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Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Additional information
Short description of key information:
No effect on fertility or on feti during reproductive tests. NOAEL > 1000 mg/kg bw/day

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Dose descriptor:
NOAEL
1 000 mg/kg bw/day

Toxicity to reproduction: other studies

Additional information

Further studies on reproduction are not proposed based on the followings:

1.1          Introduction

The basis for a weight of evidence approach consists of the following cumulative sources of confirmation:

·               The substance is of low toxicological activity.

·               The metabolism of the substance does not lead to reproductively toxic metabolites.

·               Evidence from chronic toxicity studies.

·               Evidence from reproductive toxicity studies.

1.2          The substance is of low toxicological activity;

There is no evidence of toxicity seen in any of the tests available, either short or long term

1.3          The metabolism of the substance does not lead to reproductively toxic metabolites.

Fatty acid methyl esters are metabolised as other dietary fats to fatty acids and methanol, neither of which have been shown to be reproductive toxins. Higher molecular weight aliphatic esters are readily hydrolysed to the corresponding alcohol and acid and then generally oxidised to carbon dioxide and water[1]. In addition there is data from human and animal studies that shows rapid absorption in the liver and breakdown of the substance into methanol and fatty acids; there is absence of the substance itself in the plasma/blood and in the urine. Methanol has been shown to not be a reproductive toxin.

In addition, topically applied fatty acid methyl esters can penetrate to the living cells of normal epidermis, enter into metabolism and significantly modify endogenous epidermal lipids[2].

 There is no direct evidence that exposure of people to methanol adversely affects reproduction or development. The NTP[3]states that there is minimal concern for adverse developmental effects when humans are exposed to methanol levels that result in low blood methanol concentrations, i.e., < 10 mg/L blood.Blood methanol levels of 10 mg/L or greater are not expected to result from normal dietary or occupational exposures.

1.4          Evidence from chronic toxicity studies

In a combined Repeated Dose Toxicity Study with the Reproduction/Development Toxicity Screening Test in Rats, four groups of 10 male and 10 female Sprague-Dawley rats were dosed orally by gavage once daily at levels of 0, 100, 300 and 1000 mg/kg/day. The males were treated for 2 weeks prior to mating, through until necropsy after at least 4 weeks of treatment. Females were treated for 2 weeks prior to mating, then through mating, gestation until at least Day 4 of lactation.[4]

At dose levels up to 1000 mg/kg/day, there was no obvious effects of treatment on clinical observations, necropsy findings, body weight gain or food consumption. There was no obvious indication of an effect of treatment on neurotoxicity observations or haematology, coagulation and clinical chemistry parameters. There was no obvious effect of treatment on organ weights and there were no histology findings that could be attributed to treatment with C16-C18 and C18 Unsaturated Alkyl Methyl Ester.

Under the conditions of the study, the NOEL (No Observed Effect Level) for both parental and reproductive effects was 1000 mg/kg/day.

In a 90 day on methyl oleate there were also no adverse effects seen.

1.5          Evidence from reproductive toxicity studies.

In a combined Repeated Dose Toxicity Study with the Reproduction/Development Toxicity Screening Test in Rats, four groups of 10 male and 10 female Sprague-Dawley rats were dosed orally by gavage once daily at levels of 0, 100, 300 and 1000 mg/kg/day. The males were treated for 2 weeks prior to mating, through until necropsy after at least 4 weeks of treatment. Females were treated for 2 weeks prior to mating, then through mating, gestation until at least Day 4 of lactation.[5]

At dose levels up to 1000 mg/kg/day, there was no obvious effects of treatment on clinical observations, necropsy findings, body weight gain or food consumption. There was no obvious indication of an effect of treatment on neurotoxicity observations or haematology, coagulation and clinical chemistry parameters.Mating performance, fertility, duration of gestation, survival, litter size and litter and pup weights did not indicate any obvious effect of treatment any of the dose levels applied.

Under the conditions of the study, the NOEL (No Observed Effect Level) for both parental and reproductive effects was 1000 mg/kg/day.

The 12 week study on rat and reproductive on females until 20 weeks showed no adverse effects.

1.6          Conclusion

There are no indications of effects related to reproductive toxicity from the good quality, well reported combined Repeated Dose Toxicity Study with the Reproduction/Development Toxicity Screening Test in Rats.


[1]         Mattison et al (J. Nutrition 102, 1171 (1972), J. Lipid Res 13, 325 (1972).

[2]         Philip W. Wertz and Donald T. Downing Metabolism of topically applied fatty acid methyl esters in BALB/C mouse epidermis Journal of Dermatological Science Volume 1, Issue 1, January 1990, Pages 33-37

[3]         NTP-CERHR Monograph on the Potential Human Reproductive and Developmental Effects of Methanol September 2003 NIH Publication No. 03-4478 National Toxicology Program (NTP).

[4]         C16-C18 and C18 Unsaturated Alkyl Methyl Ester: Combined Repeated Dose Toxicity Study with the Reproduction/Development Toxicity Screening Test in Rats. Test Facility Study No. 495325, Report No. 31335

[5]         C16-C18 and C18 Unsaturated Alkyl Methyl Ester: Combined Repeated Dose Toxicity Study with the Reproduction/Development Toxicity Screening Test in Rats. Test Facility Study No. 495325, Report No. 31335

Justification for classification or non-classification

No classification for reproductive toxicity is warrented at present under 67/548/EEC or Regulation 1272/2008.