Registration Dossier

Administrative data

Description of key information

Key studies were performed according to internationally recognised testing guidelines prior to the adoption of the OECD Principles of GLP in 1992.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Referenceopen allclose all

Endpoint:
skin irritation: in vivo
Remarks:
This study dates from 1981 and was conducted in a jurisdiction where toxicity testing on cosmetic ingredients was legally required to be conducted on vertebrate animals.
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Justification for type of information:
This study dates from 1981 and was conducted in a jurisdiction where toxicity testing on cosmetic ingredients was legally required to be conducted on vertebrate animals.
Reason / purpose:
read-across: supporting information
Related information:
Composition 1
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
EPA OPP 81-5 (Acute Dermal Irritation)
Deviations:
not specified
GLP compliance:
no
Remarks:
The study was conducted in the USA in 1981, before the adoption of the OECD Principles of GLP in 1992.
Test material information:
Composition 1
Species:
rabbit
Strain:
New Zealand White
Type of coverage:
occlusive
Preparation of test site:
other: two test sites per animal. Skin on one test site was abraded, and was left intact on the other test site.
Vehicle:
unchanged (no vehicle)
Controls:
not specified
Amount / concentration applied:
0.5 ml
Duration of treatment / exposure:
24 hours
Observation period:
72 hours
Number of animals:
6
Details on study design:
Six (6) New Zealand white rabbits each received a single dermal application of 0.5 milliliter of the test article on two test sites, one abraded and one intact. The test sites were occluded for 24 hours and were observed individually for erythema, edema, and other effects 24 and 72 hours after application. Mean scores from the 24 and 72 hour. readings were averaged to determine the primary irritation index. The test article was used as received.
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
24/48/72 h
Score:
1.48
Reversibility:
fully reversible within: 72 hours
Irritant / corrosive response data:
This test article is not a primary dermal irritant to rabbits under conditions of this test.
Interpretation of results:
GHS criteria not met
Conclusions:
The primary dermal irritation index score was determined to be 1.48 after 72 hours under the conditions of the test.
Executive summary:

In this guideline equivalent study ( EPA OPP 81 -5) and prior to the adoption of OECD principles of GLP, the test material (EC 205-363-0) induced a primary dermal irritation score of 1.48. The study was conducted in 6 New Zealand White rabbits across the 24, 48, & 72 hour observation periods. The test material was exposed to the test animals (intact skin and abbraded skin, 24 hours) under occlusive conditions. The result of the test is not sufficient to meet the criteria for classification as a skin irritant under the criteria of the EU Classification, Labelling, and Packaging (CLP) regulation (1272/2008).

Endpoint:
skin irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
[Please provide information for all of the points below. Indicate if further information is included as attachment to the same record, or elsewhere in the dataset (insert links in 'Cross-reference' table)]

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The following chemical groups are identical between the source and target substances:
At the central core of both substances are three ester groups. Connected to each ester group is a 17-carbon straight-chain with a methyl ester group at carbon-11 on each side chain.

The only structural difference between the source and target substances, is that on the target substance there is an unsaturated C=C at carbon position 8-9 of each side chain, whilst all of the carbons are saturated on the source substance.

Comparing the structures of the main constituents of the target substance (Figure 2) and the source substance (Figure 1), we note that both main constituents are composed of the same chemical groups (Acetyl and Ester groups). The only difference between the source and the target main constituents is the presence of the C=C double bonds, one in each chain, in the target substance.
Consequently, the overall molecular weight of the target substance is 1059.5403 which is 6.0476 units (6 H) more than the source substance which is 1065.5879.
The overall elemental composition of the 2 substances are also very similar, with the percent Carbon between 71.0-71.4%, the percent Hydrogen between 10.5-11.0% and the percent Oxygen between 18.0-18.1%.
Neither the source or target substance main constituents contain any hydrogen donor or hydrogen acceptor sites.
Predicted dermal absorption of both the source and target substance is of the 0.1 mg/kg day magnitude (appendix 1).
These similarities mean that the physical chemical properties are also very similar, in particular:
• Both are water insoluble (<1.5 µg/mL)
• Both are liquids at room temperature with complete glass transition points <-50°C and decompose before boiling (>250 °C).
• Both have a relative density of 0.955 – 0.97 g/cm3
• Both have high partition coefficients (Log KoW) of >7.2 at 35 °C pH 7
The molecular weight, number of hydrogen bond donors, number of hydrogen bond acceptors, water solubility, and partition coefficient values for both substances indicate they will have similar bioavailability.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
All identified impurities are considered to be structurally similar to the source and target substances due to the following factors:
• The impurities contain only same chemical groups as the source and target substances,
• The chemical groups in the impurities are bonded together in the same way as the source and target substances,
• The impurities have similar molecular weights as the source and target substances,
• The number of hydrogen donors and acceptors is similar to the source and target substances.
Due to the chemical nature of the identified impurities, and the structural similarity to the source and target substances, it is considered that the impurities will behave in the same way as the source and target substances. The identified impurities are therefore highly unlikely to have any impact upon the reliability or accuracy of the prediction.


