Citraconic anhydride

Endpoint summary

Description of key information

WoE: No valid data available from animal studies for citraconic anhydride. K3: Limited publications, standard guideline not followed (different procedure for exposure and not enough animals used), not GLP. These studies show a positive result for skin sensitization. This is supported by predictions made by QSAR models for maleic anhydride, benzene-1,2,4-tricarboxylic acid 1,2-anhydride and phthalic anhydride. These structural analogs are Annex VI REACH registered skin and respiratory sensitizers. Therefore citraconic anhydride is classified as a skin and respiratory sensitizer.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Remarks:

in vivo

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Limited publication, standard guideline not followed (different procedure for induction and challenge), not GLP.

Qualifier:

no guideline followed

Principles of method if other than guideline:

See methods section below.

GLP compliance:

no

Type of study:

other: non standard guinea pig test

Justification for non-LLNA method:

conducted before LLNA method was adopted

Species:

guinea pig

Route:

intradermal and epicutaneous

Vehicle:

other: olive oil and dioxane

Concentration / amount:

induction:
intradermal - 0.5% in olive oil
epicutaneous - 100%

challenge - 25% in dioxane

Route:

other: epicutaneous intact and scratch-test

Vehicle:

other: olive oil and dioxane

Concentration / amount:

induction:
intradermal - 0.5% in olive oil
epicutaneous - 100%

challenge - 25% in dioxane

No. of animals per dose:

28

Challenge controls:

No controls included in the study

Positive control substance(s):

no

Key result

Reading:

other:

Hours after challenge:

0

Group:

test chemical

Dose level:

25% in dioxane

No. with + reactions:

9

Total no. in group:

12

Clinical observations:

Not reported

Remarks on result:

positive indication of skin sensitisation

Examination of reactions obtained from citraconic anhydride sensitized guinea pigs have shown, as well as after a scratch-test as after

an epicutaneous test, immediate urticarial reactions, histologically characterized by the presence of eosinophilic leukocytes, intra- and perivascular. Afterwards erythematous reactions develop on the flank, which sometimes presents epidermal lesions and a leukocytic infiltrate extremely rich in eosinophilic leukocytes. On the nipple eczematous epidermal lesions and leukocytic infiltrate, rich in eosinophilic leukocytes were found regularly.

Interpretation of results:

sensitising

Remarks:

Migrated information Criteria used for interpretation of results: expert judgment

Conclusions:

Based on the results of this experiment the substance can be considered a sensitizer.

Executive summary:

Based on the results of this experiment the substance can be considered a sensitizer.

Reference 2

Endpoint:

skin sensitisation: in vivo (non-LLNA)

Type of information:

experimental study

Adequacy of study:

weight of evidence

Study period:

no data

Reliability:

3 (not reliable)

Rationale for reliability incl. deficiencies:

other: Limited publication, standard guideline not followed (different procedure for exposure and not enough animals used), not GLP.

Qualifier:

no guideline followed

Principles of method if other than guideline:

See methods section below.

GLP compliance:

no

Type of study:

guinea pig maximisation test

Justification for non-LLNA method:

conducted before LLNA method was adopted

Species:

guinea pig

Strain:

Hartley

Sex:

male

Details on test animals and environmental conditions:

Most studies were conducted on randomly bred Hartley strain male guinea pigs weighing approximately 300g. The animals were maintained on Purina guinea pig chow supplemented with green vegetables and water ad libitum. All animals were maintained in rooms designed to control temperature, humidity and light cycle.

Route:

other: topical + injection of Freunds adjuvant

Vehicle:

unchanged (no vehicle)

Concentration / amount:

0.1 ml for induction for the challenge: no data.

Route:

other: topical

Vehicle:

unchanged (no vehicle)

Concentration / amount:

0.1 ml for induction for the challenge: no data.

No. of animals per dose:

10

Positive control substance(s):

yes

Remarks:

diglycidyl ether of 2,2-di-(p,p'-hydroxyphenyl)propane (DER* 331 Epoxy Resin Dow Chemical U.S.A.)

