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
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

The Glycerides category covers aliphatic (fatty) acid esters of glycerol. The category contains both well-defined and UVCB substances with aliphatic acid carbon chain lengths of C2 (acetate) and C7-C22, which are mostly linear saturated and even numbered. Some of the substances in the category contain unsaturated fatty acids (e.g. oleic acid in 2,3-dihydroxypropyl oleate, CAS 111-03-5 or general fatty acids C16-22 (even) unsaturated in Glycerides, C14-18 and C16-22-unsatd., mono- and di-, CAS 91744-43-7). Some category members contain branched fatty acids. Branching is mostly methyl groups (e.g. isooctadecanoic acid, monoester with glycerol, CAS 66085-00-5 or 1,2,3-propanetriyl triisooctadecanoate, CAS 26942-95-0). In one category member the branching cannot be precisely located (Glycerides, C16-18 and C18-unsatd., branched and linear mono-, di- and tri, ELINCS 460-300-6). Hydroxylated fatty acids are present in three substances (Castor oil, CAS 8001-79-4; castor oil hydrogenated, CAS 8001-78-3 and 2,3-dihydroxypropyl 12-hydroxyoctadecanoate, CAS 6284-43-1). Hydroxylation occurs on C12 of stearic acid in all these substances. Acetylated chains are present in the last part of the category, comprising fatty acids from C8 to C18 (even) and also C18 unsaturated, additionally a C18 acetylated fatty acid is present with the acetic acid located in C12 position (e.g. Glycerides, castor oil mono-, hydrogenated acetates / 12-acetoxy-octadecanoic acid, 2,3-diacetoxy, CAS 736150-63-3). All glycerides build mono-, di- and tri-esters in variable proportions. 

The available data allows for an accurate hazard and risk assessment of the category and the category concept is applied for the assessment of environmental fate, environmental and human health hazards. Thus where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group by interpolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, 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 grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Sections 7.1 and 13) and within Chapter 5.1 of the CSR.

 

Overview of Toxicity to reproduction

CAS

Toxicity to reproduction

Developmental toxicity/ teratogenicity

142-18-7 (a)

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE(Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

111-03-5 (b)

Experimental result (Annex VIII):
NOAEL (P; male/female) ≥1000 mg/kg bw/day

--

6284-43-1

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

620-67-7

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

538-23-8

--

Experimental result:
NOAEL (mouse) = 9540 mg/kg bw/day
NOAEL (rabbit) = 2862 mg/kg bw/day

122-32-7

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

555-43-1

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

85536-07-8

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

91052-49-2

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

67701-33-1

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

67784-87-6

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

97358-80-0

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

91052-28-7

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

91052-54-9

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

77538-19-3

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
RA: CAS 112-85-6
WoE (Annex IX):
RA: CAS 736150-63-3
RA: CAS 56-81-5

WoE:
RA: CAS 56-81-5
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

91744-28-4

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

68606-18-8

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

85536-06-7

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

8001-79-4

Experimental result (Annex VIII):
NOAEL (P; rat; male/female) = 5000 mg/kg bw/day
NOAEL (P; mice; male/female) = 15000 mg/kg bw/day

--

97593-30-1 (C10 )

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

97593-30-1 (C12)

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

93572-32-8

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

91052-13-0

Experimental result (Annex VIII):
NOAEL (P; male/female) = 1000 mg/kg bw/day

Experimental result:
NOAEL (F1) ≥ 1000 mg/kg bw/day

736150-63-3

Experimental result (Annex IX):
NOAEL (P; male/female) ≥1159/2200 mg/kg bw/day
NOAEL (F1; male/female) ≥1342/2262 mg/kg bw/day

Experimental result:
NOAEL (F1/F2; male/female) ≥1342/2262 mg/kg bw/day

no CAS

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

Experimental result (Annex IX):
Dose level (F1/F2; male/female) = 9800 mg/kg bw/day (no NOAEL identified)