3. ANALOGUE APPROACH JUSTIFICATION
SKIN IRRITATION POTENTIAL IN SOURCE SUBSTANCE
The source substance was subject to an equivalent EPA OPP 81-5 (acute dermal irritation) study in the rabbit. The source substance induced a PDII of 1.48 under the conditions of the test.

SOURCE SUBSTANCE SKIN IRRITATION POTENTIAL SUMMARY
The test was conducted in 6 New Zealand white rabbits (sex not specified) at a test dose of 0.5 ml (unchanged) applied to two test sites on the flank of each animal. The treatment was applied for 24 hours to an intact test site and an abraded test site on each animal. Following treatment the animals were observed for 48 hours (total observation time 72 hours). Animals were observed for erythema, oedema, and other reactions. Reactions were scored using the Draize method.
The source substance induced a PDII of 1.48, and was considered not to be a primary dermal irritant in the rabbit under the conditions of the test.

RATIONALISATION OF HYPOTHESIS WITH SKIN IRRITATION POTENTIAL SEEN IN SOURCE SUBSTANCE
The source substance has a very low estimated Kp and DAD (see appendix 1) and is unlikely to permeate the skin in biologically significant quantities. The source substance has a molecular weight higher than 500, has a low water solubility, and high partition coefficient. The substance is therefore considered to be likely to coat the skin, rather than permeating it.
The hypothesis is proven by the results of the source substance, which induced a PDII of 1.48, and therefore could not be considered a skin irritant.

PREDICTED SKIN IRRITATION IN TARGET SUBSTANCE
The target substance has a very low estimated Kp and DAD (see appendix 1), of the same order of magnitude as the source substance. The molecular weight, water solubility and partition coefficient of the target substance are also almost identical to the source substance.
The target substance is therefore predicted to fail to induce sufficient skin irritation in the EPA OPP 81-5 (or similar) tests to be considered a skin irritant, and by extension, be considered to fulfil the criteria for skin irritation/corrosion under the Classification, Labelling, and Packaging (CLP) regulation (1272/2008).


4. DATA MATRIX
See appended document
Reason / purpose:
read-across source
Related information:
Composition 1
Test material information:
Composition 1
Irritation parameter:
primary dermal irritation index (PDII)
Basis:
mean
Time point:
24/48/72 h
Score:
1.48
Reversibility:
fully reversible within: 72 h
Remarks on result:
other: Based upon read across substance
Interpretation of results:
GHS criteria not met
Conclusions:
The registered substance was determined not to be a skin irritant using the read-across approach to an analogous substance.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Referenceopen allclose all

Endpoint:
eye irritation: in vivo
Remarks:
This study dates from 1981 and was conducted in a jurisdiction where toxicity testing on cosmetic ingredients was legally required to be conducted on vertebrate animals.
Type of information:
experimental study
Adequacy of study:
key study
Study period:
1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Justification for type of information:
This study dates from 1981 and was conducted in a jurisdiction where toxicity testing on cosmetic ingredients was legally required to be conducted on vertebrate animals.
Reference:
Composition 0
Qualifier:
equivalent or similar to
Guideline:
EPA OPP 81-4 (Acute Eye Irritation)
Deviations:
not specified
GLP compliance:
no
Remarks:
The study was conducted in the USA in 1981, before the adoption of the OECD Principles of GLP in 1992.
Test material information:
Composition 1
Species:
rabbit
Strain:
New Zealand White
Vehicle:
unchanged (no vehicle)
Controls:
yes, concurrent no treatment
Amount / concentration applied:
0.1 ml
Duration of treatment / exposure:
24 hours
Observation period (in vivo):
7 days
Details on study design:
Six (6) New Zealand white rabbits, free from visible ocular defects, each received a single intraocular application of 0.1 milliliter of the test article in one eye. The contralateral eye, remaining untreated, served as a control. The eyes of all animals remained unwashed for 24 hours. Observations of corneal opacity, iritis, and conjunctivitis were recorded 20, 48, and 72 hours after treatment, and at 4 and 7 days if irritation persisted. The test article was used as received.
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
24 h
Score:
0.3
Reversibility:
fully reversible within: 48 hours
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
48 h
Score:
0
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
72 h
Score:
0
Group Draize scores
24 h 48 h 72 h 4 d 7 d
Unwashed 0.3 0 0 - -
Interpretation of results:
GHS criteria not met
Conclusions:
The test material is not an ocular irritant to rabits under the conditions of the test.
Executive summary:

In this guideline equivalent study (EPA OPP 81 -4), conducted prior to the adoption of the OECD principles of GLP in 1992, the test material (EC 205-363-0) was not considered an ocular irritant to the rabbit. Six New Zealand White rabbits were treated with 0.1ml of the unchanged substance in one eye, the contralateral eye served as a control. Rabbits were observed for corneal opacity, iritis, and conjunctivitis at 24, 48, and 72 hours after treatment, and again 4 day and 7 days after treatment. Results were scored accoring to the Draize criteria. The test material induced a mean overal irritation score of 0.3 at 24 hours, this was fully reversible at the 48 hour observation.

