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Administrative data

Description of key information

Desmedipham has been tested for skin sensitisation in five Maximisation studies and in one Buehler study, all performed to GLP and to appropriate guidelines (K2).  No studies of respiratory sensitisation are available, and none are required.









































Test method/  speciesResultAssessmentReference
US EPA 81-6 - Guinea pig: Maximisation test.Desmedipham was found to be a skin sensitiser under the conditions of this study (35% positive reactions) on the basis of the first challenge; however, results were not confirmed in a re-challenge (20-25% positive reactions).  Classification not required based on the weight of evidence.Weight of Evidence - Test concentrations for intradermal induction were relatively low.Ullmann (1987)
OECD 406 - Guinea pig: Buehler test.Desmedipham was not a skin sensitiser.Weight of Evidence - Test concentrations for induction were relatively low. Daamen (1988)
OECD 406 - Guinea pig: Maximisation test.Desmedipham was not a skin sensitiser.Weight of Evidence - Evidence of animal ill health. Ullmann and Kups (1988)
OECD 406 - Guinea pig: Maximisation test.Desmedipham was not a skin sensitiser.Weight of Evidence - Test concentrations for intradermal induction were relatively low.  Ullmann and Kups (1988)
OECD 406 - Guinea pig: Maximisation test.Desmedipham was not a skin sensitiser.Weight of Evidence - Test concentrations for intradermal induction were relatively low.  Cuthbert and Jackson (1991)

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
Study period:
1987-07-27 to 1988-10-11
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Version / remarks:
Magnusson and Kligman test (1970)
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
Magnusson and Kligman test (1970)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
Some exceptions. During the acclimation period emaciation was observed in four female guinea pigs, but these females remained in the main study. The test of the positive control group treated with DNCB was not run under GLP-conditions in 1987.
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The study was performed prior to adoption of the OECD test guideline for the LLNA (OECD 429, 2010).
Specific details on test material used for the study:
The test material is in a white powder form.
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male/female
Details on test animals and environmental conditions:
Test system: Dunkin-Hartley albino guinea pigs
Rationale: Recognised by the international guidelines as the recommended test system
Total number of animals: 15 males animals 15 females
Age at Pretest: 7 - 8 weeks
Body weight at pre-test: Males: 406 - 412 g Females: 391 - 479 g
Identification: By unique cage number and corresponding ear tags.
Randomization: Randomly selected at time of delivery.
Acclimation: One week under test conditions after veterinary examination.
A control group is tested twice a year as a sensitivity check of the guinea pig strain. The most recent test was run during July 1987.

Standard Laboratory Conditions.
Air-conditioned with 10-15 air changes per hour and hourly monitored environment with temperature 22 + -3 degrees centigrade, relative humidity 40-70%, 12 hours artificial fluorescent light/12 hours dark, music/light period.

Accommodation
Individually in Makrolon type-3 cages with standard softwood bedding.

Diet
Pelleted standard Kliba 342, Batch 37/87 guinea pig breeding/ maintenance diet ad libitum.

Water
Community tap mater from Itingen, ad libitum. Results of analysis for contaminants are included in this report.
Route:
intradermal
Vehicle:
other: Mixture of polyethyleneglycol (PEG 400) and physiological saline (7:3)
Concentration / amount:
0.5%
Day(s)/duration:
Single intradermal injection
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Route:
epicutaneous, occlusive
Vehicle:
other: Mixture of polyethyleneglycol (PEG 400) and physiological saline (7:3)
Concentration / amount:
25%
Day(s)/duration:
Single topical induction
Adequacy of induction:
other: No signs of irritation
No.:
#1
Route:
epicutaneous, occlusive
Concentration / amount:
25%
Day(s)/duration:
Single topical exposure
Adequacy of challenge:
highest non-irritant concentration
No.:
#2
Route:
epicutaneous, occlusive
Vehicle:
other: Mixture of polyethyleneglycol (PEG 400) and physiological saline (7:3)
Concentration / amount:
25%
Day(s)/duration:
Single topical application
Adequacy of challenge:
highest non-irritant concentration
No. of animals per dose:
5 males, 5 females for the vehicle control group and 10 males, 10 females for the test article group.
Details on study design:
Preliminary study
Desmedipham caused slight erythema (grade 1) and slight edema (grade 1) at all tested concentrations (0.5, 1, 3, and 5%) administered by intradermal injection. After the epicutaneous application no skin reactions were observed on the shaved flanks of four guinea pigs at the tested concentrations of 3, 5, 10, 25% desmedipham in the vehicle. Desmedipham was diluted in polyethylene glycol (PEG 400) and physiological saline (7:3). The concentrations of the test article selected were 0.5% for intradermal injections and 25% for topical applications in the main study.

