Fatty acids, C16 and C18-unsaturated, methyl esters, chlorinated

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

Based on data available for fatty acid esters and chloroparaffin, no toxic effect to fertility is expected. 

Link to relevant study records

Reference

Endpoint:

extended one-generation reproductive toxicity - basic test design (Cohorts 1A, and 1B without extension)

Remarks:

based on test type (migrated information)

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

According to Reg. (EU) 1907/2006, the reproductive toxicity study on test substance must be reported. Nevertheless, the assessment of the reproductive toxicity of the substance can be derived from the relevant available information.
No specific studies have been performed using the Fatty acids, C16-C18(even numbered) methyl esters, chlorinated since, a read across to the studies on Medium Chain Chlorinated Paraffins/Alkanes, C14-C17, chloro has been proposed, together with publication on Ethyl oleate covering the behaviour of fatty acids methyl esters chain.
Based on chemical structure the Medium Chain Chlorinated Paraffins/Alkanes, C14-C17, chloro is produced from C14-C17 alkane via chlorination. The chlorination process will chlorinate C-H bonds more or less randomly, although it is known that the sequence would be to chlorinate each carbon atom in the chain with one chlorine atom before putting a second chlorine atom on a carbon atom which already carries one chlorine atom. The process produces numerous potential isomers and identification of individual isomers is not possible.
While, the Fatty acids, C16-C18(even numbered) methyl esters, chlorinated is produced from C16-C18 methyl esters with a similar randomly chlorination. Fatty acid esters are generally produced by chemical reaction of an alcohol (e.g. methanol) with an fatty acidin the presence of an acid catalyst. Monoesters are the final products of esterification of fatty acids with methanol.
Therefore, the study on Medium Chain Chlorinated Paraffins/Alkanes, C14-C17, chloro provides evidence about the reproductive toxicity of chlorinated compounds while, information on ethyl oleate provides evidence about the reproductive toxicity of fatty acids esters.
The literature study on ethyl oleate does not show reproductive toxicity.
In particular, a 90-day oral feeding study was performed with ethyl oleate (CAS 111-62-6) according to the 1993 FDA draft "Redbook II" guidelines (Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Additives Used in Food). The study was performed equivalent to OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents) with additional assessment of oestrus cycle and sperm parameters. The purpose of the study was to determine the safety of ethyl oleate (EO) in a 91-day feeding study in Sprague-Dawley rats. EO was mixed into AIN-93G purified diet at levels of approx. 0, 1900, 3800 and 6000 mg/kg bw/day. All diets were calorie- and fat-matched using high oleic safflower oil (HOSO) as the control fat. There were 20 male and 20 female rats per group. EO in the diet was well-tolerated and there were no toxicologically significant findings in any of the measured parameters (clinical observations, body weight gains, appearance of the faeces, ophthalmic examinations, haematology, clinical chemistry, urinalysis, organ weights, histopathology, or male and female reproductive assessments). Based on the absence of abnormalities concerning oestrus cycle, sperm characterization and histopathologic evaluations the subchronic 90-day oral NOAEL for fertility in rats for ethyl oleate was found to be approx. 6000 mg/kg bw/day.
While, the data from Medium Chain Chlorinated Paraffins/Alkanes, C14-C17, chloro demonstrated that also the presence of chlorinated compounds does not increase the reproduction toxicity.
In a one-generation study (Stamp, 2006) [CXR, 2006] conducted according to OECD Guideline 421, and to GLP, groups of 12 male and 12 female CD-strain (Sprague-Dawley) rats (F0) were fed a diet containing 0, 300, 600 or 1200 ppm Cereclor S52 (a C14-17 chlorinated paraffin; 52% chlorinated) for 4 weeks before pairing, and throughout pairing, gestation and lactation. F0 males were killed after 9 weeks of treatment (day 4 of lactation), whilst F0 females were allowed to litter and rear their offspring and were killed on day 21 of lactation (about 11-12 weeks of treatment). Additional groups of control and top dose F0 animals (5/group) were included to furnish blood, liver and milk samples for further analysis. The calculated intakes of Cereclor S52 during the various stages of the study were: F0 males pre-pairing 0, 21, 44 and 84 mg/kg bw/day; F0 females pre-pairing 0, 23, 47 and 99 mg/kg bw/day; F0 females during gestation 0, 25, 49 and 104 mg/kg bw/day and F0 females during lactation 0, 64, 121 and 212 mg/kg bw/day, for the control, 300, 600 and 1200 ppm dose groups, respectively. MCCP did not affect clinical condition, body weight gain, food intake, oestrous cycle length, mating performance, pre-coital interval, fertility, gestation length, the number of implantations, litter size, sex ratio, or offspring survival, clinical condition, body weights, body weight gains to weaning, tissue macropathology or liver weights. The 1200 ppm F0 females had marginally higher absolute and relative mean liver weights. The no-observed-adverse-effect level (NOAEL) for fertility in this study was 1200 ppm, equivalent to a parental intake of Cereclor S52 of approximately 100 mg/kg bw/day prior to giving birth.