Endpoint:
eye irritation: in vivo
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The following chemical groups are identical between the source and target substances:
At the central core of both substances are three ester groups:

Connected to each ester group is a 17-carbon straight-chain with a methyl ester group at carbon-11 on each side chain.

The only structural difference between the source and target substances, is that on the target substance there is an unsaturated C=C at carbon position 8-9 of each side chain, whilst all of the carbons are saturated on the source substance.


Comparing the structures of the main constituents of the target substance (Figure 2) and the source substance (Figure 1), we note that both main constituents are composed of the same chemical groups (Acetyl and Ester groups). The only difference between the source and the target main constituents is the presence of the C=C double bonds, one in each chain, in the target substance.
Consequently, the overall molecular weight of the target substance is 1059.5403 which is 6.0476 units (6 H) more than the source substance which is 1065.5879.
The overall elemental composition of the 2 substances are also very similar, with the percent Carbon between 71.0-71.4%, the percent Hydrogen between 10.5-11.0% and the percent Oxygen between 18.0-18.1%.
Neither the source or target substance main constituents contain any hydrogen donor or hydrogen acceptor sites.
Predicted dermal absorption of both the source and target substance is of the 0.1 mg/kg day magnitude (appendix 1).
These similarities mean that the physical chemical properties are also very similar, in particular:
• Both are water insoluble (<1.5 µg/mL)
• Both are liquids at room temperature with complete glass transition points <-50°C and decompose before boiling (>250 °C).
• Both have a relative density of 0.955 – 0.97 g/cm3
• Both have high partition coefficients (Log KoW) of >7.2 at 35 °C pH 7
The molecular weight, number of hydrogen bond donors, number of hydrogen bond acceptors, water solubility, and partition coefficient values for both substances indicate they will have similar bioavailability.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
All identified impurities are considered to be structurally similar to the source and target substances due to the following factors:
• The impurities contain only same chemical groups as the source and target substances,
• The chemical groups in the impurities are bonded together in the same way as the source and target substances,
• The impurities have similar molecular weights as the source and target substances,
• The number of hydrogen donors and acceptors is similar to the source and target substances.
Due to the chemical nature of the identified impurities, and the structural similarity to the source and target substances, it is considered that the impurities will behave in the same way as the source and target substances. The identified impurities are therefore highly unlikely to have any impact upon the reliability or accuracy of the prediction.


3. ANALOGUE APPROACH JUSTIFICATION
EYE IRRITATION POTENTIAL IN SOURCE SUBSTANCE
The source substance was subject to an equivalent EPA OPP 81-4 (acute eye irritation) study in the rabbit. The source substance induced a overall irritation score of 0.3 at 24 hours, which was completely reversible by the 48 hour observation.

SOURCE SUBSTANCE EYE IRRITATION POTENTIAL SUMMARY
The test was conducted in 6 New Zealand white rabbits (sex not specified) at a test dose of 0.1 ml (unchanged) applied to a single eye of each animal. The untreated eye served as a control for the test. The treated eye was left unwashed for 24 hours. Following treatment the animals were observed for 6 days (total observation time 7 days). Animals were observed for iritis, conjunctivitis, and corneal opacity at 24, 48, 72 hours and at 4 and 7 days. Reactions were scored using the Draize method.
The source substance induced an overall irritation score of 0.3 at 24 hours which was completely reversible by the 48 hour observation period.

RATIONALISATION OF HYPOTHESIS WITH EYE IRRITATION POTENTIAL SEEN IN SOURCE SUBSTANCE
The source substance has a very low water solubility, high partition coefficient, and a liquid physical form. The substance is therefore considered to be likely to be removed from the eye by lacrimation (tearing) before significant irritation can take place.
The hypothesis is proven by the results of the source substance, which induced an overall irritation score of 0.33 at 24 hours which was completely reversible at the 48 hour observation period, and therefore could not be considered an eye irritant.

PREDICTED EYE IRRITATION IN TARGET SUBSTANCE
The target substance has almost identical water solubility, partition coefficient, and physical properties to the source substance.
The target substance is therefore predicted to fail to induce sufficient eye irritation in the EPA OPP 81-4 (or similar) tests to be considered an eye irritant, and by extension, be considered to fulfil the criteria for eye irritation/corrosion under the Classification, Labelling, and Packaging (CLP) regulation (1272/2008).


4. DATA MATRIX
See document appended
Reason / purpose:
read-across source
Related information:
Composition 1
Test material information:
Composition 1
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
24 h
Score:
0.3
Reversibility:
fully reversible within: 48 h
Remarks on result:
other: Based upon read across substance
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
48 h
Score:
0
Remarks on result:
other: Based upon read across substance
Irritation parameter:
overall irritation score
Basis:
mean
Time point:
72 h
Score:
0
Remarks on result:
other: Based upon read across substance
Interpretation of results:
GHS criteria not met
Conclusions:
The registered substance was determined not to be an eye irritant using the read across approach to an analogous substance.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Justification for classification or non-classification

The registered substance failed to induce sufficient skin or eye irritation to meet the criteria for classification as a skin or eye irritant in accordance with the Classification, Labelling, and Packaging (CLP) regulation (1272/2008).