Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)
Type of information:
experimental study planned
Justification for type of information:
TESTING PROPOSAL ON VERTEBRATE ANIMALS for Extended one generation reproductive toxicity study (EOGRTS) via oral route of exposure.

Substance name: Hexan-6-olide

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- No existing GLP studies study available for this endpoint.
- No existing non-GLP studies study available for this endpoint.
- No historical human data available for this endpoint.
- No existing (Q)SAR information can properly assess this endpoint.
- No existing in vitro method could address this endpoint.
- No sufficient information available that could fulfill the standard information requirement through the weight of evidence approach.
- No information from structurally similar substance can be used to fulfill the standard information requirement through grouping and read-across.

CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- Extended one generation reproductive toxicity studies (EOGRTS) basic test design is the standard information requirement for substance registered for 1000 tonnes or more per year (Annex X, Section 8.7.3., column 1, of the REACH Regulation).

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:

No evidence of effect on the reproductive organs was seen in a 90-day repeated dose inhalation toxicity study at dose levels up to 45 ppm (203 mg/m3). An extended one generation reproductive toxicity study according to OECD 443 guideline, basic test design (cohorts 1A and 1B without extension to include a F2 generation) is proposed at the present time. The detailed study design of EOGRTS will be further assessed to ensure its adequate assessment of possible effects and avoid unnecessary vertebrate animal use. It is proposed that the EOGRTS study will be scheduled to run after the proposed Prenatal Developmental Toxicity Study (OECD 414) in rat has been performed. This would allow data from the OECD 414 study to be taken into account in the dose selection for the EOGRTS study.
Qualifier:
according to guideline
Guideline:
OECD Guideline 443 (Extended One-Generation Reproductive Toxicity Study)
Justification for study design:
As in accordance with the data requirements in REACH annex X.
Effect on fertility: via oral route
Endpoint conclusion:
no study available (further information necessary)
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

No studies are available with regard to reproduction and developmental toxicity of e-caprolactone. However, a well conducted 90-day inhalation study showed no macroscopic and histopathological effects on reproductive organs and also other systemic effects were not found during this study. The lack of systemic effects can be explained by the rapid hydrolysis in stomach and blood, resulting in the formation of 6-hydroxyhexanoic acid. No reproductive toxicity is expected for this simple aliphatic carboxylic acid.


Short description of key information:
Reproductive toxicity is not predicted based on an absence of effects in a 90-day inhalation study, the rapid hydrolysis of e-caprolactone under physiological conditions and the low predicted toxicity of the hydrolysis product.

Effects on developmental toxicity

Description of key information

A rabbit developmental toxicity study performed with the read-across substance adipic acid reports a NOAEL for maternal and developmental toxicity of 250 mg/kg bwd, the highest dose level tested.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
A read-across is proposed because adipic acid is structurally similar to Hexan-6-olide (e-Caprolactone), and the toxic effects on the developing foetus would be the same.
Reason / purpose for cross-reference:
read-across source
Details on maternal toxic effects:
Maternal toxic effects:no effects

Details on maternal toxic effects:
No maternal toxicity was observed. There was no effect on maternal survival.
Key result
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
There was no effect on nidation or on foetal survival. The number of abnormalities seen in either soft or skeletal tissue of the test groups did not differ from the number occurring spontaneously in the sham-treated controls. No differences between controls and treated groups were found for corpora lutea, implantations, total number of resorptions, total number of foetuses, total number of live litters and foetal weights.
Dose descriptor:
NOAEL
Effect level:
250 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Abnormalities:
not specified
Developmental effects observed:
not specified

The NOAEL for both maternal and developmental toxicity was 250 mg/kg bw/d for the apidic acid.

