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Administrative data

Description of key information

DMPPA_701-402-5 is not considered as a skin sensitiser.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1993
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
no
GLP compliance:
yes (incl. QA statement)
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
Data from a reliable in vivo test conducted before the enforcement of Commission Regulation (EU) 640/2012 of 06 July 2012 amending, for its adaptation to technical progress, Regulation (EC) \No. 440/2008 laying down test methods pursuant to Regulation (EC) No 1907/2006 of the European Parliament and of the Council on the Registration, Evaluation, Authorisation and Restriction of Chemicals (REACH) are available.
Specific details on test material used for the study:
Identification: Pyrovatex CP NEU
Description: colorless to yellowish liquid
Batch Number: 886114
Purity/ formulation: the substance (as technical product)has been investigated as FAT 80001/I but the formulation contains 2 % ethylene urea.
Stability of testarticle expiration date: July 28, 1994
Stability of test article dilution: stable for 28 days in water; unknown in Freund's Complete Adjuvant and physiological saline; excluded from the Statement of Compliance.
Storage Conditions: at room temperature (approx. 20 °C)
Safety precautions: Gloves, goggles and face mask were obligatory to assure personnel health and safety.
Species:
guinea pig
Strain:
Himalayan
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: BRL, Biological Research Laboratories Ltd. Wölferstrasse 4, CH-4414 Füllinsdorf/Switzerland.
- Females (if applicable) nulliparous and non-pregnant: not specified
- Age at study initiation: 6-8 weeks
- Weight at study initiation: Control and Test Group: 338 - 437 g, Pretest: 395-423g
- Housing: Individually in Makrolon type-3 cages (size: 22x37x15 cm) with standard softwood bedding ("Lignocel", Schill AG, CH-4132 Muttenz).
- Diet (e.g. ad libitum): Pelleted standard Kliba 342, Batch nos. 76/93 (from acclimatization start to June 25, 1993), 77/93 (from June 26 to July 20, 1993) and 78/93 (from July 21 to termination of test) guinea pig breeding/ maintenance diet ( "Kliba ", Klingentalmühle AG, CH-4303 Kaiseraugst), ad libitum.
- Water (e.g. ad libitum): Community tap water from Füllinsdorf, ad libitum. Once weekly additional supply of ascorbic acid (1 g/L) via the drinking water.
- Acclimation period: 7 days
- Indication of any skin lesions: None

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 3
- Humidity (%): 40 - 70 %
- Air changes (per hr): 10-15 air changes per hr.
- Photoperiod (hrs dark / hrs light): 12 hours artificial fluorescent light (approx. 100 lux) /12 hours dark, music during the light period.
- IN-LIFE DATES: From: To: June 7 to July 22, 1993.
Route:
intradermal
Vehicle:
other: bidistilled water
Concentration / amount:
5 %
Day(s)/duration:
Day 1
Adequacy of induction:
highest concentration used causing mild-to-moderate skin irritation and well-tolerated systemically
Route:
epicutaneous, semiocclusive
Vehicle:
other: bidistilled water
Concentration / amount:
25 %
Day(s)/duration:
Day 8
Adequacy of induction:
other: non-irritant substance, but pretreated with 10 % (Sodium Lauryl Sulfate) SLS.
No.:
#1
Route:
epicutaneous, semiocclusive
Vehicle:
other: bi-distilled water
Concentration / amount:
25 %
Day(s)/duration:
21 days
Adequacy of challenge:
highest non-irritant concentration
No.:
#2
Route:
epicutaneous, semiocclusive
Vehicle:
other: bi-distilled water
Concentration / amount:
25 %
Day(s)/duration:
35 days
Adequacy of challenge:
highest non-irritant concentration
No. of animals per dose:
10 females for the control group and 20 females for the test group. 2 females were used for the intracutaneous pretest and 4 females for the epicutaneous pretest.
Details on study design:
PRETEST:
The objective of this investigation was to identify a maximally tolerated concentration of the test article suitable for the induction phase of the main study. In addition, a suitable non-irritant concentration of the test article, by the topical route of administration, was identified for the challenge application.

The procedure employed for these investigations was as follows:
INTRADERMAL INJECTIONS:
Intradermal injections (0.1 mL/ site) were made into the clipped flank of two guinea-pigs at concentrations of 5, 3 and 1 % of the test article in bi-distilled water. The resulting dermal reactions were assessed 24 hours later. For intracutaneous induction application a 5 % test article dilution was selected.

