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Administrative data

Description of key information

Data is available for propylene glycol dibenzoate (PGDB). This data is supported by relevant information available from a structural analogue Dipropylene glycol dibenzoate (DPGDB). The justification for read across is presented as an attachment included in Section 13 of the IUCLID dossier.

Local Lymph Node Assay (LLNA) - Weak sensitiser

Read Across Guinea Pig Maximization Test (GPMT) - Not a skin sensitiser

QSAR (DEREK Nexus) and Expert Judgement - Not a skin sensitiser

Based on the cumulative weight of evidence available, it is concluded that PGDB does not have significant skin sensitisation potential

Key value for chemical safety assessment

Skin sensitisation

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted to approved guidelines and in compliance with GLP
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)
Remarks:
Copy of certificate of compliance from UK GLP Monitoring Authority included in report
Type of study:
mouse local lymph node assay (LLNA)
Species:
mouse
Strain:
other: CBA/Ca
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: UK
- Age at study initiation: 8-12 weeks
- Weight at study initiation: 17.2 to 21.5 g
- Housing: 2 per cage
- Diet: ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: >6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19-23 deg C
- Humidity (%): 40-70%
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12 h dark/12 h light

IN-LIFE DATES: From: 24 April 2014 To: 2 June 2014
Vehicle:
acetone/olive oil (4:1 v/v)
Concentration:
as supplied and then 50% and 25% of "as supplied" solution
No. of animals per dose:
2 - preliminary study
4 - main study
Details on study design:
The results of the preliminary investigations indicated that ‘as supplied’ was a suitable high concentration for administration in the main phase of the study. The low and intermediate concentrations were selected from the concentration series given in regulatory guidelines and
the concentrations administered on the main study were:

25, 50% v/v in AOO and ‘as supplied’

The positive control group received 25% v/v hexylcinnamic aldehyde in AOO based on previous experience at this laboratory.

Main phase
Groups of four mice were treated at one of three concentrations of the test substance. The mice were treated by daily application of 25 µL of the appropriate concentration of the test substance to the dorsal surface of each ear for three consecutive days (Days 1-3). The test substance was applied to the dorsal surface of each ear using an automatic micropipette and was spread over the entire dorsal surface of the ear using the tip of the pipette. Further groups of four mice received the vehicle alone or the positive control substance in the same manner and a sham control group was treated by the tip of an empty pipette being passed over the surface of the ear.

Administration of 3H-methyl Thymidine
In the main phase of the study, five days following the first topical application of test substance (Day 6) all mice were injected via the tail vein with 250 µL of phosphate buffered saline containing 3H-methyl Thymidine (3HTdR: 80 µCi/mL) giving a nominal 20 µCi to each mouse. The injection into the tail vein was carried out using a plastic syringe and needle after the mouse had been heated in a warming chamber
Positive control substance(s):
hexyl cinnamic aldehyde (CAS No 101-86-0)
Statistics:
None stated
Key result
Parameter:
SI
Value:
0.9
Test group / Remarks:
5% v/v PDGB
Key result
Parameter:
SI
Value:
1.6
Test group / Remarks:
50% v/v PGDB
Key result
Parameter:
SI
Value:
6.3
Test group / Remarks:
as supplied’ PGDB
Key result
Parameter:
SI
Value:
10.6
Test group / Remarks:
Positive Control - hexyl cinnamic aldehyde (HCA)
Key result
Parameter:
EC3
Value:
52.2
Test group / Remarks:
PGDB
Key result
Parameter:
SI
Remarks on result:
other: see Remark
Remarks:
The SI (test/control ratios) obtained for 25, 50% v/v and ‘as supplied’ PGDB were 0.9, 1.6 and 6.3 respectively. As a SI of 3 or more was recorded for the highest concentration tested (as supplied), PGDB was considered to have the potential to cause skin sensitization. Based on the results of this study the EC3 value is calculated to be 52.2% v/v. The SI for the positive control substance hexyl cinnamic aldehyde (HCA) was 10.6 which demonstrates the validity of this study.
Key result
Parameter:
other: disintegrations per minute (DPM)
Remarks on result:
other: see Remark
Remarks:
Group 3 sham control: 6808.35 dpm and 851.04 dpm/node Group 4 vehicle: 5119-65 dpm and 639.96 dpm/node Group 5 25% v/v: 9756.55 dpm and 1219.57 dpm/node Group 6 50% v/v: 19744.35 dpm and 2468.04 dpm/node Group 7 as supplied 26483.75 dpm and 3310.47 dpm/node Group 8 HCA 25% v/v 71843.55 dpm and 8980.44 dpm/node
Interpretation of results:
other: Sensitising
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
Based on an LLNA study, PGDB is regarded as a potential skin sensitizer. The EC3 value was calculated to be 52.2% v/v.
Executive summary:

