Registration Dossier

Diss Factsheets

Administrative data

Description of key information

Key value for chemical safety assessment

Skin sensitisation

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not sensitising)
Additional information:

Justification for grouping of substances and read-across

The PFAE Linear (Polyfunctional Aliphatic Ester) category consists of 16 substances, well-defined mono-constituent substances as well as related UVCB substances, respectively with varying fatty alcohol chain lengths and branching. The distinguishing feature of this category of chemicals is that they are diester derivatives of common dicarboxylic acids: namely adipic (C6), azelaic (C9) and sebacic (C10) acids. The alcohol portion of the diesters generally falls in the C3-C20 carbon number range, including linear and branched, even and odd numbered alcohols. 

In order to avoid the need to test every substance for every endpoint, the category concept is applied for the assessment of environmental fate and environmental and human health hazards. Thus where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group by interpolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, for each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across.

A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Sections 7.1 and 13) and within Chapter 5.1 of the CSR.

Endpoint specific data matrix:

 

ID No.

CAS

Skin Sensitisation

#1

6938-94-9 (a)

RA: CAS 105-99-7

#2

105-99-7

not sensitising

#3

110-33-8

RA: CAS 105-99-7

#4

1330-86-5

RA: CAS 105-99-7
RA: CAS 16958-92-2

#5

123-79-5 (b)

--

#6

103-23-1

--

#7

68515-75-3

--

#8

33703-08-1

--

#9

16958-92-2

not sensitising (human)

#10

85117-94-8

--

#11

103-24-2

inconclusive

#12

897626-46-9

not sensitising

#13

7491-02-3

not sensitising

not sensitising (human)

#14

109-43-3

RA: CAS 105-99-7

#15

122-62-3

RA: CAS 105-99-7

#16

69275-01-0

not sensitising

(a) Category members subject to registration are indicated in bold font. Only for these substances a full set of experimental results and/or read-across is given.

(b) Substances not subject to registration are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

 

Skin sensitisation

Diester of Adipic acid

CAS 105-99-7

The skin sensitising potential of Dibutyl adipate (CAS 105-99-7) was studied in female guinea pigs according to the maximisation method described in OECD guideline 406 (Mürmann, 1989).

In the induction phase, intradermal injections of the test substance at 20% in maize oil and/or FCA were applied into the clipped skin area of 20 animals. A control group, consisting of 10 animals, was injected with vehicle only and/or FCA. Since a preliminary study showed that the undiluted test substance did not induce skin irritation, the test area of control and treated animals was pre-treated with 10% sodium lauryl sulphate in vaseline to induce local irritation on Day 7. 24 hours later, the epicutaneous induction treatment with the undiluted test substance (100%) or the vehicle alone was conducted in the treated or control animals on the regions of intradermal injections for a period of 48 h. On Day 22, the challenge treatment was performed by topical application of the undiluted test substance to the skin of all animals for 24 h. No changes in body weight gain were observed between treated and control animals. No cutaneous reactions were provoked 24 and 48 h after challenge treatment with the undiluted test substance in any of the animals of the test and control groups. Therefore, the test substance had no sensitising effect on guinea pigs under the chosen experimental conditions.

Further evidence for the non-sensitising effects of Dibutyl adipate is provided from another study in guinea pigs (Potokar, 1972). Five guinea pigs were induced with the test substance at a concentration of 25% in oil by repeated intracutaneous injection (10 times) into the paravertebral shaved skin at intervals of 2 days. An additional group of 5 animals served as controls. Fourteen days after the final application, a single intracutaneous challenge treatment with the test substance at 25% in oil was performed in treated and control animals. No skin reactions were provoked in the animals of the test and control groups after challenge treatment.

In summary, based on the results in guinea pigs Dibutyl adipate is considered not to be sensitising to skin.

 

CAS 16958-92-2

In a study similar to OECD guideline 406, the skin sensitisation potential of Bis(tridecyl) adipate (CAS 16958-92-2) was investigated in female guinea pigs according to the non-adjuvant Buehler method (Bailey, 1986).

