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Key value for chemical safety assessment

Effects on fertility

Description of key information

Oral (OECD 422, read across): NOAEL rat, fertility1000 mg/kg bw/day

Oral (OECD 408, read across): NOAEL rat, fertility1000 mg/kg bw/day

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
Summary of available data used for the endpoint assessment of the target substance
Adequacy of study:
key study
Justification for type of information:
refer to the analogue justification provided in IUCLID section 13
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Key result
Dose descriptor:
NOAEL
Remarks:
reproduction
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed in the study
Remarks on result:
other:
Remarks:
Source: CAS 22393-85-7
Key result
Critical effects observed:
no
Key result
Dose descriptor:
NOAEL
Remarks:
developmental
Generation:
F1
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No adverse effects observed in the study
Remarks on result:
other:
Remarks:
Source: CAS 22393-85-7
Key result
Critical effects observed:
no
Key result
Reproductive effects observed:
no
Conclusions:
The read across approach is justified in the analogue justification. The target and source substance are considered unlikely to differ in their reproduction toxicity potential. A combined repeated dose toxicity studies with reproduction/developmental toxicity screening was performed with the source substance Tetradecyl oleate (CAS 22393-85-7) via the oral route of administration. The NOAEL for parental fertility and the developmental NOAEL was found to be ≥1000 mg/kg bw/day. Therefore, no hazard with regard to reproduction toxicity is expected for target substance Fatty acids, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS).
Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available information comprises adequate and reliable (Klimisch score ≤2) studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, eco-toxicological and toxicological profile (refer to the endpoint discussion for further details). The selected studies are thus sufficient to fulfil the standard information requirements set out in Annex VIII-X, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Justification for read across

There are no data on the reproduction toxicity of the target substance Fatty acids, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS). The assessment was therefore based on studies conducted with analogue source substances as part of a read-across approach, which is in accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.5. For each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across. A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Section 13).

Toxicity to reproduction

CAS 22393-85-7

A combined repeated dose toxicity study with a reproduction/developmental toxicity screening test was performed according to OECD Guideline 422 under GLP conditions (key study, 2014). 10 rats/sex/dose were administered 0, 100, 300 and 1000 mg/kg bw/day Tetradecyl oleate (CAS 22393-85-7) once daily, via oral gavage. Males were exposed for 28-29 days, from two weeks before mating on test day one until after mating. Females were exposed for 54 days (during 2 weeks prior to mating, during mating, during post-coitum, and during 3 days of lactation). No treatment-related parental effects were seen on viability, clinical signs, body weight (gain), food consumption, haematological parameters, clinical chemistry parameters, during observational and neurological screening, and during macroscopic and microscopic examinations. Therefore the NOAEL for parental systemic toxicity was ≥ 1000 mg/kg bw/day. In parental animals, no effects on reproductive function (qualitative sperm staging, oestrus cycle) or performance (male and female mating and fertility indices, conception index, pre-coital interval, and number of corpora luteae and implantation sites, gestation length) were observed, compared with the control animals. The testis weight, epididymis weight, and histological examination of the testes in males as well as the weight and histological examination of the uterus and ovaries in females did not reveal any substance-related effects in the parental animals. All the pregnant females gave birth to live pups with the exception of one high dose female which had a total litter loss on day 3 post-partum. This female and two females in the control group had unilateral implantation, which is not considered to be treatment-related. Therefore, a NOAEL for parental fertility of ≥ 1000 mg/kg bw/day was derived for male and female rats.

 

CAS 868839-23-0

Fertility parameters of parental animals were assessed in an oral repeated dose toxicity study performed with octanoic acid, 2-propylheptylester (CAS 868839-23-0) according to OECD guideline 408 under GLP conditions (supporting study, 2006). Doses up to 1000 mg/kg bw/day were administered by gavage on 7 days per week to 10 male and female rats per dose over an administration period of 90 days. During the last 2 weeks of administration, vaginal lavages were taken daily from all female animals to determine the stages of the oestrus cycle. All animals were sacrificed at the end of administration period. Testis weight, epididymis weight, sperm count in one testis, sperm count in one epididymis, sperm viability, and sperm morphology were assessed in male rats. There were no statistically significant differences in the mean length of the oestrus cycles and the number of complete cycles between the control group and the treatment groups. There were no statistically significant differences between the control group and the treatment groups in the mean number of viable spermatids, number of motile spermatozoa in the cauda epididymis, and in the percentage of spermatids with malformations. There were no treatment-related effects on the weight of the reproductive organs and related organs/tissues. No treatment-related findings were reported for gross pathology and histopathology. Therefore, a NOAEL for parental fertility of ≥1000 mg/kg bw/day was derived for male and female rats.

 

Overall conclusion for effects on fertility

Analogue read-across from source substances was applied for reproduction toxicity. No effects on reproductive parameters/organs were observed in the available screening study and in a sub-chronic oral repeated dose toxicity study with assessment of parental fertility parameters. The NOAEL for reproduction toxicity was at the limit dose of 1000 mg/kg bw/day. Based on the available data and following the analogue approach, absence of adverse effects on fertility is expected the target substance Fatty acids, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS).