Conclusions:
The NOAEL for both maternal and developmental toxicity was 250 mg/kg bw/d for the apidic acid used as read-across substance for Hexan-6-olide (e-Caprolactone).
Executive summary:

Rabbits were artificially inseminated on day 0, adipic acid (in water) was administered by gavage on gesatational days 6 through 18 at doses of 0, 2.5, 12, 54 and 250 mg/kg. The positive control group received a single dose of 2.5 mg/kg 6 -aminonicotinamide on day 9. On day 29 all does were subject to Caesarean section for examination of urogenital tract and foetal examination. No maternal toxicity was observed. There was no effect on maternal survival. There was no effect on nidation or on foetal survival. The number of abnormalities seen in either soft or skeletal tissue of the test groups did not differ from the number occurring spontaneously in the sham-treated controls. No differences between controls and treated groups were found for corpora lutea, implantations, total number of resorptions, total number of foetuses, total number of live litters and foetal weights. The NOAEL for both maternal and developmental toxicity was 250 mg/kg bw/d for the apidic acid. A read-across is proposed because adipic acid is structurally similar to Hexan-6-olide (e-Caprolactone), and the NOAEL for the target substance is therefore considered to be the same.

This information is used in the read-across approach and the assessment of the target substance.

Endpoint:
developmental toxicity
Type of information:
experimental study planned
Justification for type of information:
TESTING PROPOSAL ON VERTEBRATE ANIMALS for Prenatal Developmental Toxicity Study (OECD 414) in rat.

Substance name: Hexan-6-olide

CONSIDERATIONS THAT THE GENERAL ADAPTATION POSSIBILITIES OF ANNEX XI OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- No existing GLP studies study available for this endpoint.
- No existing non-GLP studies study available for this endpoint.
- No historical human data available for this endpoint.
- No existing (Q)SAR information can properly assess this endpoint.
- No existing in vitro method could address this endpoint.
- No sufficient information available that could fulfill the standard information requirement through the weight of evidence approach.
- No information from structurally similar substance can be used to fulfill the standard information requirement through grouping and read-across.

CONSIDERATIONS THAT THE SPECIFIC ADAPTATION POSSIBILITIES OF ANNEXES VI TO X (AND COLUMN 2 THEREOF) OF THE REACH REGULATION ARE NOT ADEQUATE TO GENERATE THE NECESSARY INFORMATION:
- Prenatal Developmental Toxicity Study is the standard information requirement for substance registered for 1000 tonnes or more per year (Annex X, Section 8.7.2., column 1, of the REACH Regulation).

FURTHER INFORMATION ON TESTING PROPOSAL IN ADDITION TO INFORMATION PROVIDED IN THE MATERIALS AND METHODS SECTION:

No evidence of effect on the reproductive organs was seen in a 90-day repeated dose inhalation toxicity study at dose levels up to 45 ppm (203 mg/m3). A Prenatal Developmental Toxicity Study (OECD 414) in rat is proposed at the present time. Furthermore, a dose range finding study is proposed in order to select relevant oral doses for the main study as no information from oral dosage is available on this specific substance.
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Species:
rat
Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
250 mg/kg bw/day
Species:
rabbit
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

Rabbits were artificially inseminated on day 0, adipic acid (in water) was administered by gavage on gesatational days 6 through 18 at doses of 0, 2.5, 12, 54 and 250 mg/kg (FDA, 1974). A read-across is proposed because adipic acid is structurally similar to e-Caprolactone, and the toxic effects on the developing foetus would be the same. On day 29 all does were subject to Caesarean section for examination of urogenital tract and foetal examination. No maternal toxicity was observed. There was no effect on maternal survival. There was no effect on nidation or on foetal survival. The number of abnormalities seen in either soft or skeletal tissue of the test groups did not differ from the number occurring spontaneously in the sham-treated controls. No differences between controls and treated groups were found for corpora lutea, implantations, total number of resorptions, total number of foetuses, total number of live litters and foetal weights. The NOAEL for both maternal and developmental toxicity was 250 mg/kg bw/d.

Justification for classification or non-classification

There is no indication of an effect on fertility or reproduction from the results of a 90 -day inhaltion toxicity study. e-caprolactone is rapidly hydrolysed under physiological conditions and the hydrolysis prodcut is considered unlikley to be a reproductive toxin. There was no evidence of developmental toxicity in a rabbit study performed with the read-across substance adipic acid. The available data do not therefore indicate that the substance requires classification for reproductive or developmental toxicity according to Regulation (EC) No 1272/2008 (the CLP Regulation).

Additional information