Reading:

other: Not provided

Hours after challenge:

24

Group:

other: Not provided

Dose level:

Not provided

No. with + reactions:

3

Total no. in group:

10

Clinical observations:

Not provided

Remarks on result:

positive indication of skin sensitisation

3/10 guinea pigs showed a positive response.

Interpretation of results:

sensitising

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

3/10 guinea pigs showed a positive response.

Executive summary:

3/10 guinea pigs showed a positive response.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Respiratory sensitisation

Link to relevant study records

Reference

Endpoint:

respiratory sensitisation, other

Remarks:

other: QSAR

Type of information:

(Q)SAR

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Justification for type of information:

QSAR prediction

Qualifier:

no guideline followed

Principles of method if other than guideline:

Software used
OECD QSAR Toolbox v3
DEREK NEXUS 2.0.2

The results of the QSAR analysis indicate that

1. Maleic anhydride, benzene-1,2,4-tricarboxylic acid 1,2-anhydride and phthalic anhydride are potential skin and respiratory sensitizers and this agrees with experimental data.

2. Based on the similar profiles for these 4 substances, citraconic anhydride can be classified as skin Skin Sens. 1 H317) and respiratory (Resp. Sens. 1 H334) sensitizer

Interpretation of results:

sensitising

Remarks:

expert judgment

Conclusions:

The results of the QSAR analysis indicate that
1. Maleic anhydride, benzene-1,2,4-tricarboxylic acid 1,2-anhydride and phthalic anhydride are potential skin and respiratory sensitizers and this agrees with experimental data.
2. Based on the similar profiles for these 4 substances, citraconic anhydride can be classified as skin Skin Sens. 1 H317) and respiratory (Resp. Sens. 1 H334) sensitizer.

Executive summary:

Software used

OECD QSAR Toolbox v3

DEREK NEXUS 2.0.2

Methods

Structures were drawn in Marvin Sketch software and used to generate the structure files (.mol) and SMILES codes, which were then checked for correctness and then used as input into the various software packages.

Results and discussion

A summary of the results of the analysis are shown in Table 1 on the next page. Table 2 shows a full human health profile of the four substances from the QSAR Toolbox. In Appendices 1 - 3 an explanation of the mechanisms of action identified in Table 1 is presented. Both QSAR Toolbox and DEREK NEXUS identify structural alerts for skin sensitization for all compounds. DEREK NEXUS identifies alerts for respiratory sensitization for all four compounds. Maleic anhydride, benzene-1,2,4-tricarboxylic acid 1,2-anhydride and phthalic anhydride are REACH Tier I registered substances and are all classified as

Resp. Sens. 1 H334: May cause allergy or asthma symptoms or breathing difficulties if inhaled.

Skin Sens. 1 H317: May cause an allergic skin reaction.

The predictions from the QSAR software agree with the measured data.

To determine whether the measured data from the three anhydrides can be read across to citraconic anhydride, parameters relevant to skin sensitization were compared for the 4 substances. Table 2 (highlighted in yellow) shows similar profiles for organic functional groups, groups of elements, chemical elements, protein binding, substance type and bioavailability (Lipinski). Additionally, Table 1 shows low values for log Kow and Log Kp (skin permeability coefficient). Based on these similar profiles, it can be concluded that experimental data (respiratory and skin sensitization) from these three anhydrides can be read across to citraconic anhydride.

For details see attached report.

Conclusions

The results of the QSAR analysis indicate that

1. Maleic anhydride, benzene-1,2,4-tricarboxylic acid 1,2-anhydride and phthalic anhydride are potential skin and respiratory sensitizers and this agrees with experimental data.

2. Based on the similar profiles for these 4 substances, citraconic anhydride can be classified as skin Skin Sens. 1 H317) and respiratory (Resp. Sens. 1 H334) sensitizer.

References

United Nations Economic Commission for Europe (UNECE). (2004). Globally Harmonized System of Classification and Labelling of Chemicals (GHS). Respiratory or Skin Sensitization, Chapter 3.4. pp. 151-158. Retrieved here Sept. 1, 2007.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Justification for classification or non-classification

Based on the available data the substance is classified cat.1 skin and respiratory sensitizer.