Main study
The skin sensitisation potential of technical desmedipham was assessed in 20 (10 males/10 females) Dunkin Hartley albino guinea pigs, weighing from 391 to 492 g. Additionally 10 animals (5 males/5 females) were used as a vehicle control group. The mixture of polyethyleneglycol (PEG 400) and physiological saline (7:3) was used as a dosing vehicle. DNCB (2,4-dinitro-1-clorobenzene) was used as a positive control article.
During the induction, three double intradermal injections of 0.1 ml volume were administered in the shoulder region of the test animals. The intradermal injections were a) Freund’s complete adjuvant plus the vehicle in the ratio 50:50, b) 0.5% solution of desmedipham in the vehicle, c) 0.5% desmedipham emulsified in 50:50 mixture of Freund’s complete adjuvant and the vehicle. One week later, the same area was dermally treated with desmedipham 25% in the vehicle and covered with occlusive dressings for 48 hours. The control animals were treated as above with the omission of the test article.
The challenge phase was conducted 2 weeks later. Topical applications were made with a) a 25% concentration of desmedipham in the vehicle placed on the left flank and b) with the vehicle alone placed on the right flank. The occlusive dressings were removed approximately 24 hours later. The control animals were treated in the same way as above. The second challenge was performed two weeks later using a similar method to the first challenge with the exception that the solutions (25% desmedipham, vehicle) were applied to the opposite flank. The control animals were treated with vehicle alone. The challenge site was evaluated immediately and then 24 and 48 hours after removal the patch. The Exact Fisher test for comparison of the basic probability was used in the statistical analysis.
Positive control substance(s):
yes
Remarks:
DNCB (2,4-dinitro-1-clorobenzene) was used as a positive control. The positive control test with DNCB was conducted in July 1987, when 100% of the test group animals (15) reacted positively.
Positive control results:
DNCB (2,4-dinitro-1-clorobenzene) was used as a positive control. The positive control test with DNCB was conducted in July 1987, when 100% of the test group animals (15) reacted positively.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
25%
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
25%
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Reading:
rechallenge
Hours after challenge:
24
Group:
negative control
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
rechallenge
Hours after challenge:
24
Group:
test chemical
Dose level:
25%
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
25%
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Reading:
other: Overall results (24 +48 hours)
Group:
positive control
No. with + reactions:
15
Total no. in group:
15
Remarks on result:
positive indication of skin sensitisation
Remarks:
DNCB (2,4-dinitro-1-clorobenzene) was used as a positive control. The positive control test with DNCB was conducted in July 1987, when 100% of the test group animals (15) reacted positively

No deaths occured during the test. During acclimation, emaciation was observed in 3/5 control female guinea pigs and 1/10 test female guinea pigs. With the exception of these females, the body weight gain of all other animals was not affected during the test procedure. Erythema, edema, necroses and exfoliation around the injection sites were noted in the control and test animals during the induction phase. After the first and second challenge applications, there were no skin responses in the vehicle control and test animals (0/10 and 0/20, respectively). Desmedipham technical was considered to possess no skin sensitizing potential in albino guinea pigs.


 


Positive erythema reactions after first challenge procedure.













































 After 24 hAfter 48 h
 positivenegativepositivenegative
Desmedipham technical020020
% positive reaction.0-0-
Vehicle control010010
% positive reaction.0-0-

 


Positive erythema reactions after second challenge procedure.













































 After 24 hAfter 48 h
 positivenegativepositivenegative
Desmedipham technical020020
% positive reaction.0-0-
Vehicle control010010
% positive reaction.0-0-
Interpretation of results:
GHS criteria not met
Conclusions:
Desmedipham technical (99.2%) was not found to be a dermal sensitizer in the guinea pig maximisation test. In general testing should be performed using healthy animals and in this study emaciation was observed in four females already during acclimation and then during the test period.
Executive summary:

With the procedures used in this experiment, no differences between the test group and the vehicle-treated controls were evident after the first and second epidermal challenge application of DESMEDIPHAM TECHNICAL.


DESMEDIPHAM TECHNICAL is considered to possess no skin sensitizing (contact allergenic) potential in albino guinea pigs.


No toxic symptoms were evident in the guinea pigs of either the control nor test group.


No death occurred.


The study does not meet the GHS criteria.