Experimental result:
NOAEL (rat/rabbit) = 4280/1000 mg/kg bw/day

no CAS

Modified triglyceride. Main components: 1,3-dioleoyl 2-palmitoyl triacylglycerol and 1,2-dipalmitoyl 3-oleoyl triacylglycerol (c, d)

Experimental result (Annex IX):
NOAEL (P; male/female) ≥7500 mg/kg bw/day

 

56-81-5 (c)

Experimental result (Annex IX):
NOAEL (P; male/female) ca. 2000 mg/kg bw/day

Experimental result:
NOAEL (rat/rabbit/mouse) =1310/1180/1280 mg/kg bw/day

112-85-6 (c)

Experimental result (Annex VIII):
NOAEL (P/F1; male/female) ≥1000 mg/kg bw/day

Experimental result:
NOAEL ≥1000 mg/kg bw/day

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

(b) Substances that are either already registered under REACh or not subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in normal font. Lack of data for a given endpoint is indicated by "--".

(c) Surrogate substances are either chemicals forming part of a related category of structurally similar fatty acid esters or precursors/breakdown products of category members (i.e. alcohol and fatty acid moieties). Available data on these substances are used for assessment of (eco )toxicological properties by read-across on the same basis of structural similarity and/or mechanistic reasoning as described below for the present category.

(d) Assessment of toxicological properties is conducted also taking into account available data on mixtures of synthetic and/or naturally occurring glycerides (e.g. vegetable oils), which cannot be identified by a (single) CAS/EC number. The test materials short-, medium- and long-chain triglycerides (SCT, MCT, LCT) and their combinations (e.g. MLCT, SALATRIM – a SLCT) comprise triesters of glycerol with fatty acid chain lengths of C2 and C4 (short-chain), C8 and C10 (medium-chain) and C18 saturated/unsaturated (long-chain). The substance “Modified triglyceride” contains main components: 1,3-dioleoyl 2-palmitoyl triacylglycerol and 1,2-dipalmitoyl 3-oleoyl triacylglycerol, comprising triesters of glycerol with hexadecanoic (C16) and (9Z)-Octadec-9-enoic acid (C18:1). Available data on identity and composition of the individual test material for a given study is provided in the technical dossier.

 

Toxicity to reproduction

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 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 No. 8001-79-4

The reproductive toxicity of Castor oil 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 ad libitum for a period of 13 weeks to groups of 20 animals per sex at dietary concentrations of 0.62, 1.25, 2.50, 5 and 10% (w/w). These concentrations corresponded to doses of 404, 809, 1583, 3067 and 5835 mg/kg bw/day in male rats and 401, 797, 1569, 3045, 5725 mg/kg bw/day in female rats, respectively. In mice, dietary concentrations corresponded to 917, 2022, 3800, 7823, 15017 mg/kg bw/day in males and 1153, 2282, 5009, 9627, 16786 mg/kg bw/day in females, respectively. A similar constituted 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 for reproduction (including adrenal glands, epididymis/seminal vesicles/prostate/testes or ovaries/uterus, mammary gland, pituitary gland, preputial or clitoral glands) rats and mice receiving 10% of the test substance via diet. Based on the results of this study, the NOAEL for parental fertility for male and female Fischer 344 rats is ≥5835 and ≥5725 mg/kg bw/day, respectively. In B6C3F1mice, a NOAEL of ≥15017 and ≥16786 mg/kg bw/day was set for parental fertility in males and females, respectively.

CAS No. 91052-13-0

An oral gavage screening toxicity study was performed according to OECD guideline 422 and under conditions of GLP in Crl:WI(Han) Wistar 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 of1000 mg/kg bw/day was derived for male and female Crl:WI(Han) Wistar rats.

CAS No. 736150-63-3

A Two-generation reproduction toxicity and developmental neurotoxicity study with Glycerides, castor-oil, mono, hydrogenated, acetates was performed in Sprague-Dawley Crl:CD®(SD) IGS BR 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.

