Registration Dossier

Toxicological information

Skin sensitisation

Currently viewing:

Administrative data

Endpoint:
skin sensitisation: in vivo (LLNA)
Type of information:
read-across based on grouping of substances (category approach)
Adequacy of study:
key study
Study period:
2018
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other:
Justification for type of information:
MTDID 22327 is a member of the Perfluorinated Organic Chemicals, C5-C18, category. Unlike most members of the category, MTDID 22327 is a UVCB consisting mostly of perfluoro-N-methylmorpholin e, a mixture of C5-C7 perfluoroamines, and perfluorohexane isomers. However, all of these chemicals stem from the same manufacturing process, have similar physicochemical properties including high vapor pressure and low water solubility relative to the hydrocarbon analogs (e.g., hexanes v. perfluorohexanes), and also lack any chemically reactive groups, which forms the technical basis for the category.  Members of this category are fully fluorinated, meaning that fluorine, rather than hydro gen, is bonded to all carbon atoms in the molecule.  Fluorine is the most electronegative of the el ements (fluorine has an electronegativity of 3.98 on the Pauling scale, as compared to 2.55 for car bon, 3.04 for nitrogen or 2.20 for hydrogen).  This electronegativity is expected to dominate over all other aspects of substance chemistry and is the underlying basis for similarity of substances in this category.  For example, strong electron withdrawing in perfluorinated tertiary amines results in a mo lecule with essentially no lone pair influence, and which has chemistry more similar to a branched, perfluorinated alkane than any other structure.  Because these substances exhibit similar physicochemical properties they can be considered to constitute a chemical category. The data gap for skin sensitization can therefore be addressed by read-across between category members. Because these substances exhibit similarity in their physicochemical properties and toxicological properties in mammals, and because available data indicates that parent molecules are not reactive toward biological molecules and cannot undergo bioactivation by normal enzymatic processes, they can be considered to constitute a chemical category. Data gaps for partitioning properties, mammalian and ecological toxicity can therefore be addressed by read-across and/or trend analysis between category members.  The readacross is considered reliable with restrictions and the result is suitable for use in Risk Assessment, Classification & Labelling, and PBT Analysis. See section 13 for a fuller discussion of the category approach.

Data source

Reference
Reference Type:
other: Read-Across from other internal studies
Title:
Unnamed
Year:
2018
Report date:
2018

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
other: REACH Guidance on QSARs and grouping of chemicals
Version / remarks:
May/July 2008
Deviations:
no
GLP compliance:
no
Remarks:
Source study was conducted under GLP conditions.

Test material

Constituent 1
Reference substance name:
Reaction mass of perfluoro(dimethyl - N - Butylamine ) and perfluoro (methyl - di - N - propylamine) and perfluoro (dimethyl - N - propylamine and 2,2,3,3,5,5,6,6, octafluoro-4-(trifluoromethyl)morpholine and perfluoro-N-pentane
EC Number:
908-205-5
Cas Number:
2187449-42-7
IUPAC Name:
Reaction mass of perfluoro(dimethyl - N - Butylamine ) and perfluoro (methyl - di - N - propylamine) and perfluoro (dimethyl - N - propylamine and 2,2,3,3,5,5,6,6, octafluoro-4-(trifluoromethyl)morpholine and perfluoro-N-pentane
Specific details on test material used for the study:
Read-across from category member:
Perfluoro-N-C1,3-alkyl morpholines, CAS# 1093615-61-2

Results and discussion

Positive control results:
A concurrent positive control was not evaluated in this study. A reliability check on the test system was last performed in March 2007 using the positive control substance alpha-hexyl cinnamaldehyde (HCA). In this test, stimulation indicates for the positive control stubstance at 5%, 10% and 25% concentrations were 1.3, 1.5 and 5.5, respectivley, relative to the vehicle control (acetone/olive oil 4:1 v/v). The EC3 was 15.6%. The EC3 was in the acceptable range of 2% to 20%. EC3 values for HCA for the previous 4 reliability checks ranged from 7.3% to 13.1%

In vivo (LLNA)

Results
Key result
Parameter:
SI
Value:
ca. 2.8
Test group / Remarks:
Average

Any other information on results incl. tables

DPM:

100% Test Substance: 466 DPM

Control: 154 DPM

*In additionaly treated animals:

100% Test Substance: 312 DPM

Control: 123 DPM

Stimulation Index:

100% Test Substance: 3.0

Control: 1.0

*In additionally treated animals:

100% Test Substance: 2.5

Control: 1.0

*In order to achieve more information regarding the SI=3 value, an additional group of animals was treated with 100% test substance concentration.

