Glycerides, mixed C8-10 and succinyl

Endpoint summary

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 adequate, reliable (Klimisch score 2) and consistent studies from reference substances with similar structure and intrinsic properties. Read-across is justified based on structural similarity between the source and target substances, sharing common functional groups (esters of glycerol with carboxylic acids), common precursors and breakdown products (glycerol, fatty acids and succinic acid) and similarities in toxicological properties (overall low toxicity). Refer to endpoint discussion for further details.
The selected study, in conjunction with the further available data and in a weight of evidence approach, 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

Justification for grouping of substances and read-across

There are no data available on the toxicity to reproduction of Glycerides, mixed C8-C10 and succinyl (CAS 91744-56-8). In order to fulfil the standard information requirements set out in Annex IX, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances is conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, whereby physicochemical, toxicological and ecotoxicological properties may be predicted from data for reference substance(s) by interpolation to other substances on the basis of structural similarity, 2,3-dihydroxypropyl oleate (CAS 111-03-5), glycerol trioctanoate (CAS 538-23-8), Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates (CAS 91052-13-0), Glycerides, castor-oil, mono, hydrogenated, acetates (CAS 736150-63-3), Medium-chain triglycerides (no CAS) and disodium succinate hexahydrate (CAS 6106-21-4) are selected as reference substances for assessment of the toxicity to reproduction of Glycerides, mixed C8-C10 and succinyl.

The read-across is based on structural similarity between the source and target substances, as the substance Glycerides, mixed C8-C10 and succinyl is composed of esters of glycerol with succinic acid and fatty acids with carbon chain lengths of C8 and C10. A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Overview of toxicity to reproduction

CAS#	Chemical name	Molecular weight (range)	Toxicity to reproduction – screening studies	Toxicity to reproduction – two-generation studies	Toxicity to reproduction – (pre-natal) development
91744-56-8 (a)	Glycerides, mixed C8-C10 and succinyl	470.68-1211.64	WoE: RA: CAS 111-03-5 RA: CAS 8001-79-4 RA: CAS 91052-13-0 RA: CAS 6106-21-4	WoE: RA: CAS 736150-63-3	WoE: RA: CAS 538-23-8 RA: CAS 736150-63-3 RA: Short-, medium- and long-chain triglycerides (SCT, MCT, LCT)
111-03-5 (b)	2,3-dihydroxypropyl oleate	356.55	Experimental result: NOAEL (fertility) =1000 mg/kg bw/day NOAEL (development) = 1000 mg/kg bw/day	--	--
538-23-8	Glycerol trioctanoate	470.70	--	--	Experimental result: NOAEL (teratogenicity, mouse) = 9540 mg/kg bw/day NOAEL (teratogenicity, rabbit) = 2862 mg/kg bw/day
91052-13-0	Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates	302.36-442.63	Experimental result: NOAEL (fertility) = 1000 mg/kg bw/day NOAEL (development) = 1000 mg/kg bw/day	--	--
736150-63-3	Glycerides, castor-oil, mono, hydrogenated, acetates	500.67	--	Experimental result: NOAEL (P; male/female) ≥ 1159/2200 mg/kg bw/day NOAEL (F1; male/female) ≥ 1342/2262 mg/kg bw/day	NOAEL (development, rat F1&F2; male/female) ≥ 1342/2262 mg/kg bw/day
no CAS	Short-, medium- and long-chain triglycerides (SCT, MCT, LCT)	-	--	--	Experimental result: NOAEL (pre-natal development, rat) = 4280 mg/kg bw/day NOAEL (pre-natal development, rabbit) = 1000 mg/kg bw/day
6106-21-4	Disodium succinate hexahydrate	270.14	Experimental result: NOAEL (fertility) = 1000 mg/kg bw/day NOAEL (development) = 1000 mg/kg bw/day	--	--

(a) The substance subject to the REACh Phase-in registration deadline of 31 May 2013 is indicated in bold font. Only for this substance a full set of experimental results and/or read-across is given.

(b) Reference (read-across) substances are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

 

Toxicity to reproduction – screening studies

CAS No. 111-03-5

A GLP-compliant reproductive toxicity screening study according to OECD 422 was performed with 2,3-dihydroxypropyl oleate at dose levels of 100, 300 and 1000 mg/kg bw/day (Yamaguchi, 2005). Male and female 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 rats is 1000 mg/kg bw/day.