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

In a two-generation reproduction and lactation study, the effects of long-term exposure to medium chain triglycerides (MCT) were investigated in McCollum-Wisconsin rats (Harkins and Sarett, 1968). The test substance was administered daily at a limit concentration of 19.6% via the diet to male and female animals (corresponding to approximately 9800 mg/kg bw/day, assuming a food intake of 50 g/kg bw/day). In addition, a second group was administered a diet containing a conventional dietary fat (18.5% olive oil) and a third group received a low-fat diet containing 2.5% safflower oil. The parental animals were exposed to the test substance in the diet 3 weeks before mating, during the period of mating, gestation and lactation and until weaning of the F1 generation. After weaning, the F1 generation received same diets fed to their mothers, either containing MCT (diet 1), oleo oil (diet 2) or low fat (diet 3). At 12 weeks of age, the F1 generation was divided into 3 subgroups (each consisting of 3 experimental groups). One subgroup was continued on MCT, oleo oil or low fat diets, whereas the two other subgroups were switched to the diets containing one of the other two fats. Animals of the F1 generation received the test substance for 3 weeks until weaning, during growth into adulthood, before mating, and during mating and production of the F2 generation as well as during gestation, lactation and until weaning of the F2 generation. In both generations, the number and sex of pups, weight gain, and postnatal mortality were examined. Animals which received the MCT-containing diet did not show differences in the number of pups per litter compared to animals fed with conventional dietary fats (oleo oil). During the lactation period of the F1 generation, no differences in the incidence of mortality between the MCT diet group and animals receiving conventional dietary fats (oleo oil) were noted. However, animals of the F2 generation that were continued on MCT diet at 12 weeks of age and previously received MCT diet or low fat diet, showed increased mortality rates (22% or 20%, respectively). In contrast, animals which previously received the conventional oleo oil diet did not show increased mortality after switching to the MCT diet (only 6% mortality observed). The high rates of mortality in the group receiving MCT diets for 2 generations were suggested to be a result of the lower milk secretion by the mothers of the F1 generation. Body weights of the F1 and F2 generation of the MCT group at the day of birth, during lactation, at weaning and during growth into adulthood were comparable to those of the F1 and F2 generation of the oleo oil group. Based on the results of this study, the concentration levels which caused no adverse effects in the F1 generation was established at a dietary concentration of 19.6%. Due to the increased mortality, the concentration level for adverse effects in the F2 generation was determined to be at a dietary concentration of 19.6% (ca. 9800 mg/kg bw/day).

CAS No. 56-81-5

In a two-generation reproduction toxicity study, Glycerol was administered to 10 male and 10 female Albino rats at a dose level of 2000 mg/kg bw/day via oral gavage (Wegener, 1953). Parental females received the test substance diluted in water for at least 8 weeks (before and during mating), whereas parental males were treated with the diluted test substance for at least 12 weeks (8 weeks before mating, during mating and gestation (5/10 animals), through weaning of their F1 offspring (5/10 animals). A further group of 10 animals per sex received the vehicle only and served as controls. Half of the males and female of the F1 generation were exposed to the test substance during and via lactation (5/10 litters). The selection of parental animals from the F1 generation was performed when animals were 100 days of age. All other animals not selected as parental animals were sacrificed at this time point. No effects on the reproductive performance compared to controls were observed in any animal of the P and F1 generation. In the offspring of the F1 generation, post-natal mortality was increased in the test group compared with the control. Within the first 50 days post-partum, 12/90 (13.3%) animals in the test group and 3/73 (4.1%) animals in the control group died. However, it was unclear whether this increase in post-natal mortality was related to treatment of the P generation, as no other effects in the examined parameters were observed. No information on viability of pubs of the F2 generation was available. Body weight development in animals of both the F1 and F2 generation were not altered compared to controls. Furthermore, no effects were observed in the onset of oestrous cycle in either generation. In the F1 generation, no remarkable differences between control and test group offspring were noted in the relative weights of pituitary, thyroid, adrenals and testes. The mean relative ovaries weight was increased by ca. 17% in the offspring of the test group compared with the control offspring. It was unclear whether this effect was related to treatment of the P generation, as microscopic examination of the endocrine organs did not reveal any adverse findings compared to control. Histopathological examination of pituitary gland, thyroid, adrenals, ovaries and testes in both the F1 and F2 generation did not show any adverse findings. Based onthe study, the NOAEL was set at 2000 mg/kg bw/day for parental fertility and post-natal development and effects via lactation of the F1 generation in male and female rats, respectively.