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1990-12-21 to 1991-03-18
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Remarks:
The concentration of the test substance for each induction exposure should be the highest to cause mild to moderate skin irritation. In this test, the selected concentration of 1% did not cause skin irritation differing from vehicle control. Also, the concentration used for the challenge exposure should be the highest non-irritant dose.
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
yes
Remarks:
The sensitivity of the study may have been reduced by the relatively low concentrations of desmedipham used for induction and challenge.
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Version / remarks:
Directive 92/69/EEC
Deviations:
yes
Remarks:
The sensitivity of the study may have been reduced by the relatively low concentrations of desmedipham used for induction and challenge.
GLP compliance:
yes (incl. QA statement)
Remarks:
The storage stability of the test material was not presented in the final study report. The execution of this study was not individually inspected by QA.
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The study was performed before adoption of the OECD test guideline (OECD 429) in 2010.
Specific details on test material used for the study:
The test material, a white powder, was stored in the dark under ambient conditions.
Species:
guinea pig
Strain:
Dunkin-Hartley
Remarks:
albino
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Females nulliparous and non-pregnant: yes.
- Age at study initiation: young adult (less than one year old).
- Weight at study initiation: 370-484 g.
- Housing: Twenty test group and 20 control group guinea pigs were housed 5 to a cage. Eight dose ranging guinea pigs were housed 4 to a cage in 2 further cages. Each aluminium cage had a grid floor beneath which was a peat moss filled tray.
- Diet: FD1 Guinea Pig Diet supplemented with hay, ad libitum.
- Water: ad libitum.
- Acclimation period: 7 days.

ENVIRONMENTAL CONDITIONS
- Temperature: 19-21°C
- Mean Humidity: 50%
- Photoperiod: 12 h light/dark cycle. Light hours 0700-1900 h.
Route:
intradermal
Vehicle:
paraffin oil
Concentration / amount:
The intradermal injections were (0.1 ml volume):
a) Freund’s complete adjuvant (anterior injection).
b) a 1% w/v solution of desmedipham in paraffin oil.
c) a 50:50 emulsion of test material in Freund's complete adjuvant (posterior injection).
Day(s)/duration:
single intradermal induction
Adequacy of induction:
other: The selected concentration of 1% did not cause skin irritation differing from vehicle control.
Route:
epicutaneous, occlusive
Vehicle:
paraffin oil
Concentration / amount:
25%
Day(s)/duration:
48 hours
Adequacy of induction:
not specified
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
paraffin oil
Concentration / amount:
25% w/v of desmedipham in paraffin oil
Day(s)/duration:
1 day (24 hours)
Adequacy of challenge:
highest non-irritant concentration
No. of animals per dose:
20 (10 males/10 females). Additionally, 20 animals (10 males/10 females) were used as a vehicle control group and 4 animals as a challenge dose ranging group.
Details on study design:
RANGE FINDING TESTS:
Preliminary study:
No skin irritation was noted at the treated sites after the injections with desmedipham in paraffin oil at the concentrations of 1, 2 and 5% or after treated topically with the concentration of 2, 5, 10 and 25%. A concentration of 1% w/v in paraffin oil was selected for the injection phase of induction in view of difficulties experienced with injected concentrations of 5 and 2% w/v in paraffin oil and 25% for topical applications in the main study.

MAIN STUDY
The skin sensitisation potential of technical desmedipham (Purity 98.0%) was tested on 20 (10 males/10 females) Dunkin Hartley albino guinea pigs, weighing from 370 to 484 g. Additionally, 20 animals (10 males/10 females) were used as a vehicle control group and 4 animals as a challenge dose ranging group. Paraffin oil was used as a dosing vehicle. The positive control test with DNCB was conducted in July 1990, when 63% of the test group animals reacted positively.

A. INDUCTION EXPOSURE
- No. of exposures: three double intradermal injections.
- Exposure period: 3 days
- Test groups: 20 (10 males/10 females).
- Control group: 20 (10 males/10 females).
- Site: scapular region.
- Frequency of applications: three double intradermal injections, then 1 topical application.
- Duration: 3 days, The challenge was conducted 2 weeks after the start of topical induction.
- Concentrations: 0.1 ml volume of:
a) Freund’s complete adjuvant (anteriol injection).
b) a 1% w/v solution of desmedipham in paraffin oil.
c) a 50:50 emulsion of test material in Freund's complete adjuvant (posterior injection).

After 24 hours, topical application was made with 25% w/v of desmedipham in paraffin oil to the pretreated area and covered with an occlusive dressing for 48 hour.

One hour and 24 hours after the patch removal the treated sites were assessed for irritation.