Effects on developmental toxicity

Description of key information

Oral (OECD 414, read across): NOAEL rat, developmental toxicity/teratogenicity ≥ 1000 mg/kg bw/day

Oral (OECD 422, read across): NOAEL rat, developmental ≥ 1000 mg/kg bw/day

Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Remarks:
Summary of available data used for the endpoint assessment of the target substance
Adequacy of study:
key study
Justification for type of information:
Refer to analogue justification provided in IUCLID section 13.
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: absence of toxicologically relevant effects
Remarks on result:
other: Source: CAS 91031-48-0
Key result
Abnormalities:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other:
Remarks on result:
other: Source: CAS 91031-48-0
Key result
Abnormalities:
no effects observed
Key result
Developmental effects observed:
no

Data from the source substance Fatty acids, C16-18, 2-ethylhexyl esters (CAS 91031-48-0) were selected as key results for reasons of data reliability and structural similarity. Additional data is given for the source substance tetradecyl oleate (CAS 22393-85-7). In a combined repeated dose toxicity study with a reproduction/developmental toxicity screening test no toxicologically relevant treatment related adverse effects were seen on viability, clinical signs, body weight, sex ratio, and gross pathology of F1 offspring. Based on these results, a developmental NOAEL of ≥ 1000 mg/kg was determined.

Conclusions:
The read across approach is justified in the analogue justification. The target and source substances are considered unlikely to differ in their developmental toxicity potential. In a developmental toxicity oral gavage study (OECD guideline 414) in rats with the source substance Fatty acids, C16-18, 2-ethylhexyl esters (CAS 91031-48-0) the NOAEL for developmental and maternal toxicity was found to be ≥ 1000 mg/kg/day. For the source substance tetradecyl oleate (CAS 22393-85-7) the NOAEL for developmental toxicity was found to be ≥ 1000 mg/kg/day in a study performed according to OECD guideline 422. Therefore, no hazard with regard to developmental toxicity is expected for target substance Fatty acids, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS).
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
The available information comprises adequate and reliable (Klimisch score 2) studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, eco-toxicological and toxicological profile (refer to the endpoint discussion for further details). The selected studies are thus sufficient to fulfil the standard information requirements set out in Annex VIII-IX, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.
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

Justification for read across

There are no data on the developmental toxicity of the target substance Fatty acids, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS). The assessment was therefore based on studies conducted with analogue source substances as part of a read-across approach, which is in accordance with Regulation (EC) No. 1907/2006, Annex XI, 1.5. For each specific endpoint the source substance(s) structurally closest to the target substance is/are chosen for read-across, with due regard to the requirements of adequacy and reliability of the available data. Structural similarities and similarities in properties and/or activities of the source and target substance are the basis of read-across. A detailed justification for the grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Section 13).

CAS 91031-48-0

A developmental toxicity study was performed according to OECD Guideline 414 under GLP conditions (key study, 1994). This study was selected as key study for assessment of developmental toxicity of the target substance. Twenty-four female Sprague-Dawley rats per dose were administered 0, 100, 300 and 1000 mg/kg bw/day Fatty acids, C16-18, 2-ethylhexyl esters (CAS 91031-48-0) once daily from day 6 up to day 15 of gestation via gavage in arachis oil as vehicle. Maternal animals were examined for clinical signs, mortality, body weight changes, and gross pathology. Number of abortions, pre- and post-implantation losses, total litter losses, duration of pregnancy, early and late resorptions, dead foetuses, pregnancy rate, placenta and uterus weight were assessed. In foetuses body weight changes, number of live offspring, sex ratio, external, visceral and skeletal malformations were assessed. No adverse effects on maternal toxicity, maternal developmental toxicity and foetuses were observable up to the limit dose of 1000 mg/kg/day. Based on the absence of adverse toxic effects, the NOAEL for developmental toxicity/teratogenicity and for maternal developmental toxicity is considered to be 1000 mg/kg bw/day.

CAS 22393-85-7

A combined repeated dose toxicity study with a reproduction/developmental toxicity screening test was performed according to OECD Guideline 422 under GLP conditions (key study, 2014) with tetradecyl oleate (CAS 22393-85-7). No toxicologically relevant treatment related adverse effects were seen on viability, clinical signs, body weight, sex ratio, and gross pathology of F1 offspring. Based on these results, a developmental NOAEL of ≥ 1000 mg/kg was determined.

Overall conclusion for effects on developmental toxicity

Analogue read-across from source substances was applied for developmental toxicity. No toxicologically relevant effects on F1 offspring were observed in the available screening studies. The NOAEL for developmental toxicity was 1000 mg/kg bw/day. Based on the available data and following the analogue approach, absence of adverse effects on developmental toxicity can be expected for the target substance Fatty acids, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS).

Mode of Action Analysis / Human Relevance Framework

Not applicable

Justification for classification or non-classification

According to Article 13 of Regulation (EC) No. 1907/2006 "General Requirements for Generation of Information on Intrinsic Properties of substances", information on intrinsic properties of substances may be generated by means other than tests e.g. from information from structurally related substances (grouping or read-across), provided that conditions set out in Annex XI are met. Annex XI, "General rules for adaptation of this standard testing regime set out in Annexes VII to X” states that “substances whose physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity may be considered as a group, or ‘category’ of substances. This avoids the need to test every substance for every endpoint". Since the analogue concept is applied to Fatty acids, C16, C18 and C18-unsaturated, C12-15 alcohol (linear and branched), esters (no CAS) data will be generated from data for reference source substance(s) to avoid unnecessary animal testing. Additionally, once the analogue read-across concept is applied, substances will be classified and labelled on this basis.

Based on the analogue read-across approach, the available data on reproduction toxicity (fertility and development/teratogenicity) do not meet the classification criteria according to Regulation (EC) 1272/2008 are therefore conclusive but not sufficient for classification.

Additional information

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