CAS No. 91052-13-0

An oral gavage screening toxicity study was performed according to OECD guideline 422 and under conditions of GLP in rats at doses of 0, 100, 300 and 1000 mg/kg bw/day (Otterdijk, 2010). Dilutions of the test substance in polyethylene glycol were administered once daily to groups of 10 male and 5 female rats (main animals) via gavage. A similar constituted group received the vehicle and served as a control. In addition, satellite groups of 5 males and 5 females (recovery animals) each for the control and high dose group were used to investigate 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. Main and 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. In parental animals, no effects on reproductive function (spermatogenetic and oestrus cycle) and performance (mating, fertility and conception indices, precoital time, and number of corpora lutea and implantation sites) were observed after treatment compared to controls. Testis weight, epididymis weight, and histology of testes in males as well as histology of uterus epithelium in female did not reveal any substance-related effects in the parental animals. No toxicologically relevant alterations in offspring viability indices were observed. Therefore, a NOAEL for parental fertility of 1000 mg/kg bw/day was derived for male and female rats.

CAS No. 6106-21-4

In a combined repeated dose and reproductive/developmental toxicity screening test according to OECD 422 and in compliance with GLP, male and female rats were exposed to disodium succinate hexahydrate at dose levels of 100, 300 and 1000 mg/kg bw/day (MHLW 2001). The diluted test substance was administered daily to 6 animals per sex and dose via oral gavage. Males were treated for a period of 52 days (14 days before mating, 14 days during mating and 24 days after mating), whereas females were exposed to the test substance 14 days before mating, 1-4 days during mating, 22 or 23 days during resulting pregnancies and 4 days during lactation, respectively. A similar constituted group of animals received the vehicle and acted as a control. Examination of body weights, organ weights including those of the reproduction organs, as well as parameters of haematology, clinical chemistry and urinalysis did not reveal any adverse findings attributable to treatment with the test substance. All findings observed at necropsy and histopathology were shown to be incidental and occurred without dose-dependency. No treatment-related effects on reproductive performance (copulation, fertility, gestation and implantation indices) and offspring viability (sex ratio and viability index) were observed after exposure to the test substance. Based on the results of the study, a NOAEL for parental fertility in male and female rats of 1000 mg/kg bw/day was derived.

At Day 5 of lactation, dams were sacrificed and ovaries and uterine content (no. of implantation sites, no. of corpora lutea and gravid uterus weight) was examined. In offspring, body weights, sex ratio and viability (delivery, birth, and viability indices) were determined and all animals per litter were examined for external and soft tissue abnormalities, respectively. In dams, no treatment-related effects on body weights, survival and the number of pregnant animals and implantations were observed. In offspring, no treatment-related effects on body weight, number of viable (number alive and number dead) and sex ratio were observed. No treatment-related grossly visible abnormalities and no external and soft tissue abnormalities were noted in any of the offspring examined. Since no adverse effects were observed up to the highest dose level, the NOAEL for maternal toxicity anddevelopmental toxicity in male and female rats was considered to be 1000 mg/kg bw/day.

Toxicity to reproduction – two-generation studies

CAS No. 736150-63-3

A Two-generation reproduction toxicity and developmental neurotoxicity study with Glycerides, castor-oil, mono, hydrogenated, acetates was performed in rats according to OECD guidelines 416 and 426 and in compliance with GLP (Fulcher, 2011). Groups of 28 parental animals per sex were exposed daily to the test substance at dietary concentrations of 1500, 6000 and 25000 ppm, corresponding to mean achieved dose levels of 82, 324 and 1159 mg/kg bw/day in males and mean achieved dose levels of 146, 587 and 2200 mg/kg bw/day in females, respectively. Parental males were treated with the test substance 10 weeks during maturation and throughout mating, gestation and until completion of the parental female lactation phase. Parental females received the test substance 10 weeks during maturation and throughout mating, gestation and until Day 21 of the lactation phases. After weaning, groups of 24 animals per sex of the F1 generation were exposed daily to the same dietary concentrations as their parental animals. The corresponding mean achieved dose levels in these animals were 109, 435 and 1342 mg/kg bw/day for F1 males and 160, 630 and 2262 mg/kg bw/day for F1 females, respectively. Males of the F1 generation received the diets a minimum of 10 weeks during maturation and subsequently throughout mating, gestation and until completion of the F1 female lactation phases. Females of the F1 generation were treated a minimum of 10 weeks during maturation and subsequently throughout mating, gestation and lactation phases. Between weaning and the formal start of the F1 generation, the animals continued to receive their appropriate treated diet. Animals of the F2 generation were exposed to the diets from weaning (Day 21 of age) to termination of the study on Day 70 of age. In each generation, animals administered with the high dose initially received the test material at a concentration of 15000 ppm and this was increased to 20000 ppm and finally 25000 ppm as the study progressed. Similar constituted control groups for each generation received laboratory diet enriched with Arachis oil to ensure comparable caloric intakes.

