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

Endpoint summary

Description of key information

Structural analogues do not show a significant repeated dose toxicity by oral route.

Overall, a NOAEL of 100 mg/kg bw per day can be estimated for Fatty acids, C16-C18(even numbered) methyl esters, chlorinated.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Endpoint:

sub-chronic toxicity: oral

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable deviations

Justification for type of information:

According to Reg. (EU) 1907/2006, the repeated dose toxicity of substance must be addressed and reported. Nevertheless, the assessment of the repeated dose 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 behavior 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, 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 study on Medium Chain Chlorinated Paraffins/Alkanes, C14-C17, chloro supports the lack of a significant repeated dose toxicity due to the chlorination process of carbon long chains, while study on ethyl oleate (EO) provides insight of the absence of toxicity of Fatty acids esters.
A subchronic oral feeding study was performed with EO (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. The purpose of the study was to determine the safety of ethyl oleate (EO) in a subchronic feeding study in Sprague-Dawley rats. EO was mixed into AIN-93G purified diet at levels of 0, 3.3, 6.7, and 10% by weight (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, hematology, clinical chemistry, urinalysis, organ weights, histopathology). The subchronic oral NOAEL was determined to be 10% ethyl oleate, which corresponds to approximately 5500 mg/kg bw/day when administered by daily feeding to rats for 91-days.
While, a number of studies have investigated the repeated dose oral toxicity of C14-17 chlorinated paraffins (40% or 52% chlorination) in rodents. Those allow the identification of an overall NOAEL of 100 mg/kg bw/day, from a 90-day dietary study in rats. Increased kidney and liver weights, liver enzyme induction, liver hypertrophy and slight decreases in plasma triglycerides and cholesterol levels were seen at the next higher dose of 222 mg/kg bw/day.
Overall, repeated dose toxicity of Fatty acids, C16-C18(even numbered) methyl esters, chlorinated can be estimated from data discussed above.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

effects observed, treatment-related

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITYNo treatment-related mortalities or clinical signs of toxicityBODY WEIGHT AND WEIGHT GAINReduction in body weight gain at top dose in both sexesFOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)Reduction at top dose level for both sexesWATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)not relevantOPHTHALMOSCOPIC EXAMINATIONNo treatment-related effectsHAEMATOLOGYNo toxicologically-significant changesCLINICAL CHEMISTRYSlight, but statistically significant blood biochemistry changes were noted in both sexes at the top dose (blood urea nitrogen increased by 35% and total protein increased by 13%). A statistically significant increase (25%) in serum cholesterol was also noted in females at the top dose.URINALYSISMarked decreases in urinary volume at each of weeks 5, 8, and 13 (males, 52-72% lower than controls, females 58-74% lower than controls), with concommitant increases in specific gravity and osmolality at top dose.NEUROBEHAVIOURnot examinedORGAN WEIGHTSAbsolute and relative liver weights were statistically significantly increased in males and females at 100 mg/kg bw/day and above, compared with controls. Absolute and relative kidney weights were statistically significantly increased in males and females at the top dose only. There was also a significant increase in absolute thyroid weights in males at the top dose, and in adrenal weights in both sexes. GROSS PATHOLOGYNo treatment-related effectsHISTOPATHOLOGY: NON-NEOPLASTICIn the top-dose group, hepatocellular hypertrophy in males (13/15) and females (13/15), thyroid hypertrophy and hyperplasia in males only; chronic nephritis (trace to mild) in males only; renal tubular pigment in females only;Other histopathological findings were not considered by the investigators to be treatment-related.HISTOPATHOLOGY: NEOPLASTIC (if applicable)Not applicableHISTORICAL CONTROL DATA (if applicable)Not applicable OTHER FINDINGS

Dose descriptor:

NOAEL

Effect level:

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

Sex:

male/female

Basis for effect level:

other:

Remarks on result:

other: None

Critical effects observed:

not specified

Conclusions:

No adverse treatment-related effects were seen in male and female Fischer 344 rats given Cereclor S52 in the diet for 13 weeks at nominal dose levels of 10 and 100 mg/kg bw/day, whereas at 625 mg/kg bw/day (highest tested dose) adverse effects in the thyroid, liver and kidney were seen. Based on kidney changes at 625 mg/kg bw/day, a NOAEL of 100 mg/kg bw/day is identified for this C14-17 chlorinated paraffin (52% chloination) in rats.

Endpoint conclusion

Endpoint conclusion:

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.

Organ:

liver

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available