle:
propylene glycol
Concentration / amount:
Intradermal induction: 5%; Topical induction: 100%; 1st Challenge: 50% and 25%; 2nd Challenge: 12% and 3%
Challengeopen allclose all
Route:
epicutaneous, occlusive
Vehicle:
propylene glycol
Concentration / amount:
Intradermal induction: 5%; Topical induction: 100%; 1st Challenge: 50% and 25%; 2nd Challenge: 12% and 3%
No. of animals per dose:
20 animals in test group; 10 animals in control groups.
Details on study design:
RANGE FINDING TESTS:
RANGE FINDING TEST FOR INTRADERMAL INJECTIONS
One guinea pig was injected twice with 0.1 mL of test substance at the following concentrations: 0%, 1%, 2.5%, 5%.
The injection site was assessed after 24 and 48 hours.
After 24 and 48 hours: at concentrations 0%-5% a white area with red border was observed.

RANGE FINDING TEST FOR TOPIC INDUCTION
Groups of 4 guinea pigs were tested with 4 concentrations of test substance. Each animal received respectively 4 plasters soaked with test substance formulation (12%, 25%, 50%, 100%) under occlusive condition for 24 hours. At the end of the exposure period the rests of the substance were removed with sterile physiologic saline solution and the skin on the treatment area was shaved. The skin reactions were assessed 48 and 72 hours after the start of the application. At the above mentioned concentrations no skin reaction was observed.

RANGE FINDING TEST FOR CHALLENGE
One week before the challenge a range finding test for challenge was run on 5 guinea pigs.
Each animal received respectively 4 plasters soaked with test substance formulation (12%, 25%, 50%, 100%) under occlusive condition for 24 hours. At the end of the exposure period the rests of the substance were removed with sterile physiologic saline solution and the skin on the treatment area was shaved.
The skin reactions were assessed 48 and 72 hours after the start of the application. At the above mentioned concentrations no skin reaction was observed.

On the basis of the results of the range finding tests the following concentrations were chosen: intradermal induction: 5%; Topical induction: 100%; 1st Challenge: 50% and 25%; 2nd Challenge: 12% and 3%

MAIN STUDY
Intradermal Injections

One day before the application back and flanks of the guinea pigs were shaved. Starting behind the neck left and right of the spine were performed a series of three injections, so that one of each pair lies on each side of the midline. The distances between the injections sites were 1-2 cm, the application volume was 0.1 mL per injection site.
The animals of the three groups were treated as follows:
Injection 1: a 1:1 mixture (v/v) FCA/physiological saline solution.
Injection 2: the test substance was formulated in propylene glycole.
Injection 3: the test substance at the selected concentration was formulated in a 1:1 mixture (v/v) FCA/ propylene glicole.

The animals in the control groups were treated like animals in the test group, but, the formulations for the site of injections 2 and 3 contained no test substance, but an appropriate amount of propylene glycol.

Topical Application
One week after the intradermal induction was carried out the topical induction.
The day before the treatment, parts of the animals were shaved and smeared with a 10% sodium lauryl sulfate in the preparation of paraffin oil. Respectively between the injection sites a hypoallergenic adhesive plaster (2 x 4 cm) was placed, covered with aluminium foil and secured with a fermoflex-adhesive on the skin.

The patches were treated as follows:
a) Test substance group: 0.5 mL diethyl phosphonate.
b) Control group: 0.5 mL propylene glicole.

At the end of the 48-hour exposure time the rest of the substance was removed with physiological saline solution.

B. CHALLENGE EXPOSURE
The provocations were made three or four weeks after intradermal induction.
One day before the provocations, the animals were shaved on the back and flank. 1st Provocation: Hypoallergenic adhesive plasters containing respectively 50% and 25% of the test substance were applied on the left flank of animals in the test group and 1st control group and fixed for 24 hours with a fermoflex-adhesive on the skin. On the right flank were fixed two plasters impregnated with only propylene glycol as control.
2nd Provocation: the animals belonging to the test group and to the 2nd control group were treated with 12% or with 3% test substance with method analogous to the 1st challenge. The application volume was 0.5 mL each.
At the end of the exposure time substance remains were removed with sterile saline and the skin in the treatment fields shaved.