There were no treatment-related deaths and clinical signs in parental animals. During the study period, one animal of the control, mid and high dose group each were sacrificed humanely due to non-treatment-related clinical signs.

In parental animals, no adverse effects on reproductive functions were observed, as indicated by the examination of oestrous cycles, corpora lutea count, numbers of implantation sites or litter size at birth in females as well as sperm concentration, motility or morphology and homogenisation resistant spermatid counts of epididymides and testes in males. The reproductive performance as described by mating performance, fertility indices, data on gestation and parturition and sex ratio as well as lactation data, live birth and viability indices was not altered in treated animals compared to controls. An increase in organ weights (absolute and relative) of the left testes in parental males and thyroid weights in parental females was observed. The effects were considered to be incidental and not treatment-related, since they were not dose-related and not accompanied by respective changes in histopathology. No treatment-related effects were observed in parental animals at gross pathology and histopathological examination.

In animals of the F1 and F2 generation, no effects on viability and no clinical signs were observed either as consequence of maternal treatment after birth or due to of direct treatment after weaning. Body weights and food consumption in both generations of offspring were not adversely affected by treatment with the test substance. There were no obvious effects of treatment on the sexual maturation of either sex for the F1 animals receiving the test substance. Sex ratio at birth and subsequently at Day 21 of age was similar to concurrent control in all treatment groups over both generations. The slight variations in the mean ano-genital distance on Day 1 in F1 males at 1500 ppm and F2 females at 6000 ppm as well as the marginally higher visible nipple counts in F1 females at 25000 ppm, which were observed, were considered to be incidental and not treatment-related. No adverse effects were observed on reproductive performance of animals of the F1 generation.

In both generations, organ weights were not adversely altered by exposure to the test substance. Non dose-related variations in absolute and relative organ weights were observed in spleen and uterus of females of both generations.

No effects were observed on gross pathology in offspring and there were no histopathological findings observed for male and female behavioural offspring.

The neurotoxicological examination of the F0-F1 offspring of treated animals did not reveal any treatment-related effects when compared to the current F0-F1 offspring of the untreated control animals.

Based on the results of the study, the NOAEL for reproduction toxicity in parental animals is ≥ 1159 and ≥ 2200 mg/kg bw/day for males and females, respectively. For the F1 generation, the NOAEL for reproduction toxicity in males and females is ≥ 1342 and ≥ 2262 mg/kg bw/day, respectively. These doses corresponded to a concentration of 25000 ppm of the test substance in the diet.

Conclusions for toxicity to reproduction (fertility)

There are no data available on the toxicity to reproduction (fertility) of Glycerides, mixed C8-C10 and succinyl. The substance is composed of mixed esters of glycerol with octanoic (C8), decanoic (C10) and succinic acid. Therefore, hazard assessment is conducted by means of read-across and in a weight of evidence approach with available data for esters of glycerol with fatty acids as well as for succinic acid (sodium salt).

Combined repeated dose and reproductive/developmental toxicity screening test in rats are available for 2,3-dihydroxypropyl oleate (CAS 111-03-5), Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates (CAS 91052-13-0) and disodium succinate hexahydrate (CAS 6106-21-4). No effects on reproductive parameters and post-natal offspring development were observed in any of the studies up to and including the highest dose tested. Thus, in all cases the NOAEL for fertility and offspring development were 1000 mg/kg bw/day.

A combined two-generation reproduction toxicity and developmental neurotoxicity study is available for Glycerides, castor-oil, mono, hydrogenated, acetates (CAS 736150-63-3). No effects on reproductive parameters were observed in the P and F1 generations up to and including the highest dose level of 25000 ppm in diet, corresponding to 1159 and 2200 mg/kg bw/day for the P males and females, respectively, and 1342 and 2262 mg/kg bw/day for the F1 males and females, respectively.

