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Diss Factsheets

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records
Reference
Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Background irritation was present
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
GLP compliance:
yes
Type of study:
Buehler test
Justification for non-LLNA method:
At the time of the registration this study was already existant. There was no need to perform an additional LLNA test.
Species:
guinea pig
Strain:
Hartley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Harlan Sprague Dawley, Inc
- Age at study initiation: 6-11 weeks
- Weight at study initiation: 440-493 grams
- Housing: Housed individually in wire mesh suspension cages
- Diet: ad libitum
- Water: ad libitum
- Acclimation period: 7 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 17.8-26.1
- Humidity (%): 30-70
- Photoperiod (hrs dark / hrs light): 12 hours
Route:
epicutaneous, occlusive
Vehicle:
other: mineral oil
Concentration / amount:
Induction: 5% w/v
Challenge: 1% w/v
Route:
epicutaneous, occlusive
Vehicle:
other: mineral oil
Concentration / amount:
Induction: 5% w/v
Challenge: 1% w/v
No. of animals per dose:
20 treated with test material, 10 naive control
Details on study design:
RANGE FINDING TESTS:
Primary Irritation after 6 hour patch aplication of test material in mineral oil at following concentrations:

Undiluted, 50, 25, 10, 5, 2.5, 1, 0.5 % w/v

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 3
- Exposure period: 6 hours
- Site: Left shoulder
- Frequency of applications: 6 to 7 days
- Concentrations: 5%


B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: 1 and 2 days (24 and 48 hours)
- Exposure period: 6 hours
- Control group: 10 naive not previously exposed to test material
- Concentrations: 1%
- Evaluation (hr after challenge): 24 and 48 hours
Challenge controls:
10 naive not previously exposed to test material
Positive control substance(s):
yes
Remarks:
1-Chloro-2,4,-Dinitrobenzene
Positive control results:
1-Chloro-2,4,-Dinitrobenzene: Postive for skin sensitization
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
induction: 5% w/v; challenge: 1% w/v
No. with + reactions:
3
Total no. in group:
20
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: induction: 5% w/v; challenge: 1% w/v. No with. + reactions: 3.0. Total no. in groups: 20.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
induction: 5% w/v; challenge: 1% w/v
No. with + reactions:
0
Total no. in group:
20
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: induction: 5% w/v; challenge: 1% w/v. No with. + reactions: 0.0. Total no. in groups: 20.0.
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
challenge: 1% w/v
No. with + reactions:
1
Total no. in group:
10
Remarks on result:
other: Reading: 1st reading. . Hours after challenge: 24.0. Group: negative control. Dose level: challenge: 1% w/v. No with. + reactions: 1.0. Total no. in groups: 10.0.
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
challenge: 1% w/v
No. with + reactions:
0
Total no. in group:
10
Remarks on result:
other: Reading: 2nd reading. . Hours after challenge: 48.0. Group: negative control. Dose level: challenge: 1% w/v. No with. + reactions: 0.0. Total no. in groups: 10.0.
Interpretation of results:
not sensitising
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
The irritation in 3/20 animals in the challenge phase scored after 24 hours did not persist to 48 hours, indicating an irritation response rather than a skin sensitization response.
CLP: not classified
DSD: not classified
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Justification for grouping of substances and read-across

There are no reliable data available on the skin sensitising potential of zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate). In order to fulfil the standard information requirements set out in Annex VII, Section 8.3, in accordance with Annex XI, Section 1.5 of Regulation (EC) No 1907/2006, read-across from a structurally similar substance is conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having considered the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, whereby physicochemical, toxicological and ecotoxicological properties may be predicted from data for reference substance(s) by interpolation to other substances on the basis of structural similarity, the substance Phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts (CAS 84605-29-8) is selected as reference substances for assessment of skin sensitisation.

The read-across is based on structural similarity as both chemicals belong to the substance class of Zinc alkyldithiophosphates (ZDDP) which are produced by a chemical reaction of Phosphorous pentasulfide with low molecular weight alcohols followed by a subseuqent reaction with zinc oxide. A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Overview of sensitisation

 

Target substance (a)

Source substance (b)

CAS No.

6990-43-8

84605-29-8

Chemical name

zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate)

Phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts

Skin sensitisation

Experimental result:
not reliable

 

RA: CAS 84605-29-8

Experimental result:
not sensitising

(a) The substance subject to the REACh Phase-in registration deadline of 31 May 2013 is indicated in bold font. Only for this substance a full set of experimental results and/or read-across is given.

(b) Reference (read-across) substance(s) are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

 

Skin sensitisation

CAS 6990-43-8

Two studies, a Local Lymph Node Assay (LLNA) and a Guinea Pig Maximization Test (GPMT), are available in which the skin sensitising properties of zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) have been investigated. Due to relevant methodological deficiencies, the results of these studies were considered not reliable and therefore insufficient for hazard assessment.