EPIDERMAL APPLICATIONS:
The both flanks of each of 4 guinea pigs were clipped and shaved just prior to the application. Thereafter patches of filter paper ( 2 x 2 cm) were saturated with the undiluted test article and with test article concentrations of 75 %, 50 % and 25 % in bi-distilled water and applied to the clipped and shaved flanks. The patches were covered by a strip of aluminum foil and firmly secured by elastic plaster wrapped around the trunk and covered with impervious adhesive tape. This procedure ensured the intensive contact of the test article. The dressings were removed after an exposure period of 24 hours and the reaction sites were assessed 24 and 48 hours after removal of the bandage for erythema and oedema on
a numerical basis according to Draize described above.

The allocation of the different test sites on the animals was alternated in order to minimize site to site variation in responsiveness.
For the epidermal induction and challenge procedure a 25% test substance dilution was selected.


MAIN STUDY
INDUCTION
Intradermal injections:
An area of dorsal skin from the scapular region (approximately 6 x 8 cm) was clipped free of hair. Three pairs of intradermal injections (0.1 mL/ site) were made at the border of a 4 x 6 cm area in the clipped region as follows:

Test group:
1) Freund's complete adjuvant 50:50 with physiological saline.
2) The test article, diluted to 5% with bi-distilled water.
3) The test article diluted to 5% by emulsion in a 50:50 mixture of Freund's complete adjuvant and physiological saline.

Control group:
1) Freund's complete adjuvant 50:50 with physiological saline.
2) Bi-distilled water.
3) 1:1 mixture of bi-distilled water and Freund's complete adjuvant.

Epidermal applications:
On test day 7 and approximately 24 hours prior to the epidermal application the scapular area (approximately 6 x 8 cm) was clipped, shaved free of hair, and the test area was pretreated with 10 % Sodium-Lauryl-Sulfate (SLS) in paraffinum perliquidum. The SLS was massaged into the skin with a glass rod without bandaging. This SLS-concentration enhances sensitization by provoking a mild inflammatory reaction.

On test day 8 a 2 x 4 cm patch of filter paper was saturated with the test article (25 % in bi-distilled water) and placed over the injection sites of the test animals. The patch was covered with aluminum foil and firmly secured by an elastic plaster wrapped around the trunk of the animal and secured with impervious adhesive tape. The dressings were left in place for approximately 48 hours. The epidermal application procedure described ensured intensive contact of the test article.

The guinea-pigs of the control group were treated as described above with the omission of test article (bi-distilled water only).
Reaction sites were assessed for erythema and oedema 24 and 48 hours after removal of the dressing, using the numerical grading system according to Draize.

FIRST CHALLENGE
The test and control guinea-pigs were challenged two weeks after the epidermal induction application. The test and control guinea-pigs were treated in the same way. Hair was clipped and shaved from a 5 x 5 cm area on the left and right flank of each guinea-pig just prior to the application. Two patches (2 x 2 cm) of filter paper were saturated with the test article at 25 % in bi-distilled water (left flank) and the vehicle only (bi-distilled water, applied to the right flank) using the same method as for the epidermal application. The dressings were removed approximately 24 hours later. The sites were assessed for erythema and oedema 24 and 48 hours after removal of the dressing, using the numerical scoring system according to Draize.

SECOND CHALLENGE
A second challenge was performed two weeks after the first challenge. The treatment procedure for the animals of the test group was similar as described for the first challenge with the exception that the applications on flanks of all the guinea-pigs were inverted. The control animals were treated with the vehicle alone on the left flank.
Positive control substance(s):
yes
Remarks:
2 - Mercaptobenzothiazole
Positive control results:
50 % of animals showed positive reaction. (5/10)
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
25%
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
24
Group:
test chemical
Dose level:
25%
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
48
Group:
test chemical
Dose level:
25%
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
25%
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
25%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
48
Group:
negative control
Dose level:
25%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
2nd reading
Hours after challenge:
24
Group:
negative control
Dose level:
25%
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
Dose level:
25%
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
no indication of skin sensitisation
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
25%
No. with + reactions:
5
Total no. in group:
10
Remarks on result:
positive indication of skin sensitisation

No systemic symptoms were observed in the animals.

Interpretation of results:
GHS criteria not met
Conclusions:
The test item was found to be a non-skin sensitizer.
Executive summary:

To assess the allergenic potential of PYROVATEX CP NEU in albino guinea pigs the Maximization-Test of B. Magnusson and A.M. Kligman (1969) was used. 10 females were used as control group and 20 females were used as test group. This test was performed in accordance with OECD TG 406. For validation of the sensitivity of test method and test system used, a known moderate sensitizer (2 - Mercaptothaizole) was selected as a positive control.

For testing Pyrovatex CP NEU, based on pretest, following induction doses were selected for main study; 5 % for Intradermal induction, 25 % for epicutaneous induction and first/second challenge. No sensitising reactions were seen either in the test or control groups.

Conclusion:

From the results described above no allergenic potency of the test article PYROVATEX CP NEU was concluded. The results were interpret according to the rating of Magnusson and Kligman (1969) thus this test article is considered be a non-sensitizer.