Overall, the available data provide sufficient weight of evidence leading to the conclusion that the substance Glycerides, mixed C8-C10 and succinyl is not toxic to reproduction.

Short description of key information:

Based on read-across from glycerides and succinic acid (sodium salt) and in a weight of evidence approach, no hazard was identified.

All available short- and long-term studies on toxicity to reproduction resulted in NOAELs ≥ 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 structural analogues and surrogates. 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

Based on read-across from glycerides and succinic acid (sodium salt) and in a weight of evidence approach, no hazard was identified.

All available studies on developmental toxicity and teratogenicity resulted in NOAELs ≥ 1000 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, reliable (Klimisch score 2) and consistent studies from references substances with similar structure and intrinsic properties. Read-across is justified based on structural similarity between the source and target substances, sharing common functional groups (esters of glycerol with carboxylic acids), common precursors and breakdown products (glycerol, fatty acids and succinic acid) and similarities in toxicological properties (overall low toxicity). Refer to endpoint discussion for further details.
The selected study, in conjunction with the further available data and in a weight of evidence approach, 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

Justification for grouping of substances and read-across

There are no data available on the toxicity to reproduction of Glycerides, mixed C8-C10 and succinyl (CAS 91744-56-8). In order to fulfil the standard information requirements set out in Annex IX, 8.7, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances is conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, whereby physicochemical, toxicological and ecotoxicological properties may be predicted from data for reference substance(s) by interpolation to other substances on the basis of structural similarity, 2,3-dihydroxypropyl oleate (CAS 111-03-5), glycerol trioctanoate (CAS 538-23-8), Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates (CAS 91052-13-0), Glycerides, castor-oil, mono, hydrogenated, acetates (CAS 736150-63-3), Medium-chain triglycerides (no CAS) and disodium succinate hexahydrate (CAS 6106-21-4) are selected as reference substances for assessment of the toxicity to reproduction of Glycerides, mixed C8-C10 and succinyl.

The read-across is based on structural similarity between the source and target substances, as the substance Glycerides, mixed C8-C10 and succinyl is composed of esters of glycerol with succinic acid and fatty acids with carbon chain lengths of C8 and C10. A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Overview of toxicity to reproduction

CAS#	Chemical name	Molecular weight (range)	Toxicity to reproduction – screening studies	Toxicity to reproduction – two-generation studies	Toxicity to reproduction – (pre-natal) development
91744-56-8 (a)	Glycerides, mixed C8-C10 and succinyl	470.68-1211.64	WoE: RA: CAS 111-03-5 RA: CAS 91052-13-0 RA: CAS 6106-21-4	WoE: RA: CAS 736150-63-3	WoE: RA: CAS 538-23-8 RA: CAS 736150-63-3 RA: Short-, medium- and long-chain triglycerides (SCT, MCT, LCT)
111-03-5 (b)	2,3-dihydroxypropyl oleate	356.55	Experimental result: NOAEL (fertility) =1000 mg/kg bw/day NOAEL (development) = 1000 mg/kg bw/day	--	--
538-23-8	Glycerol trioctanoate	470.70	--	--	Experimental result: NOAEL (teratogenicity, mouse) = 9540 mg/kg bw/day NOAEL (teratogenicity, rabbit) = 2862 mg/kg bw/day
91052-13-0	Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates	302.36-442.63	Experimental result: NOAEL (fertility) = 1000 mg/kg bw/day NOAEL (development) = 1000 mg/kg bw/day	--	--
736150-63-3	Glycerides, castor-oil, mono, hydrogenated, acetates	500.67	--	Experimental result: NOAEL (P; male/female) ≥ 1159/2200 mg/kg bw/day NOAEL (F1; male/female) ≥ 1342/2262 mg/kg bw/day	NOAEL (development, rat F1&F2; male/female) ≥ 1342/2262 mg/kg bw/day
no CAS	Short-, medium- and long-chain triglycerides (SCT, MCT, LCT)	-	--	--	Experimental result: NOAEL (pre-natal development, rat) = 4280 mg/kg bw/day NOAEL (pre-natal development, rabbit) = 1000 mg/kg bw/day
6106-21-4	Disodium succinate hexahydrate	270.14	Experimental result: NOAEL (fertility) = 1000 mg/kg bw/day NOAEL (development) = 1000 mg/kg bw/day	--	--

(a) The substance subject to the REACh Phase-in registration deadline of 31 May 2013 is indicated in bold font. Only for this substance a full set of experimental results and/or read-across is given.

