Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 2 due to read-across) from a reference substance 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, ecotoxicological and toxicological profile (refer to the endpoint discussion for further details).
The selected study is 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 fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information
Analogue justification

Data on the reproduction toxicity of 1,2,3-propanetriyl triisooctadecanoate (CAS No. 26942-95-0) are not available. The assessment was therefore based on studies conducted with analogue 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 analogue read-across applied is provided in the technical dossier (see IUCLID Section 13) and within Chapter 5.1 of the CSR.

Effects on fertility

CAS 91052-13-0

An oral gavage screening toxicity study was performed according to OECD guideline 422 and under GLP- conditions in Crl:WI(Han) Wistar rats receiving 100, 300 and 1000 mg/kg bw/day of Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates (CAS 91052-13-0) (Otterdijk, 2010). Dilutions of the test substance in polyethylene glycol or the vehicle alone were administered once daily to groups of 10 male and 5 female rats (main groups) via gavage. In addition, satellite groups of 5 males and 5 females (recovery animals) each for the control and high dose group were used to investigate the reversibility of effects during a 14-day post-exposure recovery period. Furthermore, 10 females (repro animals) were added to each group for the assessment of reproduction and developmental toxicity. The main and recovery groups 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 (during 2 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation). In parental animals, no effects on reproductive function (spermatogenetic and oestrus cycle) or performance (mating, fertility and conception indices, precoital time, and number of corpora lutea and implantation sites) were observed after treatment compared with the control animals. The testis weight, epididymis weight, and histological examination of the testes in males as well as the histological examination of the uterus epithelium in females did not reveal any substance-related effects in the parental animals. No toxicologically relevant changes in the offspring viability indices were observed. Therefore, a NOAEL for parental fertility of1000 mg/kg bw/day was derived for male and female rats.

CAS 111-03-5

A GLP-compliant reproductive toxicity screening study was performed according to OECD 422 with 2,3-dihydroxypropyl oleate (CAS 111-03-5) at dose levels of 100, 300 and 1000 mg/kg bw/day (Yamaguchi, 2005). Male and female Sprague Dawley rats (12 per sex and group, except for 1000 mg/kg bw/day: only 7 males) received the test substance in corn oil once daily via gavage. A control group, consisting of 7 males and 12 females, was treated with the vehicle alone. The duration of treatment was 42 days (14 days prior to mating and 28 days thereafter) in males and 42-52 days (from 14 days before mating to day 4 of lactation) in females, respectively. Satellite groups of 5 animals per sex, each for the control and test groups, were used to investigate reversibility of effects during a 14-day post-exposure recovery period. In parental animals, no difference in reproductive function was observed compared to controls. Reproductive performance (copulation, fertility, gestation indices) and offspring viability (delivery, live birth, sex ratio and viability indices) in treated animals were comparable to controls. No substance-related changes in organ weights and histopathology of reproductive organs in males and females were observed. Based on the results of the study, the NOAEL for reproductive toxicity in male and female Sprague Dawley rats is ≥1000 mg/kg bw/day.