Based on a primary irritation test, the induction treatment of the main assay was performed with the test substance at concentrations of 50% (w/w) in Squibb Mineral oil. In the induction phase, the diluted test substance was applied to the clipped skin of the flank of 10 animals using an occlusive dressing. During induction, three consecutive topical applications for a period of 6 h were performed at intervals of 7 days. A group of 10 animals served as controls. After a 19-day rest period, the challenge exposure was performed in control and treated animals. Since the test substance at 50% solution caused significant dermal responses, test substance at a concentration of 25% in Squibb Mineral oil was used for challenge treatment. The test substance was applied to the clipped skin of the right flank of the animals for 6 h and skin reactions were evaluated 24 and 48 h after application. The test substance at 25% (w/w) solution caused positive skin reactions in 9/10 treated animals 24 and 48 h after challenge exposure. Since positive reactions were also observed in the control group, a rechallenge was performed one week later. The treated animals and additional 5 (naïve) control animals were rechallenged with test substance at concentrations of 12.5% and 20% in Squibb Mineral oil. At 24 and 48 h reading, positive skin reactions were seen in 3/10 and 2/10 animals rechallenged with the test substance at 12.5%, whereas 4/10 animals at 24 and 48 h after rechallenge positively responded to 20% of the test solution. No positive skin reactions were observed in any of the animals of the control group. During the study no test substance-related clinical signs and no effects on body weight gain were observed. The sensitivity of the assay was confirmed with the positive control 2,4-Dinitrochlorobenzene (0.1% in 70% ethanol), which showed the expected results in the test animals (10/10 animals with positive results). Based on these results, the test substance was found to be a sensitiser in guinea pigs in the non-adjuvant Buehler test.

Thus, the skin sensitisation potential of Bis(tridecyl) adipate was further investigated in a Human Repeated Insult Patch Test (HRIPT) in 104 volunteers (Zimmermann, 1987). The undiluted test substance (0.2 mL) was applied to the skin of the back of 19 male and 85 female subjects, either under occlusive (55 subjects) or under semi-occlusive (49 subjects) conditions. A series of 9 induction patches were applied for a period of 3 weeks on Mondays, Wednesdays and Fridays. The patches with the test substance were removed after 24 hours, and reactions were scored after a rest period of 24 or 48 hours. After the induction phase, a further rest period of two weeks followed. Then, the challenge patch was applied for 24 hours to a virgin site of the back and reactions were scored after 24, 48, and 72 hours. No skin sensitisation reactions were observed in the subjects, neither under occlusive nor under semi-occlusive conditions. Based on these results, the test substance was not found to be a human skin sensitizer.

The non-sensitising potential of the test substance was further supported in a Human Repeated Insult Patch Test in 94 volunteers, which was performed under similar conditions as described above (Bailey, 1987). The test substance was applied to 43 subjects under occlusive conditions and 51 subjects under semi-occlusive conditions. No skin sensitisation reactions were scored 48, 72, and 96 hours after the 24-h challenge exposure, neither under occlusive nor under semi-occlusive conditions. Therefore, the test substance was not regarded to be a skin sensitizer under the conditions of this test.

Although the non-adjuvant Buehler test in female guinea pigs revealed a positive result (Bailey, 1986), there is strong evidence from the human sensitisation data to show that the test substance is not a sensitizer in humans.

 

Diester of Azelaic acid

CAS 103-24-2

The skin sensitising potential of Bis(2-ethylhexyl) azelate (CAS 103-24-2) was investigated in a Local Lymph Node Assay (LLNA) in mice according to OECD guideline 429 and in compliance with GLP (Bradshaw, 2012).