(b) Reference (read-across) substances are indicated in normal font. Lack of data for a given endpoint is indicated by “--“.

 

Toxicity to reproduction – (pre-natal) development

CAS No. 538-23-8

The teratogenic potential of Glycerol trioctanoate was investigated in mice at dose volumes of 2 and 10 mL/kg bw/day, corresponding to doses of 1908 and 9540 mg/kg bw/day, as 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 pregnancy. Two similar constituted control groups received saline or soybean oil as vehicle, respectively. At Day 18 of pregnancy, dams were sacrificed and maternal and foetal examinations were performed. In dams, no substance-related effects on the number of implantations and early resorptions were observed compared to controls. 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 and cervical vertebra). Based on these results, a NOAEL of 9540 mg/kg bw/day was derived for teratogenicity in male and female mice.

In a further teratogenicity study, the undiluted test substance was administered once daily at a dose volume of 3 mL/kg bw/day (approximately 2862 mg/kg bw/day based on a density of density of 0.954 g/mL) via gavage to 8 female rabbits during Day 7 and 16 of pregnancy (Ohta et al., 1970). Two control groups of 8 females each were gavaged with 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 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, a NOAEL of 2862 mg/kg bw/day was derived for teratogenicity in male and female rabbits.

CAS No. 736150-63-3

A Two-generation reproduction toxicity and developmental neurotoxicity study with Glycerides, castor-oil, mono, hydrogenated, acetates was performed in rats according to OECD guidelines 416 and 426 and in compliance with GLP (Fulcher, 2011). Groups of 28 parental animals per sex were exposed daily to the test substance at dietary concentrations of 1500, 6000 and 25000 ppm, corresponding to mean achieved dose levels of 82, 324 and 1159 mg/kg bw/day in males and mean achieved dose levels of 146, 587 and 2200 mg/kg bw/day in females, respectively. Parental males were treated with the test substance 10 weeks during maturation and throughout mating, gestation and until completion of the parental female lactation phase. Parental females received the test substance 10 weeks during maturation and throughout mating, gestation and until Day 21 of the lactation phases. After weaning, groups of 24 animals per sex of the F1 generation were exposed daily to the same dietary concentrations as their parental animals. The corresponding mean achieved dose levels in these animals were 109, 435 and 1342 mg/kg bw/day for F1 males and 160, 630 and 2262 mg/kg bw/day for F1 females, respectively. Males of the F1 generation received the diets a minimum of 10 weeks during maturation and subsequently throughout mating, gestation and until completion of the F1 female lactation phases. Females of the F1 generation were treated a minimum of 10 weeks during maturation and subsequently throughout mating, gestation and lactation phases. Between weaning and the formal start of the F1 generation, the animals continued to receive their appropriate treated diet. Animals of the F2 generation were exposed to the diets from weaning (Day 21 of age) to termination of the study on Day 70 of age. In each generation, animals administered with the high dose initially received the test material at a concentration of 15000 ppm and this was increased to 20000 ppm and finally 25000 ppm as the study progressed. Similar constituted control groups for each generation received laboratory diet enriched with Arachis oil to ensure comparable caloric intakes.

In animals of the F1 and F2 generation, no effects on viability and no clinical signs were observed either as consequence of maternal treatment after birth or due to of direct treatment after weaning.

Body weights and food consumption in both generations of offspring were not adversely affected by treatment with the test substance. There were no obvious effects of treatment on the sexual maturation of either sex for the F1 animals receiving the test substance. Sex ratio at birth and subsequently at Day 21 of age was similar to concurrent control in all treatment groups over both generations. The slight variations in the mean ano-genital distance which were observed on Day 1 in F1 males at 1500 ppm and F2 females at 6000 ppm as well as the marginally higher visible nipple counts in F1 females at 25000 ppm were considered to be incidental and not treatment-related.

In both generations, organ weights were not adversely altered by exposure to the test substance. Non-dose-related variations in absolute and relative organ weights were observed in spleen and uterus of females of both generations.