CAS 8001-79-4

The reproductive toxicity of Castor oil (CAS 8001-79-4) was investigated in Fischer 344 rats and B6C3F1 mice in a GLP-conform study similar to OECD guideline 408 (NTP, 1992). The test substance was administered daily for a period of 13 weeks to groups of 20 animals/sex at dietary concentrations of 0.62, 1.25, 2.50, 5 and 10% (w/w). This corresponded to 404, 809, 1583, 3067 and 5835 mg/kg bw/day in male rats, and 401, 797, 1569, 3045 and 5725 mg/kg bw/day in female rats, respectively. In mice, the dietary percentage corresponded to 917, 2022, 3800, 7823 and 15017 mg/kg bw/day in males, and 1153, 2282, 5009, 9627 and 16786 mg/kg bw/day in females, respectively. The control group of rats and mice was treated with the plain diet. To screen for potential reproductive toxicity, sperm motility and morphology were evaluated at necropsy, and vaginal cytology was evaluated on core-study animals during the week just preceding necropsy. Exposure to the test substance did not produce any adverse effects on male (testes weight, epididymal sperm motility, density, or testicular spermatid head count) or female (oestrus cycle length, or time spent in each phase of the cycle) reproductive parameters in rats and mice. No histopathological changes were observed in organs relevant to reproduction (including adrenal glands, epididymis/seminal vesicles/prostate/testes or ovaries/uterus, mammary gland, pituitary gland, preputial or clitoral glands) in rats and mice receiving 10% (w/w) of the test substance. Based on the results of this study, the NOAEL for fertility for male and female Fischer 344 rats is ≥ 5835 and ≥ 5725 mg/kg bw/day, respectively. In B6C3F1-mice, a NOAEL of ≥ 15017 and ≥ 16786 mg/kg bw/day was set for fertility in males and females, respectively.

 

Overall conclusion foreffects on fertility

There are no available studies on the toxicity to reproduction and fertility of 1,2,3-propanetriyl triisooctadecanoate. Therefore read-across to source substances was applied.

The potential for reproductive toxicity of the source substances Tetradecyl oleate (CAS 22393-85-7), 2,3-dihydroxypropyl oleate (CAS 11-03-5) and Castor oil (CAS 8001-79-4) was assessed in two reproductive/developmental screening studies (OECD 422) and a repeated dose toxicity study (OECD 408) including reproductive parameters. The NOAEL value for fertility was considered to be higher than the currently applied limit dose value of 1000 mg/kg bw/day. Therefore, no hazard to reproduction was identified. Based on the available data and following the analogue approach, the target substance 1,2,3-propanetriyl triisooctadecanoate is considered to not affect fertility.

 


Short description of key information:
Oral: OECD 422, rat, NOAEL fertility = 1000 mg/kg bw/day
Oral: OECD 422, rat , NOAEL systemic = 1000 mg/kg bw/day

Justification for selection of Effect on fertility via oral route:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Effects on developmental toxicity

Description of key information
Oral: OECD 414, rabbit, NOAEL development = 2862 mg/kg bw/day
Oral: OECD 414, rabbit , NOAEL systemic = 2862 mg/kg bw/day
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises adequate and reliable studies (Klimisch score 2) 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, ecotoxicological and toxicological profile (refer to the endpoint discussion for further details).
The selected study is 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

Analogue justification

Data on the developmental toxicity/teratogenicity of 1,2,3-propanetriyl triisooctadecanoate (CAS No. 26942-95-0) are not available. The assessment was therefore based on studies conducted with analogue 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 analogue read-across applied is provided in the technical dossier (see IUCLID Section 13) and within Chapter 5.1 of the CSR.

Developmental toxicity/teratogenicity

CAS 538-23-8

The teratogenic potential of Glycerol trioctanoate (CAS 538-23-8) was investigated in ICR-JCL mice at dose volumes of 2 and 10 mL/kg bw/day, equivalent to doses of 1908 and 9540 mg/kg bw/day (calculated from a density of 0.954 g/mL) (Ohta et al., 1970). The test substance was diluted in a mixture of 1.2% Tween 80/0.8% Span 80 in water and administered once daily to groups of 20 females via gavage between day 7 and 12 of gestation. Two control groups received saline or soybean oil as vehicle, respectively. On Day 18 of pregnancy, dams were sacrificed and maternal and foetal examinations were performed. In the dams, no substance-related effects on the number of implantations and early resorptions were observed compared to control dams.Litter size and weights, the number of viable foetuses (number alive and number dead) and the sex ratio were comparable between treated and control animals. External, soft tissue and skeletal examination of exposed foetuses did not reveal any treatment-related effects compared to controls. Most findings in treated foetuses (curled tail, cleft palate and club foot) also occurred in controls or were of incidental nature (assimilation of ribs andcervical vertebra).Based on these results, a NOAEL of9540 mg/kg bw/day was derived for teratogenicity in male and female ICR-JCL mice.