The SI (test/control ratios) obtained for 25, 50% v/v and ‘as supplied’ PGDB were 1.4, 2.9 and 5.2 respectively. As a SI of 3 or more was recorded for the highest concentration tested (as supplied), PGDB was considered to have the potential to cause skin sensitization. Based on the results of this study the EC3 value is calculated to be 52.2% v/v. The SI for the positive control substance hexyl cinnamic aldehyde (HCA) was 10.6 which demonstrates the validity of this study.

PGDB is regarded as a potential skin sensitizer.

Endpoint:
skin sensitisation, other
Remarks:
other: in silico QSAR assessment
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Widely available and used Industry In silico modelling programme used to assess skin sensitisation endpoint
Justification for type of information:
QSAR prediction
Qualifier:
no guideline followed
Principles of method if other than guideline:
The structure of PGDB was assessed by DEREK NEXUS which is a knowledge-based expert system designed to apply structure-activity relationships to compounds for which little or no data exists and hence to aid in the assessment of their potential toxicity. Any predictions made by DEREK NEXUS should be used in conjunction with other assessment techniques. As with all In Silico modelling programmes the results of the predictions are very reliant upon information that is available in databases, which occasionally may incorrectly predict a compound to be non-toxic.
The DEREK NEXUS knowledge base contains a large number of rules that associate a chemical structure with one or more toxicity endpoints. When a structural alert is identified a reasoning programme assigns a probability to the expression of toxicity by the test compound.
GLP compliance:
no
Remarks:
QSAR
Justification for non-LLNA method:
in silico QSAR assessment
Remarks on result:
other: The structure of propylene glycol dibenzoate assessed by DEREK Nexus did not trigger any alerts for skin sensitisation.

DEREK NEXUS is a knowledge-based expert system designed to apply structure-activity relationships to compounds for which little or no data exists and hence to aid in the assessment of their potential toxicity. DEREK NEXUS was developed from DEREK for Windows and is being continually refined as new knowledge becomes available. Any predictions made by DEREK NEXUS should be used in conjunction with other assessment techniques. As with all In Silico modelling programmes the results of the predictions are very reliant upon information that is available in databases, which occasionally may incorrectly predict a compound to be non-toxic.

 

The DEREK NEXUS knowledge base contains a large number of rules that associate a chemical structure with one or more toxicity endpoints. When a structural alert is identified a reasoning programme assigns a probability to the expression of toxicity by the test compound. 

The potential skin sensitisation of propylene glycol dibenzoate was assessed using the toxicity prediction programme DEREK NEXUS.

The endpoints searched were:


Skin sensitisation                                  Photoallergenicity

  

Toxicity to the following groups was assessed: mammals and bacteria

Interpretation of results:
other: Not sensitising
Remarks:
Criteria used for interpretation of results: other: In silico modelling assessment
Conclusions:
The structure of propylene glycol dibenzoate assessed by DEREK Nexus did not trigger any alerts for skin sensitisation.
Executive summary:

The structure of propylene glycol dibenzoate assessed by DEREK Nexus did not trigger any alerts for skin sensitisation.