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: 1 day
- Exposure period: 1 day
- Test groups: 19 (One of the test group animals was sacrificed prior to challenge due to an open wound on back. This was not considered to have affected the integrity of the study.)
- Control group: 20 (10 males/10 females).
- Site: the left flank.
- Concentrations: 25% desmedipham in paraffin.
- Evaluation (hr after challenge): 24 and 48 hours after removal the patch.
Challenge controls:
20 (10 males/10 females).
Positive control substance(s):
yes
Remarks:
The positive control test with DNCB was conducted in July 1990, when 63% of the test group animals reacted positively.
Positive control results:
The positive control test with DNCB was conducted in July 1990, when 63% of the test group animals reacted positively.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
25%
No. with + reactions:
0
Total no. in group:
19
Clinical observations:
No effects were observed
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
25%
No. with + reactions:
0
Total no. in group:
19
Clinical observations:
No effects were observed
Remarks on result:
no indication of skin sensitisation
Reading:
other: Overall (24 +48 hours)
Group:
positive control
No. with + reactions:
12
Total no. in group:
19
Remarks on result:
positive indication of skin sensitisation
Remarks:
The positive control test with DNCB was conducted in July 1990, when 63% of the test group animals reacted positively.

One of the test group animals was sacrificed prior to challenge due to an open wound on its back. This was not considered to have affected the integrity of the study. The body weight gain of all animals was not affected during the test procedure. In induction irritation was noted in the test and control groups.  The incidence of positive animals after the challenge application were 0/20 and 0/19, respectively in the vehicle control and test group. Desmedipham technical was not found to be a dermal sensitizer in guinea pigs. See the results' tables in the file attached in "Overall remarks, attachments".

Interpretation of results:
GHS criteria not met
Conclusions:
Desmedipham was not found to be a dermal sensitizer in this maximisation test.
Executive summary:

The sensitisation potential of Desmedipham, was investigated by means of the Magnusson-Kligman Maximisation Test in guinea pigs.  Induction with Desmedipham was at concentrations of 1% (injection) and 25% (topical) w/v in paraffin oil. Challenge was at a concentration of 25% w/v  in paraffin oil.  At challenge, none of the test or control group animals treated with Desmedipham at a concentration of 25% w/v in paraffin oil showed a positive response.  There is no evidence from the test results that Desmedipham is a sensitiser in guinea pigs.

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1988-05-10 to 1988-10-11
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
study well documented, meets generally accepted scientific principles, acceptable for assessment
Remarks:
The Buehler test, as a non-adjuvant test is considered to be less sensitive than adjuvant-type tests such as the maximisation test. According to the Guideline 406, the concentrations of test substance used for each exposure in the Buehler test should be the highest to cause mild irritation and for challenge exposure the highest non-irritating dose. Generally, four graded levels (25%, 50%, 75% and 100%) of test material are utilized in the topical range-finding irritation screening procedure. Optimally the topical range-finding study should produce no systemic toxicity and a spectrum of dermal responses that includes grades 0, ±, 1, 2 unless the test substance is not dermally irritating at 100%.
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
May 1981
Deviations:
yes
Remarks:
The sensitivity of the study may have been reduced by the relatively low concentrations of desmedipham used for induction and challenge.
GLP compliance:
yes (incl. QA statement)
Type of study:
Buehler test
Justification for non-LLNA method:
The study was performed before adoption of the OECD test guideline (OECD 429) in 2010.
Specific details on test material used for the study:
Fine white powder with little lumps
Species:
guinea pig
Strain:
Dunkin-Hartley
Remarks:
albino
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Females nulliparous and non-pregnant: yes
- Age at study initiation: 2 months
- Weight at study initiation: 309 to 407 g
- Housing: The animals were housed in metal cages with wire-mesh floors.
- Diet: standard guinea pig diet, including ascorbic acid (1600 mg/kg).
- Water: free access to tap-water.

ENVIRONMENTAL CONDITIONS
- Temperature: 19-25°C
- Humidity (%): between 60 and 80
- Photoperiod: 12 hours light, 12 hours dark
Route:
epicutaneous, occlusive
Vehicle:
other: 1% aqueous methyl cellulose
Concentration / amount:
0.5 ml 50% of desmedipham
Day(s)/duration:
3 times weekly for 3 weeks / 6 hours
Adequacy of induction:
other: The selected concentration did not cause skin irritation differing from vehicle control
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
other: 1% aqueous methyl cellulose
Concentration / amount:
0.5 ml desmedipham at 50% and 0% (w/w)
Day(s)/duration:
Exposure: 6 hours.
Examined for sensitisation 24 and 48 hours after patch removal.
Adequacy of challenge:
highest non-irritant concentration
No. of animals per dose:
The test was performed on a group of 20 female Dunkin Hartley albino guinea pigs. Additionally, 10 females were used as a vehicle control group and 4 animals as a dose ranging group.
Details on study design:
RANGE FINDING TESTS:
Primary irritation:
In the primary irritation test no skin irritation or signs of toxicity were observed in any of the five treated animals. Four female guinea pigs were exposed epicutaneously (0.05 ml/site) to several concentrations (5%, 10%, 25%, 50%) of the test article in aqueous methyl cellulose for 24 hours. Additonally one animal was treated (0.5 ml/site) with 50% test article in the vehicle for 24 hours to assess the toxicity of the test substance. The concentration of 50% technical desmedipham was selected for topical applications in the main study.