Positive control substance(s):
not specified

Results and discussion

In vivo (non-LLNA)

Resultsopen allclose all
Reading:
1st reading
Hours after challenge:
48
Group:
test chemical
Dose level:
50%
No. with + reactions:
12
Total no. in group:
20
Clinical observations:
skin reddening
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: test group. Dose level: 50%. No with. + reactions: 12.0. Total no. in groups: 20.0. Clinical observations: skin reddening.
Reading:
1st reading
Hours after challenge:
72
Group:
test chemical
Dose level:
50%
No. with + reactions:
12
Total no. in group:
20
Clinical observations:
skin reddening
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 72.0. Group: test group. Dose level: 50%. No with. + reactions: 12.0. Total no. in groups: 20.0. Clinical observations: skin reddening.
Reading:
1st reading
Hours after challenge:
48
Group:
test chemical
Dose level:
25%
No. with + reactions:
6
Total no. in group:
20
Clinical observations:
skin reddening
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: test group. Dose level: 25%. No with. + reactions: 6.0. Total no. in groups: 20.0. Clinical observations: skin reddening.
Reading:
2nd reading
Hours after challenge:
72
Group:
test chemical
Dose level:
25
No. with + reactions:
7
Total no. in group:
20
Clinical observations:
skin reddening
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: test group. Dose level: 25. No with. + reactions: 7.0. Total no. in groups: 20.0. Clinical observations: skin reddening.
Reading:
1st reading
Hours after challenge:
48
Group:
test chemical
Dose level:
12%
No. with + reactions:
7
Total no. in group:
20
Clinical observations:
skin reddening
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: test group. Dose level: 12%. No with. + reactions: 7.0. Total no. in groups: 20.0. Clinical observations: skin reddening.
Reading:
2nd reading
Hours after challenge:
72
Group:
test chemical
Dose level:
12%
No. with + reactions:
6
Total no. in group:
20
Clinical observations:
skin reddening
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: test group. Dose level: 12%. No with. + reactions: 6.0. Total no. in groups: 20.0. Clinical observations: skin reddening.
Reading:
1st reading
Hours after challenge:
48
Group:
test chemical
Dose level:
3%
No. with + reactions:
4
Total no. in group:
20
Clinical observations:
skin reddening
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: test group. Dose level: 3%. No with. + reactions: 4.0. Total no. in groups: 20.0. Clinical observations: skin reddening.
Reading:
2nd reading
Hours after challenge:
72
Group:
test chemical
Dose level:
3%
No. with + reactions:
4
Total no. in group:
20
Clinical observations:
skin reddening
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: test group. Dose level: 3%. No with. + reactions: 4.0. Total no. in groups: 20.0. Clinical observations: skin reddening.
Reading:
1st reading
Hours after challenge:
48
Group:
negative control
Dose level:
50%
No. with + reactions:
2
Total no. in group:
10
Clinical observations:
skin reddening
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 50%. No with. + reactions: 2.0. Total no. in groups: 10.0. Clinical observations: skin reddening.
Reading:
1st reading
Hours after challenge:
72
Group:
negative control
Dose level:
50%
No. with + reactions:
1
Total no. in group:
10
Clinical observations:
skin reddening
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 72.0. Group: negative control. Dose level: 50%. No with. + reactions: 1.0. Total no. in groups: 10.0. Clinical observations: skin reddening.
Reading:
1st reading
Hours after challenge:
48
Group:
negative control
Dose level:
25%
No. with + reactions:
1
Total no. in group:
10
Clinical observations:
skin reddening
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 25%. No with. + reactions: 1.0. Total no. in groups: 10.0. Clinical observations: skin reddening.
Reading:
1st reading
Hours after challenge:
72
Group:
negative control
Dose level:
25%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no effect observed
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 72.0. Group: negative control. Dose level: 25%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: no effect observed.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
12%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no effect observed
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 12%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: no effect observed.
Reading:
2nd reading
Hours after challenge:
72
Group:
negative control
Dose level:
12%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no effect observed
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: negative control. Dose level: 12%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: no effect observed.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
3%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no effect observed
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: 3%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: no effect observed.
Reading:
2nd reading
Hours after challenge:
72
Group:
negative control
Dose level:
3%
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no effect observed
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 72.0. Group: negative control. Dose level: 3%. No with. + reactions: 0.0. Total no. in groups: 10.0. Clinical observations: no effect observed.
Group:
positive control
Remarks on result:
other: The validity of the Maximization Test according to Magnussen and Kligman is regularly tested:
Remarks:
Alpha-cinnamic aldehyde: Bayer Report no. 21251 (Dreist 1992); 2-mercaptobenzothiazole: Bayer Report no. 21367 (Dreist 1992), 4-aminobenzoeicacid ethylester: Bayer Report no. 21368 (Dreist 1992).