Endpoint:
skin sensitisation: in vivo (non-LLNA)
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
23 July 1997 - 22 August 1997
Reliability:
1 (reliable without restriction)
Justification for type of information:
A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.
Reason / purpose for cross-reference:
read-across: supporting information
Qualifier:
according to guideline
Guideline:
EPA OTS 798.4100 (Skin Sensitisation)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EU Method B.6 (Skin Sensitisation)
Deviations:
no
Qualifier:
according to guideline
Guideline:
OECD Guideline 406 (Skin Sensitisation)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Notification Yakushin 1 No. 24 11 September 1989, Pharmaceutical Affairs Bureau, MOHW "Skin Sensitization Tests".
Deviations:
no
GLP compliance:
yes
Type of study:
guinea pig maximisation test
Justification for non-LLNA method:
Scientifically acceptable GMPT asay conducted prior to the date that the revised guidance was issued.
Species:
guinea pig
Strain:
Dunkin-Hartley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: D Hall, Newchurch, Staffordshire, England
- Age at study initiation: Approximately 4 to 7 weeks
- Weight at study initiation: 325 to 438 g
- Housing: Housed in groups of five in suspended metal cages with wire mesh floors.
- Diet: Vitamin C enriched guinea pig diet FD2 was provided ad libitum. Hay was given weekly.
- Water: drinking water providede ad libitum
- Acclimation period: 5 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 to 28.5°C
- Humidity (%): 44 to 66%
- Air changes (per hr): 15
- Photoperiod: 12 hours light per 24 hour period


IN-LIFE DATES: From: 23 July 1997 To: 22 August 1997
Route:
intradermal and epicutaneous
Vehicle:
other: None for induction injection and application; Alembicol D for the challenge application.
Concentration / amount:
Used as supplied for topical and intradermal injection induction exposures; Used as supplied and as 50% (v/v) in Alembicol D for the topical challenge exposure.
Route:
epicutaneous, semiocclusive
Vehicle:
other: None for induction injection and application; Alembicol D for the challenge application.
Concentration / amount:
Used as supplied for topical and intradermal injection induction exposures; Used as supplied and as 50% (v/v) in Alembicol D for the topical challenge exposure.
No. of animals per dose:
20 for test substance group and test substance vehicle control group; 10 for positive control group and vehicle control group to positive control group.
Details on study design:
RANGE FINDING TESTS:
The intradermal and topical irritancy of a range of dilutions of the test substance was investigated to identify where possible (a) concentrations of the test substance that would produce irritation suitable for the induction phase of the main study and (b) a maximum non-irritant concentration by the
topical route of administration for the challenge phase. Animals for these investigations were pre treated with an intradermal injection of Freund's
complete adjuvant (FCA) 50:50 with water for irrigation (Ph Eur) at least one week prior to the start of the preliminary investigations.

The procedure employed for these investigations was as follows:
Intradermal injections - Intradermal injections (0.1 mL/site) were made into the clipped flank of a total of four guinea pigs, using a range of
concentrations of the test material in a suitable vehicle. As no adverse reactions were observed for the first two guinea pigs receiving concentrations 0.1 - 10% v/v, further concentrations (20-100% v/v) were investigated. The resulting dermal responses were assessed approximately 24 and 72
hours later.

Topical application - Approximately 0.5 mL of each of a range of concentrations of the test substance in a suitable vehicle was applied to patches of
surgical gauze (20 x 20mm). These were placed on the clipped and shaved flanks of each of four guinea pigs. The patches were covered by a strip of "Blenderm" and firmly secured by "Elastoplast" wound round the trunk and covered with "Sleek impervious" plastic adhesive tape. After an exposure
period of approximately 6 hours, the dressings were removed and the reaction sites were assessed for erythema and oedema on a numerical basis
according to the system given. Further examination ofthe sites was carried out approximately 24 and 48 hours after removal of the dressings.