MAIN STUDY
The test was performed on a group of 20 female Dunkin Hartley albino guinea pigs. Additionally, 10 females were used as a vehicle control group and 4 animals as a dose ranging group. Technical desmedipham was diluted in 1% aqueous methyl cellulose. The positive control test was carried out in May 1987 at which time 50% of the test group animals reacted positively to the concentration of 1% formaldehyde after challenge phase.

A. INDUCTION EXPOSURE
- No. of exposures: 9
- Exposure period: 6 days
- Test groups: 1 group of 20 females
- Control group: 10 vehicle control females
- Site: scapular region (left side)
- Frequency of applications: 3 times weekly for 3 weeks
- Duration: 3 times weekly for 3 weeks/ 6 hours
- Concentrations: 0.5 ml 50% of technical desmedipham in 1% aqueous methyl cellulose.

B. CHALLENGE EXPOSURE
- Day(s) of challenge: Ten days after the last induction treatment
- Exposure period: 6 hours
- Test groups: 20 females.
- Control group: 10 females
- Site: right flank skin
- Concentrations: 0.5 ml desmedipham at 50% and 0% (w/w) concentrations in 1% aqueous methyl cellulose.
- Evaluation (hr after challenge): 24 and 48 hours.
Challenge controls:
10 females: control animals were challenged to 0% (w/w) concentrations of the test substance in aqueous methyl cellulose 1%.
Positive control substance(s):
yes
Remarks:
A positive control experiment was carried out in order to validate the animals and the test procedure. Test substance : formaldehyde solution 37% Induction and challenge phases: 1% and 5% (w/w) in Milli-RO water.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
0.5 ml desmedipham at 50% (w/w)
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
No effects observed
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
0.5 ml desmedipham at 50% (w/w)
No. with + reactions:
1
Total no. in group:
20
Clinical observations:
No effects observed
Remarks on result:
no indication of skin sensitisation
Reading:
other: Overall (24 + 48 hours)
Group:
positive control
No. with + reactions:
10
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation

One test animal showed red spots (grade 1) as a reaction to the test substance at the 48 hour readings in the challenge phase. No other positive skin responses were observed following the challenge. No signs of toxicity were observed in any of the animals during the study. Desmedipham was not a skin sensitiser in guinea pigs under the Buehler test method.

Interpretation of results:
GHS criteria not met
Conclusions:
Desmedipham was not a skin sensitiser in guinea pigs using the Buehler test method. The study was acceptable.
Executive summary:

A sample of Desmedipham was evaluated by the Buehler test to determine its sensitizing potential. The experimental group consisted of 20 animals were subjected to nine epicutaneous occlusive induction exposures with 0.5 ml 50% of desmedipham in aqueous methyl cellulose 1%. The control animals were treated in a similar manner with a patch moistened with 0.5 ml aqueous methyl cellulose 1%.


Ten days after the last induction treatment, all animals were challenged with desmedipham at 50% and 0% (w/w) concentrations in aqueous methyl cellulose 1%. No positive skin response (grade 2 or more) was observed to the challenge. Only one experimental animal showed red spots in reaction to the test substance. Desmedipham was not a skin sensitiser in guinea pigs using the Buehler test method. The study was acceptable.

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1987-07-27 to 1988-11-11
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Version / remarks:
Magnusson and Kligmann test (1970)
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
Magnusson and Kligmann test (1970)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Remarks:
The main study was performed in compliance with the principles of GLP, but the test of the positive control group treated with DNCB was not run under GLP-conditions in 1987.
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The study was performed prior to adoption of the OECD test guideline for the LLNA (OECD 429, 2010).
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male/female
Details on test animals and environmental conditions:
Species: Dunkin-Hartley albino guinea pigs (DUHA KFM)
Rationale: Recognized by the international guidelines as the recommended test system.
Number of animals: 15 males and 15 females
Initial age (at pairing): 7 - 8 weeks
Initial body weight (post coitum): Males (397 - 500 g); Females (386 - 473 g)
Acclimation: One week under test conditions after veterinary examination.
Identification: Individual cage number and corresponding ear tag .
Randomization: One week under test conditions after veterinary examination.


Standard Laboratory Conditions.
Air-conditioned with 10-15 air changes per hour and hourly monitored environment with temperature 22+-3 degrees centigrade, relative humidity 40-70%, 12 hours artificial fluorescent light/12 hours dark, music/light period.

Accommodation
Individually in Makrolon type-3 cages with standard softwood bedding.