Based on a range-finding test in one female CBA/CaOlaHsd mouse, the undiluted test substance (100%) and concentrations of 25% and 50% (v/v) in acetone/olive oil (4:1 v/v) were selected for the treatment of mice in the main study. In this experiment, 4 female CBA/CaOlaHsd mice per test group were treated with the test substance or vehicle alone, respectively. The test substance or the vehicle were applied on the external surface of each ear (25 µL/ear) for three consecutive days. Five days after the first topical application, the cell proliferation of pooled lymph nodes per group was measured by incorporation of ³H-methyl thymidine and expressed as the amount of radioactive disintegration per minute (DPM). The DPM/lymph node for each test group were 5244.83, 5178.42 and 8048.58 at concentrations of 25%, 50% and 100% of the test substance, respectively. For the control group, a DPM/lymph node of 1553.82 was determined. Based on these results, stimulation indices of 3.38, 3.33 and 5.18 were calculated for treatment concentrations of 25%, 50% and 100%, respectively. No local or systemic toxicity and no effects on body weights were observed. The historical positive control substance α-Hexylcinnamaldehyde (25% in acetone:olive oil (4:1 v/v)) produced a stimulation index (SI) of 5.76, thus meeting the reliability criteria for the LLNA (SI > 3).

As no other category member showed sensitising potential, no structural alerts could be identified (OECD toolbox 3.0, 2012) for any of the category members, and the test substance is unlikely to penetrate the skin ( 0.00001 mg/cm²/event, QSAR, Danish EPA, 2010) the result of the above mentioned LLNA is regarded as inconclusive. To clarify the sensitising properties of the test substance a battery of vitro tests estimating the potential of protein adduct formation of the test substance or its metabolites in skin will be performed.

 

CAS 897626-46-9

In a study according to OECD guideline 406, the skin sensitisation potential of Bis(2-octyldodecyl) azelate (CAS 897626-46-9) was investigated in female guinea pigs according to the non-adjuvant Buehler method (Richeux, 2013).

Based on a primary irritation test, the induction treatment of the main assay was performed with the neat test substance (100%). In the induction phase, the test material was applied to the shorn skin of the scapular zone of 20 animals using an occlusive dressing. During induction, three consecutive topical applications for a period of 6 h were performed at intervals of 7 days. A group of 10 animals served as controls and received paraffin oil. After a 14-day rest period, the challenge exposure was performed in control and treated animals. The test substance was applied to the shorn skin of the left flank of the animals for 6 h and skin reactions were evaluated 24 and 48 h after application. Accordingly, a patch without test material was applied to the animals’ right flanks. No positive skin reactions were observed in any of the animals of the test group and the control group. During the study no mortality occurred and no effects on body weight gain were observed. The sensitivity of the test species was confirmed with the positive control substance α-Hexylcinnamaldehyde (CAS 101-86-0) routinously tested in this laboratory (data of the three latest positive control tests are provided in the study report).

Based on these results, Bis(2-octyldodecyl) azelate was found to be a not sensitising in guinea pigs under the conditions of the non-adjuvant Buehler test.

 

Diester of Sebacic acid

CAS 7491-02-3

The skin sensitising potential of Diisopropyl sebacate (CAS 7491-02-3) was studied in male and female Dunkin-Hartley guinea pigs according to the maximisation method described in OECD guideline 406 (Manciaux, 1999). In the induction phase, intradermal injections of the test substance at 75% in maize oil and/or FCA were applied into the skin at the shoulder region of 10 males and 10 females. A control group, consisting of 5 males and 5 females, was injected with vehicle only and/or FCA. Since a preliminary study showed that the undiluted test substance did not induce skin irritation, the test area of control and treated animals was pre-treated with 10% sodium lauryl sulphate (SDS) in petrolatum to induce local irritation on Day 7. 24 hours later, the epicutaneous induction treatment with the undiluted test substance (100%) or the vehicle 435630 alone was conducted in the treated or control animals on the regions of intradermal injections for a period of 48 h. On Day 22, the challenge treatment was performed by topical application of the undiluted test substance to the posterior right flanks of all animals for 24 h. No clinical signs and no mortality were noted during the study. The body weight development was comparable in control and test animals. No cutaneous reactions were provoked 24 and 48 h after challenge treatment with the undiluted test substance in any of the animals of the test and control groups. Therefore, the test substance had no sensitising effect on guinea pigs under the chosen experimental conditions.

The skin sensitisation potential of Diisopropyl sebacate (CAS 7491-02-3) in humans was investigated in a Repeat Insult Patch Test according to the method of Marzulli and Maibach (Cathalot, 2002).