MAIN STUDY
A. INDUCTION EXPOSURE
- No. of exposures: 2 (One by intradermal injections, one by topical application)
- Exposure period: 8 days (6 days following injections plus two days following dermal application).
- Test groups: 1) FCA in water (50/50 v/v); 2) Test substance as supplied; 3) Test substance in FCA (50/50 v/v).
- Control group: Vehicle control for test substance, Positive control (hexyl cinnamic aldehyde (HCA)), Vehicle control for positive control.
- Site: Scapular region
- Frequency of applications: As noted above.

B. CHALLENGE EXPOSURE
- No. of exposures: 1
- Day(s) of challenge: One day, two weeks after topical induction.
- Exposure period: 24 hours
- Test groups: Test group and vehicle control group were exposed to 0.2 mL test substance and 0.2 mL test substance in Alembicol D (50% v/v).
- Control group: Positive control groups were exposed to HCA and HCA 50% in Alembicol D
- Site: Test substance or HCA as supplied was applied to an anterior site; test substance or HCA in Alembicol D was applied to the posterior site.
- Evaluation (hr after challenge): 24 and 48

Challenge controls:
The control and test animals were challenged topically two weeks after the topical induction application using Benzoflex 9- 88 as supplied and 50% v/v in Alembicol D.
Positive control substance(s):
yes
Remarks:
Hexyl cinnamic aldehyde
Positive control results:
Evidence of skin sensitization was produced by hexyl cinnamic aldehyde (HCA) in all ten test animals thus confirming sensitivity of this test method.
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
test chemical
Dose level:
0.2 mL, material as supplied or 50% in Alembicol
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
No signs of ill health or toxicity were recorded.
Remarks on result:
other: see Remark
Remarks:
Reading: 1st reading. . Hours after challenge: 24.0. Group: test group. Dose level: 0.2 mL, material as supplied or 50% in Alembicol. No with. + reactions: 0.0. Total no. in groups: 20.0. Clinical observations: No signs of ill health or toxicity were recorded..
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
test chemical
Dose level:
0.2 mL, material as supplied or 50% in Alembicol
No. with + reactions:
0
Total no. in group:
20
Clinical observations:
No signs of ill health or toxicity were recorded.
Remarks on result:
other: see Remark
Remarks:
Reading: 2nd reading. . Hours after challenge: 48.0. Group: test group. Dose level: 0.2 mL, material as supplied or 50% in Alembicol. No with. + reactions: 0.0. Total no. in groups: 20.0. Clinical observations: No signs of ill health or toxicity were recorded..
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
positive control
Dose level:
10% v/v
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
evidence of skin sensitization
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
positive control
Dose level:
10% v/v
No. with + reactions:
10
Total no. in group:
10
Clinical observations:
evidence of skin sensitization
Remarks on result:
positive indication of skin sensitisation
Key result
Reading:
1st reading
Hours after challenge:
24
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no evidence of skin sensitization
Remarks on result:
no indication of skin sensitisation
Key result
Reading:
2nd reading
Hours after challenge:
48
Group:
negative control
Dose level:
0
No. with + reactions:
0
Total no. in group:
10
Clinical observations:
no evidence of skin sensitization
Remarks on result:
no indication of skin sensitisation
Interpretation of results:
other: Not sensitising
Remarks:
Criteria used for interpretation of results: EU
Conclusions:
In this study DPGDB did not produce evidence of skin sensitization (delayed contact hypersensitivity) in any of the twenty test animals.
Evidence of skin sensitization was produced by hexyl cinnamic aldehyde (HCA) in all of the ten positive control test animals thus confirming the sensitivity of the method.
Executive summary:

Key data is available for propylene glycol dibenzoate (PGDB). This data is supported by relevant information available from a structural analogue Dipropylene glycol dibenzoate (DPGDB). The justification for read across is presented as an attachment included in Section 13 of the IUCLID dossier.