Diet
Pelleted standard Kliba 342, Batch 37/87 guinea pig breeding/ maintenance diet.

Water
Community tap water from ad libitum.
Route:
intradermal
Vehicle:
other: polyethylene glycol (PEG 400) and physiological saline (7:3)
Concentration / amount:
Three double injections of 0.1 mL
Adequacy of induction:
other: Erythema, edema, necroses and exfoliation around the injection sites were noted in control and test animals during the induction phase
Route:
epicutaneous, occlusive
Vehicle:
other: polyethylene glycol (PEG 400) and physiological saline (7:3)
Concentration / amount:
Three double injections of 0.1 ml. 25% for epicutaneous.
Day(s)/duration:
48 hours
Adequacy of induction:
not specified
No.:
#1
Route:
epicutaneous, occlusive
Vehicle:
other: non-irritant
Concentration / amount:
25%
Day(s)/duration:
24 hours
Adequacy of challenge:
not specified
No.:
#2
Route:
epicutaneous, occlusive
Vehicle:
other: non-irritant
Concentration / amount:
25%
Day(s)/duration:
24 hours
Adequacy of challenge:
not specified
No. of animals per dose:
5 males, 5 females for the vehicle control group and 10 males, 10 females for the test article group.
Details on study design:
Preliminary study
In the preliminary study desmedipham caused slight erythema (grade 1) and slight edema (grade 1) at concentrations of 0.5, 1, 3 and 5% desmedipham administered by intradermal injection. After epicutaneous application no skin reactions were observed at concentrations of 3, 5, 10, 25% desmedipham. The test material was diluted in polyethylene glycol (PEG 400) and physiological saline (7:3). The concentrations of the test article selected were 0.5% for intradermal injections and 25% for topical applications in the main study.

Main study
The skin sensitisation potential of desmedipham analytical grade was tested on 20 (10 males/10 females) Dunkin Hartley albino guinea pigs, weighing from 386 to 500 g. Additionally 10 animals (5 males/5females) were used as a vehicle control group. A solution of polyethylene glycol (PEG 400) and physiological saline (7:3) was used as a dosing vehicle. During the induction three double intradermal injections of 0.1 ml volume were administered in the shoulder region of the test animals. The intradermal injections were a) Freund’s complete adjuvant with the vehicle in the ratio 50:50, b) a 0.5% solution of desmedipham in the vehicle, c) a 0.5% desmedipham emulsified in 50:50 mixture of Freund’s complete adjuvant and the vehicle. One week later the same area was dermally treated with desmedipham 25% in vehicle and covered with an occlusive dressings for 48 hours. The control animals were treated as above with the omission of the test article. The challenge was conducted 2 weeks later. Topical applications were made with a) a concentration 25% of desmedipham in vehicle (non-irritant) placed on the left flank and b) the vehicle alone placed on the right flank using the same method as for the epidermal application. The occlusive dressings were removed approximately 24 hours later. The control animals were treated with the same way as above. The second challenge was performed two weeks later using a similar method as the first challenge with the exception that these two solutions a) and b) were applied to the opposite flank. The control animals were treated with vehicle alone. The challenge site was evaluated immediately and then 24 and 48 hours after removal of the patch. The Exact Fisher test for comparison of the basic probability was used in the statistical analysis.
Challenge controls:
Vehicle only.
Positive control substance(s):
yes
Remarks:
The positive control test with DNCB was completed in July 1987.
Positive control results:
All (15/15) positive control group animals reacted positively.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
25%
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
25%
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Reading:
other: Overall (24+ 48 hours)
Group:
positive control
No. with + reactions:
15
Total no. in group:
15
Remarks on result:
positive indication of skin sensitisation
Interpretation of results:
GHS criteria not met
Conclusions:
No evidence of skin sensitisation potential was seen under the conditions of this study.
Executive summary:

With the procedures used in this experiment, no differences between the test group and the vehicle-treated controls were evident after the first and second epidermal challenge application of DESMEDIPHAM ANALYTICAL GRADE. DESMEDIPHAM ANALYTICAL GRADE is considered to possess no skin sensitizing (contact allergenic) potential in albino guinea pigs.  No deaths occured during the test. The body weight gain of all animals was not affected during the test procedure. Erythema, edema, necroses and exfoliation around the injection sites were noted in control and test animals during the induction phase. The incidence of positive animals after the first and second challenge application were 0/10 and 0/20, respectively in the vehicle control and test group. Desmedipham (analytical grade) was considered to possess no skin sensitizing potential in albino guinea pigs.  Desmedipham analytical grade (99.8%) was not found to be a dermal sensitizer in the guinea pig maximisation test. The study was acceptable.