For induction treatment, the test substance was applied three times a week for 48 h to the skin of the back of 53 healthy volunteers under occlusive conditions for a period of 3 weeks. During induction, cutaneous reactions were evaluated directly as well as 24 and 48 h after patch removal. After a two week recovery period, a challenge exposure was performed using an occlusive dressing for 48 h either on the site of induction or at an unexposed site of the skin. None of the subjects showed any sensitisation reaction to the test material and only one volunteer showed slight irritation on Day 9 of induction.

Based on these results, there is evidence provided that Diisopropyl sebacate is not sensitising to human skin.

CAS 69275-01-0

The skin sensitising potential of Bis(2-octyldodecyl) sebacate (CAS 69275-01-0) was studied in female guinea pigs similar to the maximisation method described in OECD guideline 406 (Kästner, 1986).

In the induction phase, intradermal injections of the test substance at 0.5% in paraffin and/or FCA were applied into the clipped skin area of 20 animals. A control group, consisting of 10 animals, was injected with vehicle only and/or FCA. 24 hours later, the epicutaneous induction treatment with the 10% test substance or the vehicle alone was conducted in the treated or control animals on the regions of intradermal injections for a period of 48 h. On Day 22, the challenge treatment was performed by topical application of the 5% test substance to the skin of all animals for 24 h. No changes in body weight gain were observed between treated and control animals. No cutaneous reactions were provoked 24 and 48 h after challenge treatment with 5% test substance in any of the animals of the test and control groups.

Therefore, Bis(2-octyldodecyl) sebacate had no sensitising effect on guinea pigs under the chosen experimental conditions.

 

Conclusion for sensitisation

Within the PFAE linear category four guinea pig maximisation tests (CAS 105-99-7, CAS 89626-46-9, CAS 69275-01-0, CAS 7491-02-3), and two human repeated insult patch tests (CAS 16958-92-2 and CAS 7491-02-3) gave no indication for sensitising potential for the category members. The result of one local lymph node assay was regarded as inconclusive (CAS 103-24-2). Sensitising properties were not predicted for any category member (OECD toolbox 3.0, 2012). In addition, to elicit these sensitising properties a substance needs to penetrate the skin, dermal penetration rates are predicted to be very low to very low (0.000009 - 0.00200 mg/cm²/event) for members of the PFAE linear category (QSAR, Danish EPA, 2010). Thus this isolated incidence is not regarded to affect the overall assessment of the category and therefore the category members of the PFAE linear group were considered not to be skin sensitising.

 

References

Gubicza, L. et al. (2000). Large-scale enzymatic production of natural flavour esters in organic solvent with continuous water removal. Journal of Biotechnology 84(2): 193-196.

Lilja, J. et al. (2005). Esterification of propanoic acid with ethanol, 1-propanol and butanol over a heterogeneous fiber catalyst. Chemical Engineering Journal, 115(1-2): 1-12.

Liu, Y. et al. (2006). A comparison of the esterification of acetic acid with methanol using heterogeneous versus homogeneous acid catalysis. Journal of Catalysis 242: 278-286.

Danish (Q)SAR database, Danish EPA, 2010
http://qsar.food.dtu.dk/

Radzi, S.M. et al. (2005).High performance enzymatic synthesis of oleyl oleate using immobilised lipase from Candida antartica. Electronic Journal of Biotechnology 8: 292-298.

Takahashi et al. (1981). Elimination, distribution and metabolism of di- (2-ethylhexyl) adipate (DEHA) in rats. Toxicology, 22, 223-233.

Zhao, Z. (2000). Synthesis of butyl propionate using novel aluminophosphate molecular sieve as catalyst. Journal of Molecular Catalysis 154(1-2): 131-135.


Migrated from Short description of key information:
The overall assessment of the available information gave no indication for sensitising properties of the category members.

Respiratory sensitisation

Endpoint conclusion
Endpoint conclusion:
no study available

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the group concept is applied to the members of the PFAE linear Category, data will be generated from representative reference substance(s) within the category to avoid unnecessary animal testing. Additionally, once the group concept is applied, substances will be classified and labeled on this basis.

Therefore, based on the group concept, all available data on sensitisation do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.

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