CAS No. 112-85-6

In a combined repeated dose and reproductive/developmental toxicity screening test according to OECD 422 and in compliance with GLP, male and female Sprague Dawley rats were exposed to docosanoic acid at doses of 100, 300 and 1000 mg/kg bw/day (Nagao et al., 2002). The test substance in corn oil was administered daily to 13 animals per sex and dose via gavage. Males were treated for a period of 42 days, whereas females were exposed to the test substance 14 days prior to mating and until Day 3 of lactation. A similar constituted group received the vehicle and acted as a control. Testis and epididymis weight in males were not affected by treatment. No effects on reproductive performance (copulation, fertility, gestation and implantation indices) and offspring viability (delivery, birth, live birth, 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 Sprague Dawley rats ≥ 1000 mg/kg bw/day was set.

Overall conclusion for toxicity to reproduction

The available data on the toxicity to reproduction of Glycerides comprise several short- and long-term studies in rats and mice via the oral route. Available data from surrogate substances including the hydrolysis products glycerol and docosanoic acid are likewise taken into account for assessment. No effects on reproductive parameters/organs were observed in any of these screening and two-generation studies. NOAEL values for reproduction toxicity were all at or well above the currently applied limit dose value of 1000 mg/kg bw/day. Thus, no hazard to reproduction was identified.

Based on the available data and following the category approach, all members of the Glycerides category are considered to be not toxic to reproduction.


Short description of key information:
All available studies on toxicity to reproduction of Glycerides resulted in NOAELs ≥ 1000 mg/kg bw/day:
Reproductive/developmental toxicity screening studies (OECD 422): NOAEL (male/female) ≥ 1000 mg/kg bw/day
Two-generation reproduction toxicity and developmental neurotoxicity study (OECD 416/426): NOAEL (P; male/female) ≥ 1159/2200 mg/kg bw/day NOAEL (F1; male/female) ≥ 1342/2262 mg/kg bw/day

Effects on developmental toxicity

Description of key information
All available studies on developmental toxicity and teratogenicity of Glycerides resulted in NOAELs ≥ 1000 mg/kg bw/day:
Rat: NOAEL (F1/F2 ≥ 1342/2262 mg/kg bw/day (OECD 416/426)
Rabbit: NOAEL = 1000 mg/kg bw/day (similar to OECD 414)
Mouse: NOAEL = 9540 mg/kg bw/day (teratogenicity study)
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
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

The Glycerides category covers aliphatic (fatty) acid esters of glycerol. The category contains both well-defined and UVCB substances with aliphatic acid carbon chain lengths of C2 (acetate) and C7-C22, which are mostly linear saturated and even numbered. Some of the substances in the category contain unsaturated fatty acids (e.g. oleic acid in 2,3-dihydroxypropyl oleate, CAS 111-03-5 or general fatty acids C16-22 (even) unsaturated in Glycerides, C14-18 and C16-22-unsatd., mono- and di-, CAS 91744-43-7). Some category members contain branched fatty acids. Branching is mostly methyl groups (e.g. isooctadecanoic acid, monoester with glycerol, CAS 66085-00-5 or 1,2,3-propanetriyl triisooctadecanoate, CAS 26942-95-0). In one category member the branching cannot be precisely located (Glycerides, C16-18 and C18-unsatd., branched and linear mono-, di- and tri, ELINCS 460-300-6). Hydroxylated fatty acids are present in three substances (Castor oil, CAS 8001-79-4; castor oil hydrogenated, CAS 8001-78-3 and 2,3-dihydroxypropyl 12-hydroxyoctadecanoate, CAS 6284-43-1). Hydroxylation occurs on C12 of stearic acid in all these substances. Acetylated chains are present in the last part of the category, comprising fatty acids from C8 to C18 (even) and also C18 unsaturated, additionally a C18 acetylated fatty acid is present with the acetic acid located in C12 position (e.g. Glycerides, castor oil mono-, hydrogenated acetates / 12-acetoxy-octadecanoic acid, 2,3-diacetoxy, CAS 736150-63-3). All glycerides build mono-, di- and tri-esters in variable proportions.