No effects were observed on gross pathology in offspring and there were no histopathological findings observed for male and female behavioural offspring.

The neurotoxicological examination of the F0-F1 offspring of treated animals did not reveal any treatment-related effects when compared to the current F0-F1 offspring of the untreated control animals.

Based on the results of the study, the NOAEL for developmental toxicity in male and female rats of the F1 and F2 generation was 1342 and 2262 mg/kg bw/day, respectively. These doses corresponded to a concentration of 25000 ppm of the test substance in the diet.

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 rats were investigated during Days 6 to 15 of gestation (Henwood, 1997). The animals (25 or 29 for the low and high dose, respectively) 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/d by intravenous infusion via the caudal vein for a 4-h period per day. 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. At 4280 mg/kg bw/day, maternal toxicity occurred and involved an increased incidence of necropsy findings on the tail, which was considered to be due to extravasation of the MCT:LCT lipid test article into perivascular areas. In addition to tail effects, there was a trend toward an increasing incidence of necropsy findings in the high-dose group, including enlarged lymph nodes, enlarged spleen, hydronephrosis/enlarged renal pelvis, small thymus, and small red lung foci. There were no significant group differences in pre-implantation or post-implantation loss or in the mean percentage of live or resorbed foetuses in treated animals. No dead foetuses were found and the mean foetal sex ratios and the mean foetal body weight of the treated animals were comparable to those of controls. No test substance-related external, soft tissue, or skeletal malformations were noted in the foetuses of exposed mothers. Based on the results of the study, the NOAEL for developmental toxicity in male and female rats was established at 4280 mg/kg bw/day.

In the same study, 15 female rabbits were treated daily with MCT (Medium Chain Triglycerides) by a 5-h intravenous infusion via a marginal ear vein at doses of 1000 and 4280 mg/kg bw/d from gestation day 6 through 19 (Henwood, 1997). A similar constituted control group was injected with 0.9% saline. Administration of the test substance resulted in lower maternal food consumption and significant body weight loss during treatment at 4280 mg/kg bw/day. All pregnant animals had at least one viable foetus at scheduled caesarean section on GD 29. The observed foetal effects (i.e. increased resorptions, decreased foetal 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. Based on these results, the NOAEL for developmental toxicity was set at 1000 mg/kg bw/day in rabbits.

Conclusions for toxicity to reproduction (development)

There are no data available on the developmental toxicity/teratogenicity of Glycerides, mixed C8-C10 and succinyl. The substance is composed of mixed esters of glycerol with octanoic (C8), decanoic (C10) and succinic acid. Therefore, hazard assessment is conducted by means of read-across and in a weight of evidence approach with available data for esters of glycerol with fatty acids as well as for succinic acid (sodium salt).

The available data on the developmental toxicity/teratogenicity comprise reproductive/developmental toxicity screening studies with 2,3-dihydroxypropyl oleate (CAS 111-03-5), Glycerides, C8-18 and C18-unsatd. mono- and di-, acetates (CAS 91052-13-0) and disodium succinate hexahydrate (CAS 6106-21-4) (see Toxicity to reproduction), as well as (pre-natal) developmental toxicity studies with glycerol tridecanoate (CAS 538-23-8), Glycerides, castor-oil, mono, hydrogenated, acetates (CAS 736150-63-3) and Medium-chain triglycerides. Only one study reported foetal effects in rabbits given 4280 mg/kg bw/day of Medium Chain Triglycerides, attributable to maternal toxicity. The substance did not produce any effects in rats at the same dose level and in rabbits given 1000 mg/kg bw/day.

Altogether, no effects on (pre-natal) development were observed in any of studies in rats, rabbits and mice. NOAEL values for (pre-natal) developmental toxicity were all at or well above the currently applied limit dose value of 1000 mg/kg bw/day. Thus, no hazard was identified.

Overall, the available data provide sufficient weight of evidence leading to the conclusion that the substance Glycerides, mixed C8-C10 and succinyl has no toxic effects on intrauterine development.

Justification for selection of Effect on developmental toxicity: via oral route:

Hazard assessment is conducted by means of read-across from structural analogues and surrogates. 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

Based on read-across from structural analogues and surrogates, the available data on the toxicity to reproduction of Glycerides, mixed C8-C10 and succinyl do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classifiaction.