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

Two fully reliable key studies (Klimisch 1) are available, conducted according to OECD 406 and GLP, showing no sensitization potential of DMPPA_701-402-5. In a guinea pig maximization test (Arcelin, G. 1993) the allergenic potential of PYROVATEX CP New was assessed. PYROVATEX CP New (77 % DMPPA_701-402-5) as technical product has been investigated. In addition to the active ingredient, the formulation contains 2 % formaldehyde scavenger. In this study 0 % of the animals were positive after treatment with the test substance concentration of 25 % in double-distilled water. According to EEC classification criteria described in guidelines 91/325/EEC this test article is considered to be no skin sensitizer.

The possible allergenic potential of Aflammit KWB (80 % DMPPA_701-402-5) when administered topically to albino guinea pigs was assessed in a Bühler Test (Ott, M. 2006). Aflammit KWB has a similar composition as PYROVATEX CP New but without the 2 % formaldehyde scavenger. In this study none of the animals of the test group were observed with skin reactions after the challenge treatment with Aflammit KWB. Therefore, the test item does not have to be classified and labelled as a skin sensitizer.

Moreover,

78.5 % DMPPA_701-402 -5 without formaldehyde scavenger) has been tested for its sensitization potential (Test Nr. 781930, Ciba-Geigy limited Toxicology, Basel, 1978). This study has been performed before guidelines and is therefore classified as Klimisch 2 and used as a supporting study. 

DMPPA_701-402-5

was found to be devoid of skin-sensitizing potential in albino guinea-pigs and is therefore not classified as a skin sensitizer.

78.5 % DMPPA_701-402-5 without the formaldehyde scavenger (Arcelin, G. 1992) has been tested and revealed to be a skin sensitizer. The fact that in absence of the formaldehyde scavenger, the guinea pig Maximization-Test is positive, is suggesting that formaldehyde is triggering the sensitization potential of DMPPA_701-402-5. Indeed, the product will always have a formaldehyde scavenger in its final composition and for this reason, the test performed with PYROVATEX CP New is representing a more realistic exposure scenario.

Aflammit KWB has also been tested in a Maximisation Test and shows to be a marginal skin sensitizer (Jai Research Foundation, 2004). However, when Aflammit KWB (no formaldehyde scavenger), is applied topically, no skin sensitization potential can be observed (Ott, M. 2006). This supports the weight of evidence approach, not to classify DMPPA_701-402-5 as a sensitizer. Indeed, the risk of exposure of DMPPA_701-402-5 for consumer is assessed more realistically by a topical application, as shown by the maximization test performed on cotton 100 % treated with Aflammit KWB (Ott, M. 2006), showing no sensitization potential. This result has been confirmed with a sensitization test with epidermal application of cotton-fabrics treated with DMPPA_701-402-5 (Test No. 781930). In addition to those tests also studies performed on saliva extract have been performed and are supporting the weight of evidence approach, like the skin permeability test with pig ear skin, which has been performed with an extract from fabrics treated with PYROVATEX CP new (CCR, 1993). The test article did not penetrate through the pig ear skin. An immunotoxicity test with a saliva extract of textile sample treated with PYROVATEX CP new revealed as well to have no immunotoxic potential (CCR 1994). Moreover, an epikutan patch tests showed no irritation or allergic reaction to PYROVATEX CP New in human volunteers (Tronnier, H. 1989).

In conclusion, based on the weight of evidence approach presented above and the fact that the sensitization potential of DMPPA_701-402-5 has been assessed by two different companies, having two different production processes, showing in both cases equivocal results, is demonstrating that DMPPA_701-402-5 has not the potential to support a classification and has shown no skin sensitization potential when considering realistic exposure scenarios.

The reslts of the studies can be summarized as follows: The driver for skin sensitization in the product is due to remaining formaldehyde. If a formaldehyde scavenger is added, or less formaldehyde present, no skin sensitization potential is remaining. Second, treated fabric does not display any skin sensitization potential. Furthermore, also a human patch-test conducted on a large group of healthy volunteers did not show any skin sensitization potential. Saliva extracts from treated fabrics also failed to induce a skin sensitization in animal tests and in an in vitro test on pig ears also no skin penetration potential of the test substance extracted from treated fabrics could be demonstrated which is a pre-requisite for inducing skin sensitization through skin contact with the treated fabric.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Skin sensitisation

Based on the above stated assessment of the skin sensitisation potential of DMPPA_701-402-5 the substance does not need to be classified according to CLP ( Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.

Respiratory sensitisation:

As no data on respiratory sensitisation is available for DMPPA_701-402-5 a classification is not possible according to CLP ( Regulation (EC) No 1272/2008 of the European Parliament and of the Council) as implementation of UN-GHS in the EU.