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Effects on fertility

Additional information

An 28 day oral gavage screening study (van Otterdijk, 2010) was performed according to OECD guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction/Developmental Toxicity Screening Test) in Crl:WI(Han) (outbred, SPF-Quality) Wistar Han rats with Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates (CAS No. 91052 -13 -0). Doses of 0, 100, 300 and 1000 mg/kg bw/d were given to groups of four Main groups of 10 male and 5 female rats. Additionally, 5 Recovery group males and females in the control and high dose group were allowed 14 days of recovery.

An additional 10 females were added to each group for the assessment of reproduction and developmental toxicity. Recovery animals were exposed for at least 28 days from start of treatment up to termination or start of recovery. Females used for the assessment of reproduction/developmental toxicity were exposed for 41-49 days, i.e. during 2 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation.

Gonadal function was examined by histological evaluation of reproductive organs. Mating behavior, conception, parturition, clinical signs, mortality, body weight, food consumption, gross pathology, organ weights, histopathology, mating index, fertility index, number of implantation sites, duration of pregnancy, birth index, live birth index, pregnancy index, litter size, litter weight, pup weight, sex ratio, survival index, viability index were determined for all dose groups. No treatment related abnormalities were observed. Therefore a NOAEL for parental fertility of 1000 mg/kg bw/d was found.

Structural analogue read-across from Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates (CAS No. 91052-13-0) for mammalian toxicity was judged to be justified for the following reasons: This read across substance is also a glyceride, containing mainly C12-14 fatty acid and actetate moiety as well as glycerol. It’s an organic liquid with a pour point of -8 °C and a melting point of 357.85 °C and a vapour pressure < 0.01 Pa at room temperature. In contrast to the glycerides of the fatty acid glyceride category, it has a higher water solubility of 8.75 mg/L, which might influence its environmental distribution, but not the mammalian metabolism upon systemic uptake. Therefore it is expected to feed into the same mammalian physiological pathways as the members of the fatty acid glyceride category, like citric acid cycle, sugar synthesis and lipid synthesis. These processes are described in detail within the category justification.

A 90 day oral feeding study with Castor oil (CAS No. 8001 -79 -4) was performed equivalent to OECD Guideline 408 in F344/N rats and B6C3F1 mice (Irwin, NTP report 1992). The test substance was mixed at concentrations of 0, 0.62, 1.25, 2.50, 5.00, 10.0 % (w/w) to the diet and the animals were fed ad libitum for 13 weeks. 10 animals per sex and per dose were used. The highest dose was equivalent to approx. 5.7 g/kg bw/day for rats and approx. 15 g/kg bw/day for mice. No matings were performed, but male and female fertility parameters were analyzed in rats and mice including oestrous cycle length, caudal weight, epididymal weight, testis weight, sperm count/g testis, sperm motility (%) and histopathology of organs relevant for reproduction (including adrenal glands, epididymis/seminal vesicles/prostate/testes or ovaries/uterus, mammary gland, pituitary gland, preputial or clitoral glands). A complete histopathologic examination was conducted on all rats and mice from the control and 10% dose groups.

No significant changes were noted in a screening for male reproductive endpoints, including sperm count and motility, and no changes were observed in the length of oestrous cycles of rats or mice given diets containing castor oil. No histopathologic abnormalities were found in the reproductive organs.

A NOAEL of 5000 mg/kg bw/day for rats and a NOAEL of 15000 mg/kg bw/day for mice could be identified based on parental fertility parameters.


Short description of key information:
For Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates (CAS No. 91052 -13 -0) a NOAEL for parental fertility of 1000 mg/kg bw/d in rats could be identified.
For Castor oil (CAS No. 8001-79-4) a NOAEL for parental fertility of 5000 mg/kg bw/d in rats and 15000 mg/kg bw/d in mice could be identified.

Effects on developmental toxicity

Description of key information
For Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates (CAS No. 91052 -13 -0) a developmental NOAEL of 1000 mg/kg bw/d was found in rats.
Intravenously administered 20% lipid emulsion containing a 3:1 ratio of MCT (Medium Chain Triglycerides):LCT (Long Chain Triglycerides) revealed a NOAEL of 4280 mg/kg bw/day.
Additional information

In the same study as described above (van Otterdijk, 2010) with Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates (CAS No. 91052 -13 -0) a total number of 432 pups was euthanized at the age of 4 days. Based on litter size and weights, number viable (number alive and number dead), sex ratio, postnatal growth, postnatal survival, grossly visible external and soft tissue abnormalities a developmental NOAEL of 1000 mg/kg bw/d was found for Wistar rats.

A developmental toxicity study with rats and rabbits was conducted with a 20% lipid emulsion containing a 3:1 ratio of MCT (Medium Chain Triglycerides):LCT (Long Chain Triglycerides) (Henwood, 1997). Doses of 1000 and 4280 mg/kg bw/d were given intravenously from gestation day 6 through 15 (rats) or GD 7 through 19 (rabbits). The intravenous route of administration was used because the lipid emulsion is intended for intravenous human administration as a component of parenteral nutrition. The dose was administered daily to rats by intravenous infusion via a caudal vein and to rabbits via a marginal ear vein. In rats there were no treatment related direct teratogenic effects observed. In rabbits administration of the test article resulted in lower maternal food consumption and significant body weight loss during treatment at the highest dose level. Therefore, the observed foetal effects (i.e., increased resorptions, decreased fetal body weights, and increased incidence of morphological anomalies) were assumed to be the result of dietary deprivation, maternal toxicity, or both, rather than a direct teratogenic effect of the test article. The NOAEL was therefore set to be 4280 mg/kg bw /day for developmental toxicity for both, rats and rabbits.

Justification for classification or non-classification

According to DSD (67/548/EEC) or CLP (1272/2008/EC) classification criteria for reproduction, no classification is required.