Any other information on results incl. tables

Table. 1 Individual findings of challenges. Concentration: 50%. SKIN REDDENING

 

          First control group
 

    Test substance patch

    Control patch
 Animal No.  48 h*  72*  48h*  72*
 1  0  0  0  0
 2  0  0  0  0
 3  0  0  0  0
 4  0  0  0  0
 5  0  0  0  0
 6  1  1  0  0
 7  1  0  0  0
 8  0  0  0  0
 9  0  0  0  0
 10  0  0  0  0
 

          Test substance group
 21  0  0  0  0
 22  1  1+  0  0
 23  0  0+  0  0
 24  1  1+ 0   0
 25  0  0+  0  0
 26  1  1+  0  0
 27  0  0  0  0
 28  1  1+  0  0
 29  0  0+  0  0
 30  1  1+  0  0
 31  1  1  0  0
 32  1  1+  0  0
 33  0  0  0 0 
 34  1  1  0  0
 35  0  0  0  0
 36  1  1  0  0
 37  0  0  0  0
 38  1  0  0  0
 39  1  0  0  0
 40  1  0  0  0

* Findings made 48 and 72 h after start of the expsoure.

+ Treatment area squamous in places.

Table. 2 Individual findings of challenges. Concentration: 50%. FORMATION OF EDEMAS.

 

          First control group
 

    Test substance patch

    Control patch
 Animal No.  48 h*  72*  48h*  72*
 1  0  0  0  0
 2  0  0  0  0
 3  0  0  0  0
 4  0  0  0  0
 5  0  0  0  0
 6 0  0  0  0
 7 0  0  0  0
 8  0  0  0  0
 9  0  0  0  0
 10  0  0  0  0
 

         Test substance group
 21  0  0  0  0
 22  0  0  0  0
 23  0  0  0  0
 24  0  0 0   0
 25  0  0  0  0
 26  0  0  0  0
 27  0  0  0  0
 28 0  0  0  0
 29  0   0  0  0
 30  0  0  0  0
 31 0  0  0  0
 32  0  0  0  0
 33  0  0  0 0 
 34  0  0  0  0
 35  0  0  0  0
 36  0  0  0  0
 37  0  0  0  0
 38  0  0  0  0
 39  0  0  0  0
 40  0  0  0  0

Table.3 Individual findings of challenges. Concentration: 25%. SKIN REDDENING

 

          First control group
 

    Test substance patch

    Control patch
 Animal No.  48 h*  72*  48h*  72*
 1  0  0  0  0
 2  0  0  0  0
 3  0  0  0  0
 4  0  0  0  0
 5  0  0  0  0
 6 0  0  0  0
 7 0  0  0  0
 8  0  0  0  0
 9  1  0  0  0
 10  0  0  0  0
 

         Test substance group
 21  2  1  0  0
 22  1   0+  0  0
 23  0   0+  0  0
 24  1  0 0   0
 25  0  0+  0  0
 26  1   0+  0  0
 27  0  0  0  0
 28 1   1+  0  0
 29  0   0  0  0
 30  0   0+  0  0
 31 1  0  0  0
 32  0  0  0  0
 33  0  0  0 0 
 34  0  0  0  0
 35  0  0  0  0
 36  0  0  0  0
 37  0  0  0  0
 38  0  0  0  0
 39  0  0  0  0
 40  0  0  0  0

* Findings made 48 and 72 h after start of the exposure.

+ Treatment area squamous in places.

Table. 4 Individual findings of challenges. Concentration: 25%. FORMATION OF EDEMAS

 

          First control group
 

    Test substance patch

    Control patch
 Animal No.  48 h*  72*  48h*  72*
 1  0  0  0  0
 2  0  0  0  0
 3  0  0  0  0
 4  0  0  0  0
 5  0  0  0  0
 6 0  0  0  0
 7 0  0  0  0
 8  0  0  0  0
 9  0  0  0  0
 10  0  0  0  0
 

         Test substance group
 21  0  0  0  0
 22  0   0  0  0
 23  0   0  0  0
 24  0  0 0   0
 25  0   0  0  0
 26  0   0  0  0
 27  0  0  0  0
 28 0   0  0  0
 29  0   0  0  0
 30  0   0  0  0
 31 0  0  0  0
 32  0  0  0  0
 33  0  0  0 0 
 34  0  0  0  0
 35  0  0  0  0
 36  0  0  0  0
 37  0  0  0  0
 38  0  0  0  0
 39  0  0  0  0
 40  0  0  0  0

* Findings made 48 and 72 h after start of the exposure.