The available data allows for an accurate hazard and risk assessment of the category and the category concept is applied for the assessment of environmental fate, environmental and human health hazards. Thus where applicable, environmental and human health effects are predicted from adequate and reliable data for source substance(s) within the group by interpolation to the target substances in the group (read-across approach) applying the group concept in accordance with Annex XI, Item 1.5, of Regulation (EC) No 1907/2006. In particular, 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 grouping of chemicals and read-across is provided in the technical dossier (see IUCLID Sections 7.1 and 13) and within Chapter 5.1 of the CSR.

 

Overview of Toxicity to reproduction

CAS

Toxicity to reproduction

Developmental toxicity/ teratogenicity

142-18-7 (a)

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE(Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

111-03-5 (b)

Experimental result (Annex VIII):
NOAEL (P; male/female) ≥1000 mg/kg bw/day

--

6284-43-1

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

620-67-7

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

538-23-8

--

Experimental result:
NOAEL (mouse) = 9540 mg/kg bw/day
NOAEL (rabbit) = 2862 mg/kg bw/day

122-32-7

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

555-43-1

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

85536-07-8

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

91052-49-2

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

67701-33-1

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

67784-87-6

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

97358-80-0

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

91052-28-7

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

91052-54-9

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

77538-19-3

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
RA: CAS 112-85-6
WoE (Annex IX):
RA: CAS 736150-63-3
RA: CAS 56-81-5

WoE:
RA: CAS 56-81-5
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

91744-28-4

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

68606-18-8

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

85536-06-7

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

8001-79-4

Experimental result (Annex VIII):
NOAEL (P; rat; male/female) = 5000 mg/kg bw/day
NOAEL (P; mice; male/female) = 15000 mg/kg bw/day

--

97593-30-1 (C10 )

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

97593-30-1 (C12)

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

93572-32-8

WoE (Annex VIII):
RA: CAS 91052-13-0
RA: CAS 8001-79-4
RA: CAS 111-03-5
WoE (Annex IX):
RA: CAS 736150-63-3

WoE:
RA: CAS 736150-63-3
RA: CAS 538-23-8
RA: MCT

91052-13-0

Experimental result (Annex VIII):
NOAEL (P; male/female) = 1000 mg/kg bw/day

Experimental result:
NOAEL (F1) ≥ 1000 mg/kg bw/day

736150-63-3

Experimental result (Annex IX):
NOAEL (P; male/female) ≥1159/2200 mg/kg bw/day
NOAEL (F1; male/female) ≥1342/2262 mg/kg bw/day

Experimental result:
NOAEL (F1/F2; male/female) ≥1342/2262 mg/kg bw/day

no CAS

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

Experimental result (Annex IX):
Dose level (F1/F2; male/female) = 9800 mg/kg bw/day (no NOAEL identified)

Experimental result:
NOAEL (rat/rabbit) = 4280/1000 mg/kg bw/day

no CAS

Modified triglyceride. Main components: 1,3-dioleoyl 2-palmitoyl triacylglycerol and 1,2-dipalmitoyl 3-oleoyl triacylglycerol (c, d)

Experimental result (Annex IX):
NOAEL (P; male/female) ≥7500 mg/kg bw/day

 

56-81-5 (c)

Experimental result (Annex IX):
NOAEL (P; male/female) ca. 2000 mg/kg bw/day

Experimental result:
NOAEL (rat/rabbit/mouse) =1310/1180/1280 mg/kg bw/day

112-85-6 (c)

Experimental result (Annex VIII):
NOAEL (P/F1; male/female) ≥1000 mg/kg bw/day

Experimental result:
NOAEL ≥1000 mg/kg bw/day

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

(b) Substances that are either already registered under REACh or not subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in normal font. Lack of data for a given endpoint is indicated by "--".