A study was performed to assess the skin sensitization potential of the test substance DPGDB to guinea pigs. The study was conducted in accordance with OECD, EC and US EPA test guidelines, and in compliance with GLP.

The test substance was used as supplied for topical and intradermal injection induction exposures and as supplied and as a 50% (v/v) solution in Alembicol D for topical challenge exposure.

Hexyl cinnamic aldehyde was used as positive control. Evidence of skin sensitization was seen in all animals treated with this substance, but no reactions were observed in the control group, confirming the sensitivity of the method. 

No evidence of toxicity or ill health were recorded for any animal exposed to the test substance. There were no dermal reactions seen in any of the test animals, therefore all these animals gave negative responses.

DPGDB did not produce evidence of skin sensitization (delayed contact hypersensitivity) in any of the animals tested.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed (sensitising)
Additional information:

Data is available for propylene glycol dibenzoate (PGDB). This data is supported by relevant information available from a structural analogue Dipropylene glycol dibenzoate (DPGDB). The justification for read across is presented as an attachment included in Section 13 of the IUCLID dossier.

In an OECD Guideline 429 LLNA study (Huntingdon Life Sciences, 2014f; Klimisch score = 1), the SI (test/control ratios) obtained for 25, 50 % v/v and ‘as supplied’ PGDB were 1.4, 2.9 and 5.2, respectively. As a SI of 3 or more was recorded for the highest concentration tested (as supplied), PGDB was considered to have the potential to cause skin sensitization. Based on the results of this study the EC3 value was calculated to be 52.2% v/v. The SI for the positive control substance hexyl cinnamic aldehyde (HCA) was 10.6 which demonstrates the validity of this study. In this local lymph node assay, PGDB was considered to be a potential skin sensitizer.

The structure of propylene glycol dibenzoate was also assessed by DEREK Nexus (LSR Associates Ltd., 2014; Klimisch score = 2) and did not trigger any alerts for skin sensitisation. A weight of evidence assessment (Earl, L., 2015) concluded that PGDB does not have significant skin sensitisation potential and should not be classified as a skin sensitizer (This expert judegment report is presented as an attachment in Section 13 of the IUCLID dossier). Additionally, in a OECD Guideline 406 guinea pig maximization study (Huntingdon Life Sciences, 1998j; Klimisch score = 1), conducted according to Magnusson & Kligman, the skin sensistisation potential of DPGDB was evaluated in guinea pigs. Evidence of skin sensitization was seen in all animals treated by the positive control substance, Hexyl cinnamic aldehyde, confirming the sensitivity of the method. Guinea pigs were treated with stock DPGDB for the intradermal injection (as 50:50 in FCA) and topical induction phases, and stock and 50% in Alembicol D for the topical challenge phase. At the end of the challenge phase, no positive reactions were observed in the test material-treated animals.

Based on the cumulative weight of evidence available, it is concluded that PGDB does not have significant skin sensitisation potential and should not be classified as a skin sensitizer according to CLP (Regulation (EC) No 1272/2008).

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

Data is available for propylene glycol dibenzoate (PGDB). This data is supported by relevant information available from a structural analogue Dipropylene glycol dibenzoate (DPGDB). The justification for read across is presented as an attachment included in Section 13 of the IUCLID dossier.

LLNA data is available and shows that PGDB is a very weak skin sensitiser. A weight of evidence assessment of the skin sensitization hazard of PGDB (Earl, L., 2015) has been generated to ensure that the correct decision is taken on the classification of PGDB as a skin sensitiser/non sensitiser. The report contains a review of LLNA accuracy of predictions, physicochemical and hazard data of the substance, its metabolites and impurities and closely related substances and computational prediction tools to detect skin sensitisation structural alerts. Taking into consideration the weight of evidence available from the LLNA assay, the expert judgement report, and resutls from the guinea pig maximization test conducted using structural analogue DPGDB, it was concluded that PGDB does not have significant skin sensitisation potential and should therefore, not be classified as a skin sensitizer according to the EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008.