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1987-01-12 to 1987-07-01
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
according to guideline
Guideline:
EPA OPP 81-6 (Skin Sensitisation)
Qualifier:
equivalent or similar to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Version / remarks:
Magnusson and Kligman
Deviations:
no
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Version / remarks:
Magnusson and Kligman
Deviations:
yes
Remarks:
The concentration of the test substance for each induction exposure should be the highest to cause mild to moderate skin irritation. In this test, the selected concentration of 0.5% caused only slight erythema and slight edema.
GLP compliance:
yes (incl. QA statement)
Remarks:
The study was performed in compliance with the principles of GLP, but the test of positive control group treated with DNCB was not run under GLP-conditions in 1986.
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
The study was performed prior to adoption of the OECD test guideline for the LLNA (OECD 429, 2010).
Specific details on test material used for the study:
Description: light beige coloured fine powder
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male/female
Route:
intradermal
Vehicle:
other: solution of polyethylene glycol (PEG 400) and physiological saline (7:3).
Concentration / amount:
0.5%; 0.1 mL / site
Day(s)/duration:
Single intradermal induction
Adequacy of induction:
other: The selected concentration of 0.5% caused only slight erythema and slight edema in the pre test
Route:
epicutaneous, occlusive
Vehicle:
other: polyethylene glycol (PEG 400) and physiological saline (7:3)
Concentration / amount:
25%
Day(s)/duration:
Single topical induction
Adequacy of induction:
other: No skin irritation was observed in the study and a dose higher than 25% (used for topical application was not tested. Furthermore, 10% sodium lauryl sulphate in vaseline was not used to induce irritation
Route:
epicutaneous, occlusive
Vehicle:
not specified
Concentration / amount:
25 %
Day(s)/duration:
24 hours
Adequacy of challenge:
not specified
No. of animals per dose:
5 males, 5 females for the vehicle control group and 10 males, 10 females for the test article group.
Details on study design:
Preliminary study
In the preliminary study, skin reactions to desmedipham were tested on two guinea-pigs by intradermal injections (0.1 ml/site) or epidermal applications. The test material was diluted in a solution of polyethylene glycol (PEG 400) and physiological saline (7:3). Desmedipham caused well-defined erythema (grade 2) and well-defined edema (grade 2) at concentrations of 1, 3, and 5% and slight erythema (grade 1) and slight edema (grade 1) at concentrations of 0.1, 0.3 and 0.5% 24 hours after the intradermal injection. No skin reactions were observed after epicutaneous application at concentrations of 3, 5, 10 and 25% of desmedipham during the exposure period of 24 hours. The concentrations of the test article selected were 0.5% for intradermal injections and 25% for topical applications in the main study.

Main study
The test was performed on groups of 10 male and 10 female Dunkin Hartley albino guinea pigs, weighing from 380 to 470 g. Additionally 5 males and 5 females were used as vehicle control group. The test material, technical desmedipham (Code: SN 38107, Batch 320033, Purity 98.0%) was diluted in a solution of polyethylene glycol (PEG 400) and physiological saline (7:3). In the induction phase, three double intradermal injections of 0.1 ml volume were administered in the clipped shoulder region of the test animals. The intradermal injections were a) Freund’s complete adjuvant plus the vehicle in the ratio 50:50, b) 0.5% solution of desmedipham in the vehicle, c) emulsion of 0.5% solution of desmedipham in the vehicle and Freund’s complete adjuvant plus vehicle in the ratio 50 : 50. One week later the same area was dermally treated with 25% desmedipham in vehicle and covered with occlusive dressing for 48 hours. The control animals were treated as above with the omission of the test article. The challenge phase was conducted 2 weeks later. A topical application with a 25% concentration of desmedipham in vehicle was made on the left flank of each guinea pig and covered with occlusive dressing for 24 hours. The control animals were treated with the vehicle alone. The second challenge was performed two weeks later using a similar method as in the first challenge with the exception that the right flanks of all guinea pigs (also the control animals) were treated with the test article. The challenge site was evaluated immediately and then 24 and 48 hours after removal of the bandage. The Exact Fisher test for comparison of the basic probability was used in the statistical analysis .
Positive control results:
DNCB (2,4- dinitro-chlorobenzene) was used as positive control. In the test of positive control carried out during June 1986, DNCB possessed a strong sensitizing potential in Dunkin Hartley albino guinea pigs, the incidence of positive animals treated with DNCB after challenge application being 8/15 (53%).
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
25%
No. with + reactions:
7
Total no. in group:
20
Remarks on result:
positive indication of skin sensitisation
Remarks:
Response >30%
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
25%
No. with + reactions:
7
Total no. in group:
20
Remarks on result:
positive indication of skin sensitisation
Remarks:
Response >30%
Reading:
rechallenge
Hours after challenge:
24
Group:
negative control
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
rechallenge
Hours after challenge:
48
Group:
negative control
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
rechallenge
Hours after challenge:
24
Group:
test chemical
Dose level:
25%
No. with + reactions:
4
Total no. in group:
20
Remarks on result:
no indication of skin sensitisation
Remarks:
Response <30%
Key result
Reading:
rechallenge
Hours after challenge:
48
Group:
test chemical
Dose level:
25%
No. with + reactions:
5
Total no. in group:
20
Clinical observations:
None
Remarks on result:
no indication of skin sensitisation
Remarks:
Response <30%
Reading:
other: Overall response (24 + 48 hours)
Group:
positive control
No. with + reactions:
8
Total no. in group:
15
Remarks on result:
positive indication of skin sensitisation
Remarks:
Separate study with DNCB (June 1986)