(c) Surrogate substances are either chemicals forming part of a related category of structurally similar fatty acid esters or precursors/breakdown products of category members (i.e. alcohol and fatty acid moieties). Available data on these substances are used for assessment of (eco )toxicological properties by read-across on the same basis of structural similarity and/or mechanistic reasoning as described below for the present category.

(d) Assessment of toxicological properties is conducted also taking into account available data on mixtures of synthetic and/or naturally occurring glycerides (e.g. vegetable oils), which cannot be identified by a (single) CAS/EC number. The test materials short-, medium- and long-chain triglycerides (SCT, MCT, LCT) and their combinations (e.g. MLCT, SALATRIM – a SLCT) comprise triesters of glycerol with fatty acid chain lengths of C2 and C4 (short-chain), C8 and C10 (medium-chain) and C18 saturated/unsaturated (long-chain). The substance “Modified triglyceride” contains main components: 1,3-dioleoyl 2-palmitoyl triacylglycerol and 1,2-dipalmitoyl 3-oleoyl triacylglycerol, comprising triesters of glycerol with hexadecanoic (C16) and (9Z)-Octadec-9-enoic acid (C18:1). Available data on identity and composition of the individual test material for a given study is provided in the technical dossier.

 

Developmental toxicity/teratogenicity

CAS No. 538-23-8

The teratogenic potential of Glycerol trioctanoate was investigated in ICR-JCL 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 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 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 ofdensity 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 Sprague-Dawley Crl:CD®(SD) IGS BR 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 Crl:CD BR 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 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) 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.

CAS No. 56-81-5

A pre-natal developmental toxicity study with glycerol was performed in Wistar rats, which were exposed to the test substance during Days 6-15 of gestation (Morgareidge, 1974). At least 25 females received the test substance diluted in water by oral gavage at dose levels of 13.1, 60.8, 282 and 1310 mg/kg bw/day, respectively. Additional animals were included in the study, which were treated with the vehicle only (negative control; 25 animals) or with 250 mg/kg bw/day aspirin (positive control; 29 animals). Parental animals were sacrifice on Day 20 of the study, followed by the examination of the uterine content (no. of implantation sites, resorptions and live and dead foetuses). In foetuses, body weights, and sex ratio were determined and animals were examined for external, visceral (1/3 of foetuses per litter) and skeletal (2/3 of foetuses per litter) abnormalities. In parental females, no treatment-related effects on body weight, survival and the number of pregnant animals, implantations and total litter losses by resorption were observed. In foetuses, no treatment-related effects on litter size and weight, number of viable (number alive and number dead), sex ratio were observed. No grossly visible abnormalities and no external, soft tissue and skeletal abnormalities were noted in any of the foetuses. Since no adverse effects were observed up to the highest dose levels, the NOAEL for maternal toxicity and teratogenicity was set at 1310 mg/kg bw/day.

