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Administrative data

Description of key information

Acute Oral Toxicity (weight of evidence): LD50 > 5000 mg/kg bw, 2018

1. Acute Oral (Read-Across: oxacycloheptadec-7-en-2-one): LD50 > 5000 mg/kg bw, eq. or similar to OECD TG 401, 1974

2. Expert judgement: assessment of the toxicokinetics of the target substance indicates that the substance has a very low order of acute oral toxicity due to rapid metabolism and excretion. The substance would not expect to meet the classification criteria according to GHS/EU Criteria.

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records

Referenceopen allclose all

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1974
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Method equivalent or similar to guideline, non-GLP. Information is sufficient to conclude absence of classifiation and labelling when combined with other available information.
Reason / purpose:
read-across: supporting information
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
not specified
Sex:
not specified
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 5000 mg/kg bw
Doses:
5000 mg/kg bw
No. of animals per sex per dose:
Not reported
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: No
- Other examinations performed: clinical signs
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality observed.
Clinical signs:
No significant effects observed.
Interpretation of results:
GHS criteria not met
Remarks:
EU criteria not met
Conclusions:
Under the conditions of this study, the LD50 (male/female) was determined to be > 5000 mg/kg bw
Executive summary:

The study was performed according to a method equivalent or similar to OECD TG 401 to assess the acute oral toxicity potential of the test item to the rat. Following administration by oral gavage at a dose level of 5000 mg/kg bodyweight there were no mortalities and no significant clinical signs. Under the conditions of this study, the LD50 (male/female) was determined to be > 5000 mg/kg bw.

Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
1974
Reliability:
4 (not assignable)
Rationale for reliability incl. deficiencies:
other: Method equivalent or similar to guideline, non-GLP. Information is sufficient to conclude absence of classifiation and labelling when combined with other available information in weight of evidence
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH
Further information is included in attachment to IUCLID section 13.

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
The read-across is based on the hypothesis that the source and target substances have similar physico-chemical, toxicological properties and because of common metabolism they share common or similar breakdown products and therefore potential mechanisms of action. Further information is included in attachment to IUCLID section 13.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
The source and target chemicals have comparable compositions. Further information is included in attachment to IUCLID section 13

3. ANALOGUE APPROACH JUSTIFICATION
The source substance is a chemically similar substance with common metabolism and common or similar degradants of the target substance under physiological conditions. The read-across in weight of evidence indicates despite a common potential mode-of-action between source and target, no significant adverse effects are observed within in available studies. When the information is taken together by expert judgement the weight of evidence indicates that there is an absence of adverse effects associated with the target.

4. DATA MATRIX
Further information is included in attachment to IUCLID section 13.
Reason / purpose:
read-across source
Reason / purpose:
read-across: supporting information
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
Test type:
standard acute method
Limit test:
yes
Species:
rat
Strain:
not specified
Sex:
not specified
Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
MAXIMUM DOSE VOLUME APPLIED: 5000 mg/kg bw
Doses:
5000 mg/kg bw
No. of animals per sex per dose:
Not reported
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Necropsy of survivors performed: No
- Other examinations performed: clinical signs
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality observed.
Clinical signs:
No significant effects observed.
Interpretation of results:
GHS criteria not met
Remarks:
EU criteria not met
Conclusions:
The target is considered to have an LD50 (male/female) of > 5000 mg/kg bw.
Executive summary:

The study was performed on a structural analogue, according to a method equivalent or similar to OECD TG 401 to assess the acute oral toxicity potential of the test item to the rat. Following administration by oral gavage at a dose level of 5000 mg/kg bodyweight there were no mortalities and no significant clinical signs. Under the conditions of this study, the LD50 (male/female) was determined to be > 5000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating dose
5 000 mg/kg bw
Quality of whole database:
The available information as a whole meets the tonnage driven information requirements of REACH.