In the LLNA, female CBA mice were treated with the test substance at 10, 25, 50 and 100% (vehicle: acetone/corn oil (4:1)) in a preliminary irritation test, and at 25, 50 and 100% (vehicle: dimethylformamide) in the main test (van Huygevoort, 2001). Hexyl cinnamic aldehyde (10% in dimethylformamide) was used as positive control.

Skin irritation was observed at all concentrations. DPM/node values for the negative control, 25, 50 and 100% groups were 281, 1689, 5058 and 2328 respectively. Additional treatment with the vehicle and test substance at 10% resulted in DPM/node values of 129 and 927, respectively. The stimulation index (SI) values calculated for the test substance concentrations 10, 25, 50 and 100% were 7.1, 6.0, 18.0 and 8.3, respectively, without clear dose-response relationship. The positive control group, included only in the additional testing, resulted in a DPM/node value of 339 and a SI of 2.6, thus failing to prove the reliability of the assay.

This study shows two major deficiencies which together give rise to question the reliability of the study. Firstly, the positive control hexyl cinnamic aldehyde was tested at wrong concentration and in a wrong vehicle resulting in a low stimulation index (SI) of 2.6, which is not sufficient to prove a sensitising potential according to OECD guideline 429. Secondly, the test material caused irritation including scaling at all tested concentrations. Thus, the resulting SI values > 3 for all concentrations indicating a skin sensitising potential of the test substance, can be regarded as secondary effects due to irritation and cannot clearly be attributed to sensitisation. Therefore, the design of the study should be regarded as not suitable to evaluate the sensitising potential of this test substance. Hence, the results of this study are considered to be insufficient for assessment and inadequate for classification purposes due to relevant methodological deficiencies.

In the GPMT, 5 male and 5 female Pirbright White guinea pigs were intradermally induced with the test at 2 and 20% in sesame oil, and epicutaneously at 20% (Grunert, 1992). Animals were challenged with the test substance at 20%. No positive control/reliability check was included.

One animal was found dead on Day 7 after the first induction exposure. No positive reactions were observed in any animal of the negative control and test groups.

The pilot study for selection of test concentrations was not properly reported. As stated above, no positive control or reliability check was included. Additionally, for intradermal induction a wrong (higher) FCA concentration was used. Altogether, due to these relevant methodological deficiencies, the results of the study are questionable and considered insufficient for assessment.

CAS 84605-29-8

A Buehler Test was conducted with Phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts similarly to OECD guideline 406 and in compliance with GLP (Morris, 1997). The test material was used as 5% and 1% (w/v) in mineral oil for the induction and challenge phases, respectively. For epicutaneous induction, a group of 20 male and female Hartley guinea pigs was treated with the test material for 6 h under occlusive conditions, once per week for 3 weeks. For challenge, the test group and a naïve control group (10 animals) were treated once for 6 h under occlusive conditions, and skin reactions were assessed 24 and 48 h after exposure. 1-Chloro-2,4,-Dinitrobenzene was included as positive control substance.

At 24 h after challenge, 3/20 in the test group and 1/10 animals in the control group showed positive skin reactions. At 48 h post-challenge, no skin reactions were observed in the test and control groups. 1-Chloro-2,4,-Dinitrobenzene was positive for skin sensitisation.

The irritation in 3/20 animals in the challenge phase scored after 24 hours did not persist to 48 hours, indicating an irritation response rather than a skin sensitisation response.

Under the conditions of this Buehler test, the test substance was considered to be not skin sensitising in guinea pigs.

Conclusions for skin sensitisation

The substance zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) has been tested for the induction of skin sensitisation in a Local Lymph Node Assay (LLNA) and a Guinea Pig Maximization Test (GMPT)

Due to relevant methodological deficiencies in both tests, the studies were considered to be not reliable and the results insufficient for assessment.

Therefore, the available data on the structurally similar substance Phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts were used for hazard assessment by mean of read-across.

The substance Phosphorodithioic acid, mixed O,O-bis(1,3-dimethylbutyl and iso-Pr) esters, zinc salts was tested negative for skin sensitisation in a Buehler test.

Based on the available data, the substance zinc O,O,O',O'-tetrabutyl bis(phosphorodithioate) is considered to be not skin sensitising.


Migrated from Short description of key information:
Based on read-across from a structurally similar substance:
Skin sensitisation: not sensitising

Justification for selection of skin sensitisation endpoint:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall quality assessment (refer to the endpoint discussion for further details).

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on read-across from a structurally similar substance following an analogue approach, the available data on the skin sensitising potential of the substance do meet the classification criteria according to Regulation (EC) No 1272/2008 or Directive 67/548/EEC.