A further pre-natal developmental toxicity study with glycerol was performed, in which at least 15 Dutch-belted rabbits were exposed to the test substance during Days 6-18 of gestation (Morgareidge, 1974). The animals received the test substance diluted in water at dose levels of 11.8, 54.8, 254.5 and 1180 mg/kg bw/day via oral gavage. Furthermore, two additional groups of 15 animals each were included in the study, which were treated with the vehicle only (negative control) or with 2.5 mg/kg bw/day 6-aminonicotinamide (positive control). Parental animals were sacrifice on Day 29 of the study, followed by the examination of the uterine content (no. of corpora lutea, no. of implantation sites, resorptions and live and dead foetuses). In foetuses, determination of body weight and sex ratio were performed. External abnormalities were examined on Day 29, whereas neonatal survival, visceral and skeletal abnormalities were recorded on Day 30. During the study, one non-pregnant animal died at 54.8 and 1180 mg/kg bw/day, respectively, whereas one pregnant animal died at 254.5 mg/kg bw/day. No mortalities were observed in the control groups and in the 11.8 and 1180 mg/kg bw/day treatment groups. Due to the absence of a clear dose-response relationship, the mortalities observed were not considered to be toxicologically relevant. No differences in the body weights and the number of pregnancies were noted between treated and control animals. No treatment-related increase in the number of abortions was observed. The number of implantations and total litter losses by resorption were not altered by treatment with the test substance. In the control group, 1 dam showed 4 dead foetuses. One dead foetus was found in 1 dam at 54.8 mg/kg bw/day, whereas 2 and 6 dead foetuses were seen in 2 dams at 254.5 mg/kg bw/day, respectively. No dead foetuses were observed in the positive control and at 11.8 and 1180 mg/kg bw/day. Since mortality of foetuses also occurred in the negative control group and without dose-dependency among the test groups, this effect was not considered to be treatment-related. No other treatment-related changes were observed in body weights, except for a reduction in mean foetus weight by about 14% in the 254.5 mg/kg bw/day group compared with the control. No treatment-related effects on number of viable foetuses and sex ratio were noted. A number of neonatal deaths occurred in all groups without relationship to treatment. No external abnormalities in any of the foetuses examined. At 254.5 mg/kg bw/day, soft tissue examination revealed abnormalities, in 2 pups (each pup from a different dam), including medial rotation of limbs, subcutaneous edema and subcutaneous hematoma. No soft tissue abnormalities were observed in the negative control groups and at any other test groups. Furthermore, the incidence of delayed ossification was increased in the 254.5 mg/kg bw/day dose group, but without any evidence for a relationship to treatment. Since no adverse effects were observed up to the highest dose levels, the NOAEL for maternal toxicity and teratogenicity was set at 1180 mg/kg bw/day.

Furthermore, a pre-natal developmental toxicity study with glycerol was performed in CD-1 mice, which were exposed to the test substance during Days 6-15 of gestation (Morgareidge, 1974). Twenty-five females received the test substance diluted in water by oral gavage at dose levels of 12.8, 59.4, 276 and 1280 mg/kg bw/day, respectively. Additional animals were included in the study, which were treated with the vehicle only (negative control; 25 animals) or with 150 mg/kg bw/day aspirin (positive control; 24 animals). Parental animals were sacrifice on Day 17 of the study, followed by the examination of the uterine content (no. of implantation sites, resorptions and live and dead foetuses). In foetuses, body weights, and sex ratio were determined and animals were examined for external, visceral (1/3 of foetuses per litter) and skeletal (2/3 of foetuses per litter) abnormalities. In parental females, no treatment-related effects on body weight, survival and the number of pregnant animals, implantations and total litter losses by resorption were observed. In foetuses, no treatment-related effects on litter size and weight, number of viable (number alive and number dead), sex ratio were observed. No grossly visible abnormalities and no external, soft tissue and skeletal abnormalities were noted in any of the foetuses. Since no adverse effects were observed up to the highest dose levels, the NOAEL for maternal toxicity and teratogenicity was set at 1280 mg/kg bw/day.

Overall conclusion for developmental toxicity/teratogenicity

The available data on the developmental toxicity/teratogenicity of Glycerides comprise reproductive/developmental toxicity screening studies (see Toxicity to reproduction) as well as (pre-natal) developmental toxicity studies with category members and the surrogate substance glycerol (hydrolysis product). 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.

Based on the available data and following the category approach, all members of the Glycerides category are considered to have no toxic effects on intrauterine development.

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 group concept is applied to the members of the Glycerides category, data will be generated from data for reference source substance(s) to avoid unnecessary animal testing. Additionally, once the group concept is applied, substances will be classified and labelled on this basis.

Therefore, based on the group concept, the available data on toxicity to reproduction and development 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 classification.