Glycerol trioctanoate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Oral (OECD 422, read across): NOAEL rat, fertility = 1000 mg/kg bw/day

Oral (OECD 422, read across): NOAEL rat, systemic toxicity = 1000 mg/kg bw/day

Link to relevant study records

Reference

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Justification for type of information:

refer to analogue justification provided in IUCLID section 13

Reason / purpose for cross-reference:

read-across source

Key result

Dose descriptor:

NOAEL

Remarks:

parental fertility

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No adverse effects

Remarks on result:

other:

Remarks:

Source: CAS 91052-13-0

Key result

Critical effects observed:

no

Key result

Dose descriptor:

NOAEL

Remarks:

development

Generation:

F1

Effect level:

1 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no adverse effects

Remarks on result:

other:

Remarks:

Source: CAS 91052-13-0

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

no

Conclusions:

The read across approach is justified in the analogue justification. The target and source substances are considered unlikely to differ in their reproduction toxicity potential. The available data from the source substance glycerides, C8-18 and C18-unsatd. mono- and di-,acetates (CAS 91052-13-0) obtained in a screening study conducted according to OECD guideline 422 showed no adverse effects on reproduction parameters in parental rats and their F1 offspring. Therefore, no reproduction toxicity is expected for the target substance glycerol trioctanoate (CAS 538-23-8).

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

1 000 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

The available information comprises an adequate and reliable (Klimisch score 2) study 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, eco-toxicological 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

Justification for read across

There are no data on the reproduction toxicity of glycerol trioctanoate (CAS 538-23-8). 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 approach is provided in the technical dossier (see IUCLID Section 13).

Toxicity to reproduction

CAS 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 (key, 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 control group received the vehicle. 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 Crl:WI(Han) Wistar rats.

Overall conclusion for effects on fertility

There are no available studies on the toxicity to reproduction and fertility of glycerol trioctanoate (CAS 538-23-8). Therefore analogue read-across from a source substance was applied. The potential for reproductive toxicity of the source substances was assessed in reproductive/developmental screening studies (OECD 422). The NOAEL value for fertility was 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 of glycerol trioctanoate (CAS 538-23-8) is not expected to affect fertility.

Effects on developmental toxicity

Description of key information

Oral (teratogenicity study): NOAEL rabbit, developmental = 2862 mg/kg bw/day

Oral (teratogenicity study): NOAEL mouse, developmental = 9540 mg/kg bw/day

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

No soft tissue and head examinations were performed in foetuses.

Qualifier:

no guideline followed

Principles of method if other than guideline:

A teratogenicity study in mice was conducted in 1970, prior to any OECD guideline adoption.

GLP compliance:

no

Limit test:

no

Species:

mouse

Strain:

other: ICR-JCL

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Age at study initiation: 4-8 weeks
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-25
- Humidity (%): 55-60

Route of administration:

oral: gavage

Vehicle:

other: 1.2% Tween 80/0.8% Span 80 in water

Details on exposure:

PREPARATION OF DOSING SOLUTIONS:
The test substance was mixed with 1.2% (w/v)Tween 80 and 0.8% (w/v) Span 80 in water. The emulsion was prepared with Manton Gaulin Homgenizer.

VEHICLE
- Justification for use and choice of vehicle: low water solubility

Analytical verification of doses or concentrations:

no

Details on mating procedure:

No detailed information is available.

Duration of treatment / exposure:

Day 7-12 of gestation

Frequency of treatment:

daily

Duration of test:

Day 18 of gestation

Dose / conc.:

1 908 mg/kg bw/day (actual dose received)

Remarks:

2 mL/kg; calculated based on a density value of 0.954 g/mL

Dose / conc.:

9 540 mg/kg bw/day (actual dose received)

Remarks:

10 mL/kg; calculated based on a density value of 0.954 g/mL

No. of animals per sex per dose:

20 parental females

Control animals:

other: physiological saline or soybean oil

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: on Days 0, 7 and 18 of gestation

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: No

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: No
- Skeletal examinations: Yes: all per litter
- Head examinations: No

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

no effects observed

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Number of abortions:

not specified

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

not specified

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in pregnancy duration:

not specified

Changes in number of pregnant:

no effects observed

Details on maternal toxic effects:

Maternal toxic effects:no effects
Details on maternal toxic effects:
No differences were observed between test substance administration group, control group and soybean oil administration group.