+ Treatment area squamous in places.

Table. 5 Individual findings of challenges. Concentration: 12% + 3%. SKIN EDEMA.

 

          Second control group
 

    12%

    3%
 Animal No.  48 h*  72*  48h*  72*
 1  0  0  0  0
 2  0  0  0  0
 3  0  0  0  0
 4  0  0  0  0
 5  0  0  0  0
 6 0  0  0  0
 7 0  0  0  0
 8  0  0  0  0
 9  0  0  0  0
 10  0  0  0  0
 

         Test substance group
 21 0  0  0  0
 22 0  0 0  0
 23  0  0  0   0
 24  0  0 0   0
 25   0   0   0   0
 26  0   0  0  0
 27  0  0  0  0
 28 0   0  0  0
 29  0   0  0  0
 30  0   0  0  0
 31 0   0  0   0
 32  0  0  0  0
 33  0  0  0 0 
 34  0  0  0  0
 35  0  0  0  0
 36   0  0   0  0
 37  0  0  0  0
 38  0  0  0  0
 39  0  0  0  0
 40  0  0  0  0

* Findings made 48 and 72 h after start of the exposure

+ Treatment area squamous in places.

Table. 6 Individual findings of challenges. Concentration: 12% + 3%. FORMATION OF SKIN REDDENING

 

          Second control group
 

    12%

    3%
 Animal No.  48 h*  72*  48h*  72*
 1  0  0  0  0
 2  0  0  0  0
 3  0  0  0  0
 4  0  0  0  0
 5  0  0  0  0
 6 0  0  0  0
 7 0  0  0  0
 8  0  0  0  0
 9  0  0  0  0
 10  0  0  0  0
 

         Test substance group
 21 1  0  0  0
 22 1   0+ 1  0
 23   1+   0+   1+   0+
 24  0  0 0   0
 25   1+   0+   1+   0+
 26  0  0  0  0
 27  0  0  0  0
 28 0   1  0  0
 29  0   0  0  0
 30  0   0  0  0
 31 1   0+  0   0+
 32  0  0  0  0
 33  0  0  0 0 
 34  0  0  0  0
 35  0  0  0  0
 36   0+   0+   1+   0+
 37  0  0  0  0
 38  0  0  0  0
 39  1  0  0  0
 40  0  0  0  0

* Findings made 48 and 72 h after start of the exposure.

+ Treatment area squamous in places.

Based on the study results, diethyl phosphonate is skin sensitizer (Xi, R43) according to EU classification criteria. This corresponds to Category 1 for skin sensitization according to the CLP classification criteria.

In order to discuss whether or not the positive findings for diethyl phosphonate can be read across to the analogue substance, dimethyl phosphonate, a couple of parameters that pertain to the induction of skin sensitisation have been compared for both compounds: the relative potential to penetrate the stratum corneum, the relative protein-binding potential, the formation of potentially protein-reactive metabolites that can act as haptens, the relative irritation potential. The following conclusions were reached for the most relevant aspects of skin sensitisation:

1.Skin penetration: experimental data are not available, but QSAR calculations rely on the molecular weight, the water solubility and the log KOW of the compound to estimate dermal absorption. The Danish QSAR Database1predicts a moderate and high dermal absorption for diethyl phosphonate and dimethyl phosphonate respectively (0.0260 and 0.05600 mg/cm²/event for the diethyl phosphonate and dimethyl phosphonate, respectively). Hence, dermal absorption is not the limiting or discriminating factor for a potential reaction with proteins in the epidermis.

2.Protein binding:the protein-binding potential of unmetabolised diethyl phosphonate and dimethyl phosphonate is not significant. The OECD QSAR Toolbox2was used to screen the parent compounds for potential protein-reactive groups. None were found in both compounds.

3.Dermal metabolism: the OECD Toolbox contains a tool for the prediction of skin metabolites. No reactive metabolite was predicted for diethyl phosphonate and dimethyl phosphonate.

4.Skin irritation: Some experimental studies for diethyl phosphonate3and dimethyl phosphonate4 conclude that neither compound has a significant skin irritation potential (see IUCLID endpoint 7.3.1). Thus, a differential skin-sensitizing potential based on the compounds' ability to attract inflammatory cells and thereby enhancing the immune reaction cannot be identified.