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Acute Oral Toxicity:

1. Eq. to OECD 401, 1971: Read-Across SOURCE (oxacycloheptadec-7-en-2-one): The study was performed according to a method equivalent or similar to OECD TG 401 to assess the acute oral toxicity potential of the test item to the rat. Following administration by oral gavage at a dose level of 5000 mg/kg bodyweight there were no mortalities and no significant clinical signs. Under the conditions of this study, the LD50 (male/female) was determined to be > 5000 mg/kg bw.

2. Expert Judgement: In accordance with REACH Regulation (EC) No. 1907/2006 Annex XI, section 1.2 – weight of evidence, justification for not performing further acute oral toxicity studies includes expert assessment: 1. Ring opened macrocycle lactones and their aliphatic mono-carboxylic acid formed by lactone hydrolysis are present in mammals via a food and are known to be metabolised. This is demonstrated by the following considerations on esters/carboxylic acids: (i) (via the oral route) the alkyl esters are hydrolysed by lipases to free fatty acids and absorbed; (ii) the esters are hydrolysed into alcohol and acid and then metabolised into two carbon fragments for subsequent inclusion in cellular respiration processes via oxidization to carbon dioxide and water and subsequent elimination. 2. Aliphatic esters and carboxylic acids are metabolized by the same metabolic processes to that of dietary fats and are extensively metabolized by carboxylesterase enzymes that are ubiquitous across vertebrate and invertebrate species (Leinweber, FJ.  1987.  Possible physiological roles of carboxylic ester hydrolases.  Drug Metab. Rev. 18: 379-439), including in fish species (Melancon, MJ, Lech, JJ.  1979.  Xenobiotica 9: 317). Carboxylesterases are enzymes with relatively broad specificity, capable of hydrolyzing esters of a wide variety of carboxylic acids (Lehninger, AL.  1975.  Biochemistry, Johns Hopkins University, Worth Publishers.). Ester/carboxylate chain lengths from the simple C1 (methyl) to greater than C8 (octyl, ethylhexyl, etc.) are equally metabolizable. For macrocyclic lactones (esters) this was documented in Belsito et al. Food and Chemical Toxicology, 49 (2011), citing Joint FAO/WHO Expert Committee on Food Additives (JECFA) review (1998 and 2002). Ester hydrolysis is a “phase I” reaction, i.e., a first-pass activation reaction that prepares molecules for eventual conjugation and elimination. It is for this reason that this class of test item is very well tolerated via the oral route in vivo. According to ECHA Guidance on Information Requirements and Chemical Safety Assessment (Chapter R.7a: Endpoint Specific Guidance, R.7.4, July 2017) further testing is not scientifically justified.

 

Weight of Evidence Conclusion:

The applicant assesses this study by expert judgement and indicates that the weight of evidence by read-across to relevant analogue data and considering common breakdown products (expected in physiological conditions and metabolism) that there is no evidence to suggest expectation of significant toxicity at acute GHS oral toxicity: category 4 levels. There is no evidence of significant clinical signs, body weight loss and any abnormal signs in necropsy that leads to functional impairment when tested at 2000 mg/kg bw limit dose in the male/female rat. The weight of evidence indicates that the substance should not produce significant acute toxicity as to produce a requirement to classify and label for acute oral toxicity in accordance with Regulation (EC) 1272/2008.

Justification for classification or non-classification

The substance does not meet classification criteria under Regulation (EC) No 1272/2008 for acute toxicity.

The substance does not meet classification criteria under Regulation (EC) No 1272/2008: for Specific Target Organ Toxicity - Single Exposure.

 

Evaluation of available in vivo studies only; the selected studies support the conclusion that the substance does not meet the criteria for STO – SE under Regulation (EC) 1272/2008. There are no indications that would lead to obvious ‘functional disturbance’ or consistent with ‘functional impairment’. In all relevant studies body weight gains were observed. Clinical signs were non-existent or at least transient and fully reversible and not supporting of any category of classification at above the EU criteria category 4 level.