4,4'-Isopropylidenediphenol, oligomeric reaction products with 1-chloro-2,3-epoxypropane, reaction products with [(dimethylamino)methyl]phenol and piperazine

Endpoint summary

Description of key information

In Vitro:

In silico assessment of test item is considered not applicable due to the complexity of encoding this UVCB substance. The OECD 442C in chemico Direct Peptide Reactivity Assay is not applicable for addressing Key Event 1 of the skin sensitization Adverse Outcome Pathway (AOP) for complex UVCB substances. Furthermore, the two in vitro test guidelines that have been proposed for addressing Key Events 2 and 3 of the AOP , OECD 442D and OECD 442E, are considered not applicable to test item due to the poor solubility of the substance in water and organic solvents, the complex nature of the UVCB, differing estimated log Pow values, unknown toxicities of the individual constituents and their ability to interfere with the test systems. Hence negative results in these in vitro tests could not be used with confidence in an assessment of skin sensitization potential, whereas inconclusive or positive results would require testing in vivo in order to conclude on classification of the substance. Therefore, in consideration of the various points highlighted regarding non-applicability of the in silico methods, and in chemico and in vitro tests for assessment of test item, it is not possible to form a conclusion on classification of the substance without conduct of an in vivo study, this being an OECD 429 Local lymph node assay (LLNA) as required by REACH.

LLNA:

A study was performed to assess the skin sensitization potential of the test item in the CBA/Ca strain mouse following topical application to the dorsal surface of the ear based on OECD 429.

Three groups, each of four animals, were treated with 50 μL (25 μL per ear)of the test item as a suspension in proplyene glycol at concentrations of 10% 5% or 2.5% w/w. A further group of four animals was treated with proplyene glycol alone.

The Stimulation Index expressed as the mean radioactive incorporation for each treatment group divided by the mean radioactive incorporation of the vehicle control group are 1.71, 2.00, 2.93 for concentrations of 10%, 5% or 2.5% w/w, respectively.

The test item was considered to be a non-sensitizer under the conditions of the test as no concentration of the test item resulted in a threefold or greater increase in 3HTdR incorporation compared to control values.

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Reference 1

Endpoint:

skin sensitisation: in vivo (LLNA)

Type of information:

experimental study

Adequacy of study:

key study

Study period:

01 February 2018 - 27 February 2018

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay)

Version / remarks:

2010

Deviations:

no

Qualifier:

according to guideline

Guideline:

EU Method B.42 (Skin Sensitisation: Local Lymph Node Assay)

Version / remarks:

EC No. 440/2008

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Type of study:

mouse local lymph node assay (LLNA)

Specific details on test material used for the study:

Batch Number: 161129
Purity: 100%
Appearance: pale brown powder
Expiry Date: 28 November 2018

Species:

mouse

Strain:

CBA/Ca

Sex:

female

Details on test animals and environmental conditions:

Female CBA/Ca (CBA/CaOlaHsd) strain mice were supplied by Envigo RMS B.V., Inc., Horst, The Netherlands. On receipt the animals were randomly allocated to cages. The animals were nulliparous and non pregnant. After an acclimatization period of at least 5 days the animals were selected at random and given a number unique within the study by indelible ink marking on the tail and a number written on a cage card. At the start of the study the animals were in the weight range of 15 to 23 g, and were 8 to 12 weeks old.

The animals were housed in suspended solid floor polypropylene cages furnished with softwood woodflakes. Free access to mains tap water and food (2014C Teklad Global Rodent diet supplied by Envigo RMS (UK) Limited, Oxon, UK) was allowed throughout the study.
The temperature and relative humidity were set to achieve limits of 19 to 25 ℃ and 30 to 70%, respectively. The rate of air exchange was at least fifteen changes per hour and the lighting was controlled by a time switch to give 12 hours continuous light and 12 hours darkness.

Vehicle:

propylene glycol

Concentration:

10%, 5% or 2.5% w/w in proplyene glycol

No. of animals per dose:

four

Details on study design:

As no toxicological information was available regarding the systemic toxicity/irritancy potential of the test item, a preliminary screening test was performed using mice, one mouse per test item concentration. The mice were treated by daily application of 25 µL of the test item at concentrations of 25 or 10% w/w in proplyene glycol, to the dorsal surface of each ear for three consecutive days (Days 1, 2, 3). The mice were observed twice daily on Days 1, 2 and 3 and once daily on Days 4, 5 and 6. Local skin irritation was scored daily. Any clinical signs of toxicity, if present, were also recorded. The body weight of each mouse was recorded on Day 1 (prior to dosing) and on Day 6.

