Oligomeric reaction products of 4,4'-propane-2,2-diyldiphenol and 2-methyloxirane and 2-(chloromethyl)oxirane

Endpoint summary

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Reference

Endpoint:

skin sensitisation: in vivo (LLNA)

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

26 July 2012 - 21 August 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: GLP compliant study conducted in accordance with international guidelines.

Justification for type of information:

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Common functional groups and similar composition.

EP-4000s and the registered substance are very similar. They are UVBC substances and both are oligomeric reaction products of 4,4'-propane-2,2-diyldiphenol and 2-methyloxirane and 2-(chloromethyl)oxirane where constituents are structurally related. EP-4000s contains less than 0.1% monochlorinated constituents while the registered substance contains approximately 10% monochlorinated constituents. As these are otherwise structurally similar to other constituents it can be reasonably expected that EP-4000s and the registered substance will have essentially the same properties.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

EP4000s:
Purity 79.7-90%, 3 main components F, E, C
Impurities:
5 known by-products 18%
6 unknown impurities 2.4%
Water 0.1%
Chlorinated impurities <0.1%

Aliphaticdiol diglycidyl ether:
Purity 92.57%, 3 main components F, E, C
Impurities:
5 known by-products (same identity as EP-400s) 14.37%
Water none
Two new impurities (I and J) 10.48% in total

Further details are provided in Section 13 Assessment Reports

3. ANALOGUE APPROACH JUSTIFICATION

Terminal epoxides groups are known sensitizers and EP-4000s, which contains this group in its main components, has been tested and found to be a skin sensitizer with a positive result at all levels tested. Aliphaticdiol diglycidyl ether comprises 10% of new components which contain an epoxide group and therefore it can be expected that the same test result will be obtained if this new mixture was tested. As no new information would be obtained by the testing of Aliphaticdiol diglycidyl ether it is proposed that the test result for EP-4000s is read across and that Aliphaticdiol diglycidyl ether is classified as Skin Sens 1B.

Note: According to the OECD toolbox, primary alkyl chlorides are not a structural alert for sensitization so the only functional group to consider is the terminal epoxide group as discussed above.

Overall conclusion – no new information would be gained by testing Aliphaticdiol diglycidyl ether for skin sensitisation.

Reason / purpose for cross-reference:

read-across source

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

Qualifier:

according to guideline

Guideline:

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

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Type of study:

mouse local lymph node assay (LLNA)

Species:

mouse

Strain:

CBA

Sex:

female

Details on test animals and environmental conditions:

TEST ANIMALS
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 17.7 to 22.9 g
- Housing: Animals were housed inside a barriered rodent facility and were allocated without conscious bias to cages within the treatment groups.
They were housed two animals per cage, in solid bottomed polycarbonate cages with a stainless steel mesh lid. Each cage contained a quantity of autoclaved wood flake bedding, additionally Nestlets and a plastic shelter were included for environmental enrichment.
- Diet (e.g. ad libitum): standard rodent diet
- Water (e.g. ad libitum): Portable water taken from the public supply was freely available via polycarbonate bottles
fitted with sipper tubes.
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 23°C
- Humidity (%): 40-70%
- Photoperiod (hrs dark / hrs light): 12hrs dark/12hrs light

Vehicle:

acetone/olive oil (4:1 v/v)

Concentration:

25, 50% w/v and 'as supplied'

No. of animals per dose:

2 mice in the preliminary investigations and 4 female mice in each of the three treated groups

Details on study design:

TREATMENT PREPARATION AND ADMINISTRATION: The mice were treated by daily application of 25 µL of the appropriate concentration or control (vehicle or positive), to the dorsal surface of both ears for three consecutive days.

The proliferative response of the lymph node cells (LNC) from the draining auricular lymph nodes was assessed five days following the initial application, by measurement of the incorporation of 3H-methyl Thymidine (3HTdR) by B-scintillation counting of LNC suspensions.
The response was expressed as radioactive disintegrations per minute per lymph node (dpm/node) and as the ratio of 3HTdR incorporation into LNC
of test nodes relative to that recorded for control nodes (test/control ratio), termed as Stimulation Index (SI).

Positive control substance(s):

hexyl cinnamic aldehyde (CAS No 101-86-0)

Positive control results:

The SI for the positive control substance hexyl cinnamic aldehyde was 4.0, which demonstrates the validity of this study.

