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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
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:
October 1981
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study without detailed documentation
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.
Cross-reference
Reason / purpose:
read-across: supporting information
Reference
Endpoint:
acute toxicity: oral
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
ACUTE ORAL TOXICITY POTENTIAL IN SOURCE SUBSTANCE
The source substance was subject to an OECD 401 limit test acute oral toxicity study in the rat. No toxicological effects were reported during the study. The LD50 was set according to the dose level used, at >5000 mg/kg bw.

SOURCE SUBSTANCE ACUTE ORAL TOXICITY POTENTIAL SUMMARY
The test was conducted in 5 male and 5 female albino rats (not otherwise specified) at the single test dose of 5000 mg/kg bw via gavage. No toxicological effects were reported during the observation period following the acute dosing (14 days). No mortality was observed during the entire test period. No toxicological effects were observed during gross necropsy of the test animals.

RATIONALISATION OF HYPOTHESIS WITH ACUTE ORAL TOXICITY POTENTIAL SEEN IN SOURCE SUBSTANCE
The source substance does not fulfil Lipinski’s rule of five and as such is not expected to be orally active (bioavailable) (see section 2.2). As such the source substance is not expected to be absorbed via oral ingestion and is likely to be excreted in the faeces.
The hypothesis is proven by the results of the source substance, which failed to induce any toxicological effects after acute oral exposure., and therefore could not be considered acutely toxic via the oral route.

PREDICTED ACUTE ORAL TOXICITY IN TARGET SUBSTANCE
The target substance does not fulfil Lipinski’s rule of five and as such is not expected to be orally active (bioavailable).
The target substance is therefore predicted to fail to induce toxicological effects after acute oral exposure in an OECD 401 (or similar) test, and by extension, be considered to fulfil the criteria for acute toxicity under the Classification, Labelling, and Packaging (CLP) regulation (1272/2008).


4. DATA MATRIX
See appended document for full data matrix.
Reason / purpose:
read-across source
Related information:
Composition 1
Test material information:
Composition 1
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Remarks on result:
other: Based upon read across substance
Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral LD50 in the rat of the registered material was determined to be >5000 mg/kg bw using a read-across approach to an analogous substance.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1981
Report Date:
1981

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Version / remarks:
12 May 1981
Deviations:
yes
Remarks:
Only a single dose level was used in the study. This is considered not to effect the reliability of the test result.
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 type:
standard acute method
Limit test:
yes

Test material

Reference
Name:
Unnamed
Type:
Constituent
Test material form:
liquid

Test animals

Species:
rat
Strain:
other: Albino, not otherwise specified.
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation:
222-270g

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Doses:
5000 mg/kg bw
No. of animals per sex per dose:
5 male:5 female
Control animals:
not specified
Details on study design:
Ten (5M:5F) albino rats, 222-270 g, each received a single oral dose of the test article at a dose level of 5 grams per kilogram bodyweight. Animals were observed for pharmacologic activity and drug toxicity 1, 3, 6, and 21‘ hours after treatment, and daily thereafter for a total of 14 days. Non-survivors and animals surviving the ill day observation period were subjected to gross necropsy, with all findings noted. The test article was used as received (Sp.g. = 0.98).

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality was observed during the test period.
Clinical signs:
Not reported.
Body weight:
Not reported.
Gross pathology:
No effects were observed during gross necropsy.

Applicant's summary and conclusion

Interpretation of results:
GHS criteria not met
Conclusions:
The acute oral LD50 in the rat of the test material was determined to be >5000 mg/kg bw under the conditions of the test.
Executive summary:

In this guideline (OECD 401) study, conducted prior to the adoption of GLP, the test material (EC 205-363-0) was determined to have an acute oral LD50 to rats of >5000 mg/kg bw. The study was conducted via oral gavage at a single dose level (5000 mg/kg bw) in albino rats. No toxicological effects were reported.