No irritation/skin reactions, mortality and systemic toxicity were observed  in any of the animals examined. All nodes of all the animals were considered normal in size and body weights of the experimental animals remained in the same range.

MTDID 22327 is a member of the Perfluorinated Organic Chemicals, C5-C18, category. Unlike most members of the category, MTDID 22327 is a UVCB consisting mostly of perfluoro-N-methylmorpholine, a mixture of C5-C7 perfluoroamines, and perfluorohexane isomers. However, all of these chemicals stem from the same manufacturing process, have similar physicochemical properties including high vapor pressure and low water solubility relative to the hydrocarbon analogs (e.g., hexanes v. perfluorohexanes), and also lack any chemically reactive groups, which forms the technical basis for the category.  Members of this category are fully fluorinated, meaning that fluorine, rather than hydrogen, is bonded to all carbon atoms in the molecule.  Fluorine is the most electronegative of the elements (fluorine has an electronegativity of 3.98 on the Pauling scale, as compared to 2.55 for carbon, 3.04 for nitrogen or 2.20 for hydrogen).  This electronegativity is expected to dominate over all other aspects of substance chemistry and is the underlying basis for similarity of substances in this category.  For example, strong electron withdrawing in perfluorinated tertiary amines results in a molecule with essentially no lone pair influence, and which has chemistry more similar to a branched, perfluorinated alkane than any other structure.  Because these substances exhibit similar physicochemical properties they can be considered to constitute a chemical category. The data gap for skin sensitization can therefore be addressed by read-across between category members.

Because these substances exhibit similarity in their physicochemical properties and toxicological properties in mammals, and because available data indicates that parent molecules are not reactive toward biological molecules and cannot undergo bioactivation by normal enzymatic processes, they can be considered to constitute a chemical category. Data gaps for partitioning properties, mammalian and ecological toxicity can therefore be addressed by read-across and/or trend analysis between category members.  The readacross is considered reliable with restrictions and the result is suitable for use in Risk Assessment, Classification & Labelling, and PBT Analysis. See section 13 for a fuller discussion of the category approach.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The calculated mean stimulation index was 2.8. Based on the results of the study, category member MTDID 22327 is not a skin sensitizer.
Executive summary:

The dermal sensitizing potential of a category member was evaluated in a local lymph node assay (LLNA) in female CBA/J mice following OECD Guideline 429 (effective April 2002). In the definitive study, animals (5/group) were administered 25 µL of control (Milli-Q or Milli-U water) or 100% of the test article by topical application to the dorsum of each ear once daily for three consecutive days. Clinical observations were recorded daily. Body weights were recorded on days 1 and 6. Ear swelling measurements were recorded on days 1, 3 and 6. On day 6, the number of proliferating lymph node cells in the auricular lymph nodes were determined using a 3H-methyl thymidine method. The Stimulation Index (SI) was calculated and substances with a SI 3 are considered to be potential sensitizers. To achieve more information regarding the SI value, the study was repeated with two additional groups.  No skin reactions were observed in any animals. The positive control (hexylcinnamaldehyde) is tested once every 6 months at the contract lab and the most recent test indicated that the test method was valid.The calculated median SI was 2.8.  Based on the results of this study, the category members do not have to be classified and have no obligatory labeling requirement of skin sensitization according to the Globally Harmonized System of Classification and Labeling of Chemicals (GHS).

Because these substances exhibit similarity in their physicochemical properties and toxicological properties in mammals, and because available data indicates that parent molecules are not reactive toward biological molecules and cannot undergo bioactivation by normal enzymatic processes, they can be considered to constitute a chemical category. Data gaps for partitioning properties, mammalian and ecological toxicity can therefore be addressed by read-across and/or trend analysis between category members.  The readacross is considered reliable with restrictions and the result is suitable for use in Risk Assessment, Classification & Labelling, and PBT Analysis. See section 13 for a fuller discussion of the category approach.