Parameter:

SI

Value:

3.8

Remarks on result:

other: for 25% w/v

Parameter:

SI

Value:

6.3

Remarks on result:

other: for 50% w/v

Parameter:

SI

Value:

9.3

Remarks on result:

other:

Remarks:

for "As supplied"

Parameter:

other: disintegrations per minute (DPM)

Remarks on result:

other: Concentration Disintegrations per minute 25% w/v 37484.5 50% w/v 61784.4 'As supplied' 55089.9

Preliminary investigation:

There were no deaths and no signs of ill health or toxicity were observed during this study.

No erythema was observed on the ears of either mouse on Days 1 to 6.

There was no evidence of an effect of treatment on ear thickness.

There was no indication of an overt effect of treatment on bodyweight gain.

Main phase:

There were no deaths and no signs of ill health or toxicity were observed during this study.

No signs of dermal irritation were seen on the ear during the study.

There was no indication of an effect of treatment on bodyweight gain.

Interpretation of results:

sensitising

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

Potential skin sensitizer with an EC3 value calculated to be 20% w/v.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed (sensitising)

Additional information:

The study was performed (Huntingdon Life Sciences, 2012) to assess the skin sensitization potential of EP-4000S using the

local lymph node assay (LLNA). The study was designed to meet the requirements of the following guidelines: OECD Guideline 429 (Skin Sensitisation: Local Lymph Node Assay) and EU Method B.42 (Skin Sensitisation: Local Lymph Node Assay). EP-4000S was found to have induced skin sensitisation in the exposed animals; the experimentally derived EC3 value was 20% (w/v).

On this basis EP-4000S was classified as skin sensitiser Category 1B (EC3 value > 2 %).

The results discussed above for EP-4000s will be read across to Aliphaticdiol diglycidyl ether.

Justification for read across justification - EP-4000s and Aliphaticdiol diglycidyl ether are very similar substances. They are UVBC subtances and both are oligomeric reaction products of 4,4'-propane-2,2-diyldiphenol and 2-methyloxirane and 2-(chloromethyl)oxirane where consituents are structurally related. EP-4000s contains less than 0.1% monochlorinated consitiuents while Aliphaticdiol diglycidyl ether contains approximately 10% monochlorinated constituents, but as these are otherwise structurally similar to other constituents it can be reasonably expected that EP-4000s and Aliphaticdiol diglycidyl ether will have essentially the same properties.

Terminal epoxides groups are known sensitizers and EP-4000s, which contains this group in its main components,  has been tested and found to be a skin sensitizer with a positive result at all levels tested.

Aliphaticdiol diglycidyl ether comprises 10% of new components which contain an epoxide group and therefore it can be expected that the same test result will be obtained if this new mixture was tested.  As no new information would be obtained by the testing of Aliphaticdiol diglycidyl ether it is proposed that the test result for EP-4000s is read across and that Aliphaticdiol diglycidyl ether is classified as Skin Sens 1B.

 

Note: According to the OECD toolbox, v3, primary alkyl chlorides are not a structural alert for sensitization so the only functional group to consider is the terminal epoxide group as discussed abov

On this basis Aliphaticdiol diglycidyl ether is classified as skin sensitiser Category 1B (EC3 value > 2 %).

Migrated from Short description of key information:

Aliphaticdiol diglycidyl ether is regarded as a potential skin sensitizer. The EC3 value was calculated to be 20% w/v.

Justification for selection of skin sensitisation endpoint:

The Local Lymph Node Assay in the Mouse was conducted in accordance with GLP and to international guidelines and is therefore reliable and has been designated the key study.

Justification for classification or non-classification

As noted above, EP-4000S was found to have induced skin sensitisation in a murine Local Lymph Node Assay. The experimentally determined EC3 value was 20% (w/v); on the basis that this is greater than 2% EP-4000S meets the criteria for a Category 1B skin sensitiser according to the CLP Regulation (Regulation (EC) 1272/2008, as amended by the second Adaptation to Technical and scientific Progress by Regulation (EC) 286/2011).

No information is available regarding respiratory sensitisation for EP-4000S; there is therefore no basis by which to consider a classification for this endpoint.