In a second teratogenicity study, the undiluted test substance was administered once daily at a dose volume of 3 mL/kg bw/day (equivalent to 2862 mg/kg bw/day based on adensity of 0.954 g/mL) by gavage to 8 female rabbits, during Day 7-16 of gestation (Ohta et al., 1970). Two control groups of 8 females each were administered physiological saline or soybean oil, respectively. On Day 29 of gestation, animals were sacrificed and ovaries and uterine content as well as foetuses were examined. In the dams, no substance-related effects on the number of implantations or total litter losses by resorption were observed when compared to controls. No external or skeletal malformations were observed in the foetuses of exposed mothers. Litter size and weights, number of viable foetuses (number alive and number dead) and the sex ratio were comparable between control and treated animals. Based on the results of the study, the NOAEL for maternal toxicity is considered to be ≥ 2862 mg/kg bw/day. A NOAEL of ≥ 2862 mg/kg bw/day was derived for teratogenicity in male and female rabbits.

Short-, medium- and long-chain triglycerides (SCT, MCT, LCT)

In a prenatal developmental toxicity study performed similar to OECD guideline 414, the effects of Medium Chain Triglycerides (MCT) on female Crl:CD BR rats were investigated during Days 6 to 15 of gestation (Henwood, 1997). The animals received the test substance in 20% emulsion containing a 3:1 ratio of MCT:LCT (Long Chain Triglycerides) at doses of 1000 and 4280 mg/kg bw/day by intravenous infusion via the caudal vein for a 4-h period per day. There were 25 rats in the low dose and 29 in the high dose group, respectively. A control group of 25 animals received 0.9% saline. On Day 20 of gestation, dams were sacrificed and maternal as well as foetal examinations were performed. Maternal toxicity was observed in rats in the high-dose group, in the form of an increased incidence of necropsy findings on the tail; predominantly discoloration and ulceration. 1/25, 14/25, and 23/29 animals in the control, low-, and high-dose groups, respectively, showed effects ranging from mild to severe with some necrosis and partial loss of the tail. This was considered to be caused by extravasation of the MCT:LCT lipid test substance into perivascular areas. There was an increased incidence of macroscopic findings in the high-dose group, compared with the control group, including enlarged lymph nodes, enlarged spleen, hydronephrosis/enlarged renal pelvis, small thymus, and small red lung foci. These effects were considered to be substance-related for the animals in the high-dose group. Therefore, the NOAEL i.v. for maternal toxicity is considered to be 1000 mg/kg bw/day.

All the females, with the exception of one control dam, were pregnant and all pregnant females had at least one viable fetus/litter. There were no significant differences between the groups in pre-implantation or post-implantation loss or in the mean percentage of live or resorbed foetuses in treated animals. No dead foetuses were recorded, and the mean foetal sex ratios and the mean foetal body weight of the treated animals were comparable with those of the controls. No test substance-related external, soft tissue, or skeletal malformations were noted in the foetuses of treated females. Foetal skeletal variations were noted in control and treatment groups in similar frequencies. Based on the results of the study, the NOAEL for developmental toxicity in male and female Crl:CD BR rats was established at ≥ 4280 mg/kg bw/day.

In the same study, 15 female Hra:(NZW)SPF rabbits were treated daily with MCT (Medium Chain Triglycerides) with a 5-h intravenous infusion via a marginal ear vein at doses of 1000 and 4280 mg/kg bw/day from gestation day 6 through 19 (Henwood, 1997). A control group with 15 females was injected with 0.9% saline and otherwise handled the same as the treatment groups.