MAIN STUDY
Groups of four mice were treated with the test item at concentrations of 10%, 5% or 2.5% w/w in proplyene glycol. The preliminary screening test suggested that the test item would not produce systemic toxicity or excessive local skin irritation at the highest suitable concentration. The mice were treated by daily application of 25 µL of the appropriate concentration of the test item to the dorsal surface of each ear for three consecutive days (Days 1, 2, 3). The test item formulation was administered using an automatic micropipette and spread over the dorsal surface of the ear using the tip of the pipette.
A further group of four mice received the vehicle alone in the same manner.

Statistics:

not specified

Positive control results:

not specified

Key result

Parameter:

SI

Value:

1.71

Variability:

not specified

Test group / Remarks:

2.5 (%w/w)

Remarks on result:

no indication of skin sensitisation based on QSAR/QSPR prediction

Key result

Parameter:

SI

Value:

2

Variability:

not specified

Test group / Remarks:

5 (%w/w)

Remarks on result:

no indication of skin sensitisation based on QSAR/QSPR prediction

Key result

Parameter:

SI

Value:

2.93

Variability:

not specified

Test group / Remarks:

10 (%w/w)

Remarks on result:

no indication of skin sensitisation based on QSAR/QSPR prediction

Body weight change of the test animals between Day 1 and Day 6 was comparable to that observed in the corresponding control group animals over the same period.

Interpretation of results:

GHS criteria not met

Conclusions:

The test item was considered to be a non-sensitizer under the conditions of the test as no concentration of the test item resulted in a threefold or greater increase in 3HTdR incorporation compared to control values.

Executive summary:

A study was performed to assess the skin sensitization potential of the test item in the CBA/Ca strain mouse following topical application to the dorsal surface of the ear based on OECD 429.

Three groups, each of four animals, were treated with 50 μL (25 μL per ear)of the test item as a suspension in proplyene glycol at concentrations of 10% 5% or 2.5% w/w. A further group of four animals was treated with proplyene glycol alone.

The Stimulation Index expressed as the mean radioactive incorporation for each treatment group divided by the mean radioactive incorporation of the vehicle control group are 1.71, 2.00, 2.93 for concentrations of 10% 5% or 2.5% w/w, respectively.

The test item was considered to be a non-sensitizer under the conditions of the test as no concentration of the test item resulted in a threefold or greater increase in 3HTdR incorporation compared to control values.

Reference 2

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 the available in vitro test methods are not applicable for the substance and therefore an in vivo skin sensitisation study was conducted

Justification for type of information:

JUSTIFICATION FOR DATA WAIVING
In silico assessment of test item is considered not applicable due to the complexity of encoding this UVCB substance. The OECD 442C in chemico Direct Peptide Reactivity Assay is not applicable for addressing Key Event 1 of the skin sensitization Adverse Outcome Pathway (AOP) for complex UVCB substances. Furthermore, the two in vitro test guidelines that have been proposed for addressing Key Events 2 and 3 of the AOP, OECD 442D and OECD 442E, are considered not applicable to test item due to the poor solubility of the substance in water and organic solvents, the complex nature of the UVCB, differing estimated log Pow values, unknown toxicities of the individual constituents and their ability to interfere with the test systems. Hence negative results in these in vitro tests could not be used with confidence in an assessment of skin sensitization potential, whereas inconclusive or positive results would require testing in vivo in order to conclude on classification of the substance. Therefore, in consideration of the various points highlighted regarding non-applicability of the in silico methods, and in chemico and in vitro tests for assessment of test item, it is not possible to form a conclusion on classification of the substance without conduct of an in vivo study, this being an OECD 429 Local lymph node assay (LLNA) as required by REACH.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not sensitising)

Respiratory sensitisation

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Skin sensitisation:

in vivo: LLNA, SI max: 2.93< 3, not sensitising

in vitro: waived as the available in vitro test methods are not applicable for the substance

 

Respiratory sensitisation:

No data available, not minimum required data.

 

Classification:

Skin: The stimulation indexes were below 3 in all tested concentrations in the murine local lymph node assay (OECD 429). Based on criteria from Regulation (EC) 1272/2008 and amendments, the substance does not have to be classified as a skin sensitiser.