Overall, the study on EO suggests the absence of reproductive toxicity of fatty acid esters while, based on the MCCP data, it's possible to exclude the relevance of chlorination for the reproductive toxicity.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Dose descriptor:

NOAEL

Effect level:

ca. 100 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other:

Remarks on result:

other: none

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

ca. 100 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other:

Remarks on result:

other: none

Reproductive effects observed:

not specified

Conclusions:

The dietary administration to male and female rats for 4 weeks before pairing, during mating, gestation and lactation of Cereclor S52 (a C14-17 n-alkane, 52% chlorinated), at levels up to 1200 ppm, had no adverse effects on reproduction and for pre- and post-natal survival, growth and development of the F1 offspring up to weaning and can be considered the no-observed-adverse-effect level (NOAEL) for these effects in this study.
In the same way, a reproductive toxicity study on ethyl oleate suggests the absence of reproductive toxicity for fatty acid esters until about 5.5-6.0 g/kg bw per day.
Overall, reproductive toxicity of "Fatty acids, C16-C18(even numbered) methyl esters, chlorinated" can be reasonably excluded.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

100 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Medium quality as based on read across data

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Description of key information

Based on data available for fatty acid esters and chloroparaffin, no toxic effect to development is expected. 

Link to relevant study records

Reference

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:

According to Reg. (EU) 1907/2006, the developmental toxicity study on test substance must be reported. Nevertheless, the assessment of the developmental toxicity of the substance can be derived from the relevant available information.
No specific studies have been performed using the Fatty acids, C16-C18(even numbered) methyl esters, chlorinated since, a read across to the studies on Medium Chain Chlorinated Paraffins/Alkanes, C14-C17, chloro has been proposed.
Based on chemical structure the Medium Chain Chlorinated Paraffins/Alkanes, C14-C17, chloro is produced from C14-C17 alkane via chlorination. The chlorination process will chlorinate C-H bonds more or less randomly, although it is known that the sequence would be to chlorinate each carbon atom in the chain with one chlorine atom before putting a second chlorine atom on a carbon atom which already carries one chlorine atom. The process produces numerous potential isomers and identification of individual isomers is not possible.
While, the Fatty acids, C16-C18(even numbered) methyl esters, chlorinated is produced from C16-C18 methyl esters with a similar randomly chlorination. Fatty acid esters are generally produced by chemical reaction of an alcohol (e.g. methanol) with an fatty acid in the presence of an acid catalyst. Monoesters are the final products of esterification of fatty acids with methanol.
The studies on Medium Chain Chlorinated Paraffins/Alkanes, C14-C17, chloro provides insight about developmental toxicity of chlorinated compounds.
No multi-generation studies have been conducted on MCCPs. However, C14-17 chlorinated paraffins have not shown any effects on fertility or development in reliable one-generation reproduction studies and conventional teratology studies, respectively.
At the same time, fatty acid esters do not show significant reproductive toxicity to suggest the absence of concern, even for Fatty acids, C16-C18(even numbered) methyl esters, chlorinated.

Reason / purpose for cross-reference:

read-across: supporting information

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Details on maternal toxic effects:

Maternal toxic effects:no effects.
Details on maternal toxic effects: three dams died during the study (one in the control group, one in the 10 and one in the 30 mg/kg bw/day groups). Abortions occurred in the control group (1 dam) and in the 30 (2 dams) and 100 (2 dams) mg/kg bw/day groups. The mortalities and pattern of abortions seen was not indicative of a treatment-related effect.

Dose descriptor:

NOAEL

Effect level:

ca. 100 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other:

Remarks on result:

other: None

Abnormalities:

not specified

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects. Details on embryotoxic / teratogenic effects: no adverse effects seen. The number of viable foetuses was significantly increased in the 30 mg/kg bw/day dose group, but within the historical control range for this parameter.

Dose descriptor:

NOAEL

Effect level:

ca. 100 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

not specified

Basis for effect level:

other: Tetratogenicty

Abnormalities:

not specified

Developmental effects observed:

not specified

Conclusions:

No treatment-related adverse effects were seen in pregnant rabbits given a C14-17 chlorinated paraffin (52% chlorinated) by oral gavage in corn oil at dose levels up to 100 mg/kg bw/day on gestational days 6 to 27, or on their foetuses examined on gestational day 28. Therefore, the test material was not toxic to development in rabbits under the conditions of this study. Consistent results were observed in rats where NOAEL was higher than 5000 mg/kg bw per day.
Based on those studies, the chlorination process of long carbon chain does not affect the developmental toxicity. This evidence together with the absence of reproductive toxicity seen in fatty acid esters support the absence of concern for "Fatty acids, C16-C18(even numbered) methyl esters, chlorinated".

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available