1/15 animals in the control group died on GD 11 and 1/15 in the high-dose group was sacrificed after aborting on GD 20. The animal that aborted had the lowest food consumption in the group. Decreased food consumption, resulting in a decline in the health of this animal, may have contributed to the abortion and was not considered to be substance-related. There were no remarkable necropsy findings for either animal. The clinical observations in the treatment groups were limited to an increased incidence of few or no faeces, including 3/15 high-dose females with no faecal output for 1 day during the dosing period. A significant loss of body weight was observed in high-dose rabbits during gestational day 7 - 20 in maternal rabbits, accompanied by reduced food consumption. The body weight gain during GD 7-20 in animals administered 4280 mg/kg bw/day showed a significant loss of body weight of - 124.8 g. The food consumption in the highest dose group was significantly lower than that for the control group during the early post-treatment period (GD 20 to 24). The decreased food consumption observed in this study was a predicted result of the high-caloric nature of the test article. There were no substance-related findings during necropsy.

All the pregnant animals had at least one viable foetus at scheduled caesarean section on GD 29. The mean percentage of total resorptions/litter (post-implantation loss) was significantly higher and the mean percentage of live foetuses/litter was correspondingly lower in the high-dose group, compared with the control group. The mean covariate-adjusted foetal body weights (males, females, and combined) for the high-dose group were significantly lower than the control group values. Increased incidence of abortion and implant resorption among pregnant rabbits subjected to dietary deprivation have been reported previously (Matsazawa et al., 1980).

The proportion of foetuses and litters in the high-dose group with external morphological abnormalities was significantly higher than that of the control group. The most notable findings were rachischisis and short tail seen in three and two high-dose litters, respectively. Single litter incidences were noted for the low-dose group; however, these were not considered to be substance-related as there was no dose-related effect. No external abnormalities were noted for the control group. Although the incidence of litters in the high-dose group with viscerally abnormal foetuses was also higher than controls, the difference was not statistically significant. In general, soft tissue abnormalities were present in the test article-treated groups as single foetal or litter incidences restricted to three or four litters/group, suggesting a litter-related occurrence. Because no soft tissue abnormalities (with the exception of absent azygous lobe of the lung) were noted for the control litters, the relationship of the abnormalities in the test article groups to the test article is inconclusive. The proportion of foetuses in the high-dose group with single variations [skull bones unossified, more than 26 presacral vertebrae, and 12 full pairs of ribs] and total skeletal abnormalities was significantly higher than those in the control group. The proportion of litters in this group with foetuses with single malformations was also significantly higher compared with the control group. Though not statistically significant, there was a notable increase in the number of high-dose foetuses/litter with malformations of the vertebral column. The anomalies were varied in location (cervical, thoracic, sacral, and caudal) and type (malformed, misaligned, absent, and fused).

The observed foetal effects (increased number of resorptions, decreased foetal body weights, and increased incidence of morphological anomalies) were considered to be the result of dietary deprivation, maternal toxicity, or both, rather than a direct teratogenic effect of the test substance. Based on these results, the NOAEL for developmental toxicity was set at 1000 mg/kg bw/day in rabbits.

Overall conclusion fordevelopmental toxicity/teratogenicity

There are no available studies on the developmental toxicity and teratogenicity of 1,2,3-propanetriyl triisooctadecanoate. Therefore read-across from source substances was applied.

The potential for developmental toxicity and teratogenicity of the source substances Medium Chain Triglycerides andGlycerol trioctanoate (CAS 538-23-8) was assessed in prenatal developmental toxicity studies (OECD 414), performed in the rat, the rabbit and the mouse. NOAEL values for developmental toxicity/teratogenicity were all at the currently applied limit dose value of 1000 mg/kg bw/day for the i.v. exposure and above this level for the oral exposure. Therefore, no hazard to in utero development was identified. Based on the available data and following the analogue approach, the target substance 1,2,3-propanetriyl triisooctadecanoate is considered to be not toxic to development.


Justification for selection of Effect on developmental toxicity: via oral route:
Hazard assessment is conducted by means of read-across from structural analogues. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

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 1,2,3-propanetriyl triisooctadecanoate (CAS No. 26942-95-0), 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 toxicity to reproduction does not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and is therefore conclusive but not sufficient for classification. Under Regulation (EC) No. 1907/2006,