Whereas for diethyl phosphonate its skin sensitizing potential was experimentally proven, there is no such data for dimethyl phosphonate. No significant difference in protein binding, dermal metabolism or skin irritation potential is predicted by the QSAR models. However, the skin penetration of dimethyl phosphonate is predicted to be more than twice as high as for the skin sensitizer, diethyl phosphonate. With otherwise similar (bio-)chemical behaviour, dimethyl phosphonate is predicted to have an equal or higher skin sensitisation potential compared to diethyl phosphonate considering its predictably higher concentration in the dermis.

On the basis of the QSAR calculations and read across approach presented here it is assumed that dimethyl phosphonate has a skin-sensitizing potential. Thus, the data for this endpoint can be read across from the analogous substance diethyl phosphonate, and dimethyl phosphonate can be classified as a skin sensitizer (Xi, R43 and Category 1 for skin sensitization) according to EU classification criteria as a worst-case classification without the need for further testing.

1. Available at http://ecbqsar.jrc.it/

2. OECD QSAR Application Toolbox v1.1, available at ftp://qsarsext:fetch@ftp.oecd.org/TB_1.1_Install.zip

3. Suberg H. Diethylphosphit. Prüfung auf primär reizende/ätzende Wirkung an Kaninchenhaut. T5015559. Bayer AG.

4 .Thyssen J. Untersuchung zur Haut and Schleimhautverträglichkeit. T1036084. Bayer AG.

Applicant's summary and conclusion

Interpretation of results:
Category 1 (skin sensitising) based on GHS criteria
Executive summary:

Experimental data on the skin sensitizing potential of dimethyl phosphonate are not available. However, a skin sensitisation study in guinea pigs was conducted with the analogue substance diethyl phosphonate. The two compounds have similar chemical structure and are similar with respect to their skin-sensitizing properties (skin penetration, protein binding, dermal metabolism, skin irritatation).

In order to determine the potential of diethyl phosphonate as sensitizer a Magnusson and Kligman maximization was conducted on male guinea pigs according to OECD guideline 406 and GLP conditions. The test was conducted with the following test substances concentrations: intradermal induction: 5%; topical induction: 100%; 1st challenge: 50% and 25%; 2nd challenge: 12% and 3%. The test substance was formulated as a solution in propylene glycol. After the 1st challenge, 60% (at 50% dose level) and 35% (at 25% dose level) of the test group animals and 20% (at 50% dose level) and 10% (at 25% dose level) of the control animals showed positive results. After the 2nd challenge 30% (at 12% dose level) and 20% (at 3% dose level) of test group animals showed positive results.

The control animals showed no skin reactions at two concentrations. Thus, the test substance (dethyl phosphonate) showed a clear potential for skin sensitisation in the Maximisation test. Based on the study results, diethyl phosphonate is a skin sensitizer Category 1 for skin sensitization according to CLP classification criteria.

In order to discuss whether or not the positive findings for diethyl phosphonate can be read across to the analogue substance, dimethyl phosphonate, a couple of parameters that pertain to the induction of skin sensitisation have been compared for both compounds: the relative potential to penetrate the stratum corneum, the relative protein-binding potential, the formation of potentially protein-reactive metabolites that can act as haptens, the relative irritation potential. The Danish QSAR Database predicts a moderate and high dermal absorption for diethyl phosphonate and dimethyl phosphonate, respectively. The OECD QSAR Toolbox was used to screen the parent compounds for potential protein-reactive groups. None were found in both compounds. The OECD QSAR Application Toolbox predicted no reactive metabolite for diethyl phosphonate and dimethyl phosphonate. Some experimental studies for diethyl phosphonate³ and dimethyl phosphonate4 conclude that neither compound has a significant skin irritation potential. Thus, a differential skin-sensitizing potential based on the compounds' ability to attract inflammatory cells and thereby enhancing the immune reaction cannot be identified.

Whereas for diethyl phosphonate its skin sensitizing potential was experimentally proven, there is no such data for dimethyl phosphonate. No significant difference in protein binding, dermal metabolism or skin irritation potential is predicted by the QSAR models. However, the skin penetration of dimethyl phosphonate is predicted to be more than twice as high as for the skin sensitizer, diethyl phosphonate. With otherwise similar (bio-)chemical behaviour, dimethyl phosphonate is predicted to have an equal or higher skin sensitisation potential compared to diethyl phosphonate considering its predictably higher concentration in the dermis.

On the basis of the read across approach presented here it is assumed that dimethyl phosphonate has also a skin-sensitizing potential.

The data for this endpoint can be read across from the analogous substance diethyl phosphonate, and dimethyl phosphonate can be classified as a skin sensitizer Category 1 for skin sensitization according to the CLP classification criteria as a worst-case classification without the need of further testing.