One vehicle control animal was killed on day 21 of the test due to poor health condition. No other toxic symptoms were observed in the guinea pigs. With the exception of one dead animal, the body weight gain of all animals was not affected during the test. Erythema, edema, necroses and exfoliation around the injection sites were noted in the control and test animals during the induction phase. The incidence of positive animals after the first and second challenge application was 0/10 in the vehicle control group. In the test group the incidence of positive animals after the first challenge was 7/20 (35%) after both the 24 and 48 hour readings. After the second challenge, the incidence of positive animals in the test group was 4/20 (20%) and 5/20 (25%) after the 24 and 48 hour readings, respectively.

Interpretation of results:
GHS criteria not met
Remarks:
Although the dermal irritation scores following the first challenge with desmedipham (25%) indicate sensitising potential (35% response at 24 and 48 hours), findings were not replicated following the rechallenge. The incidence of reactions following the rechallenge was 20% and 25% at 24 and 48 hours, respectively.
Conclusions:
There was some evidence of skin sensitisation potential in this study, but the dermal reactions did not consistently exceed the threshold for classification.
Executive summary:

The skin sensitisation potential of desmedipham was assessed in a Maximisation study in Dunkin-Hartley guinea pigs. Intradermal induction was performed on test animals (10/sex) using paired injections of desmedipham (0.5%) and FCA. Topical induction was performed using 25% desmedipham.  Although the dermal irritation scores following the first challenge with desmedipham (25%) indicate sensitising potential (35% response at 24 and 48 hours), findings were not replicated following the rechallenge. The incidence of reactions following the rechallenge was 20% and 25% at 24 and 48 hours, respectively. While there was some evidence of skin sensitisation potential in this study, the dermal reactions did not consistently exceed the threshold for classification. A separate positive control study (reliability check) using DNCB is reported, confirming the sensitivity of the assay.

Endpoint:
skin sensitisation: in vitro
Data waiving:
study scientifically not necessary / other information available
Justification for data waiving:
an in vitro skin sensitisation study does not need to be conducted because adequate data from an in vivo skin sensitisation study are available
Justification for type of information:
JUSTIFICATION FOR DATA WAIVING
An in vitro skin sensitisation study does not need to be conducted because adequate data from in vivo skin sensitisation studies are available. Studies were performed prior to the adoption of in chemico/in vitro test methods
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Desmedipham has been tested for its skin sensitisation potential in five separate studies; four using the Maximisation design and one Buehler study.  Clear negative responses were reported for three of the Maximisation studies and the Buehler study.  The remaining Maximisation study reported a borderline positive response (35% responding) following an initial challenge that was not replicated following a second challenge application (25% responding at 24 hours, 20% responding at 48 hours).  All animals responding in this study showed a maximum of Grade 1 erythema, with no oedema present in any animal.  These minimal dermal reactions are equally consistent with an irritant response and are not considered to provide clear evidence of sensitisation.  Given the lack of consistency between the studies, a weight of evidence approach is taken to hazard classification.  Consequently, it is concluded that desmedipham is not a skin sensitiser and does not require classification as a skin sensitiser under CLP. 

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available
Additional information:

There are no studies of respiratory sensitisation for desmedipham, but no indication (e.g. from structural alerts) that desmedipham is a respiratory sensitiser. 

Justification for classification or non-classification

Desmedipham has been tested for skin sensitisation five Maximisation studies and in one Buehler study.  Clear negative responses were reported for three of the Maximisation studies and the Buehler study.  The remaining Maximisation study reported a borderline positive response following an initial challenge that was not replicated following a second challenge application.  Based on the weight of evidence, it is concluded that desmedipham is not a skin sensitiser.  Classification for skin sensitisation in any category is not required under CLP.


There are no studies of respiratory sensitisation for desmedipham, but no indication (e.g. from structural alerts) that desmedipham is a respiratory sensitiser.  Consequently, classification for respiratory sensitisation is not required.