Key result

Dose descriptor:

NOAEL

Effect level:

9 540 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity: no adverse effects

Key result

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

not examined

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
External abnormalities: cleft palate was observed in 1 foetus of control, 1 foetus of the 2 mL/kg bw/day dose group and 3 foetuses of the 10 mL/kg bw/day dose group. No cleft palate was found in foetuses receiving soybean oil. Club foot was observed in 1 foetus of control, 4 foetuses of the soybean oil control group, 3 foetuses of the 2 mL/kg bw/day dose group and 4 foetuses of the 10 mL/kg bw/day dose group.
Skeletal abnormalities: Two foetuses showed assimilation of the ribs in the 2 mL/kg bw/day dose group. One foetus showed assimilation of the cervical vertebra in the 10 mL/kg bw/day dose group. However, these effects did not follow a clear dose-dependency.

Key result

Dose descriptor:

NOAEL

Effect level:

9 540 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: teratogenicity: no adverse effects

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Table 1. Effects on foetuses of parental females treated with the test substance (2 and 10 mL/kg) and soybean oil

Groups	No of mothers	No. of fetuses	Live fetuses				Dead
			No.			Mean body weight (g)	No. of resorbed fetuses	No. of dead fetuses	Total (%)
			M.	F.	M.+F.
Control (saline)	20	232 (11.6 ± 0.39)	116	104	220	1.28 ± 0.023	11	1	12 (5.2)
Soybean oil	20	223 (11.1 ± 0.46)	101	114	215	1.26 ± 0.021	6	2	8 (3.6)
2 mL/kg	20	231 (11.5 ± 0.29)	113	107	220	1.29 ± 0.023	9	2	11 (4.8)
10 mL/kg	20	232 (11.6 ± 0.40)	107	112	219	1.26 ± 0.030	12	1	13 (5.6)

M.: male, F.: female

(Mean ± standard error)

Table 2. Malformations in foetuses of parental females treated with the test substance (2 and 10 mL/kg) and soybean oil

Group	Malformed
	No. (%)		Number of fetuses: Type
	Ex	Sk
Control (saline)	3 (1.4)	0	1: Curled tail 1: Cleft palate 1: Club foot
Soybean oil	4 (1.9)	0	4: Club foot
2 mL/kg	4 (1.8)	2 (0.9)	1: Cleft palate 3: Club foot 2: Assimilation of the ribs
10 mL/kg	7 (3.2)	1 (0.5)	3: Cleft palate 4: Club foot 1: Assimilation of the cervical vertebra

Ex: external malformation

Sk: skeletal malformation

Conclusions:

CLP/EU GHS criteria not met, no classification required according to Regulation (EC) No 1272/2008.

Reference 2

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Remarks:

No soft tissue and head examinations were performed in foetuses.

Qualifier:

no guideline followed

Principles of method if other than guideline:

A teratogenicity study in rabbits was conducted in 1970, prior to the adoption of any OECD guideline.

GLP compliance:

no

Limit test:

no

Species:

rabbit

Strain:

not specified

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Kansai Institute for Experimental Animals, Japan
- Weight at study initiation: 2.5-3.8 kg (range)
- Diet: ad libitum
- Water: ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22-25
- Humidity (%): 55-60

Route of administration:

oral: gavage

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

not specified

Details on mating procedure:

No detailed information is available.

Duration of treatment / exposure:

Day 7-16 of gestation

Frequency of treatment:

daily

Duration of test:

Day 29 of gestation

Dose / conc.:

2 862 mg/kg bw/day (actual dose received)

Remarks:

3 mL/kg bw; calculated based on a density value of 0.954 g/mL

No. of animals per sex per dose:

8 parental females

Control animals:

other: physiological saline and soybean oil

Details on study design:

- Dose selection rationale: in a preliminary study, mortality was observed after administration of the test substance at 5 and 10 mL/kg bw/day. Therefore, a dose of 3 mL/kg bw/day was selected for treatment in this study.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes

BODY WEIGHT: Yes
- Time schedule for examinations: Day 0, 7 and 18 of gestation

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: No
- Number of corpora lutea: No
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: No

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: No
- Skeletal examinations: Yes: all per litter
- Head examinations: No

Clinical signs:

not specified

Mortality:

not specified

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No major differences in mean body gain during gestation period was seen between control rabbits and rabbits treated with soybean oil or glycerol trioctanoate.

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Neuropathological findings:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Number of abortions:

no effects observed

Pre- and post-implantation loss:

no effects observed

Total litter losses by resorption:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Changes in pregnancy duration:

not specified

Changes in number of pregnant:

no effects observed

Details on maternal toxic effects:

Maternal toxic effects: No differences were observed between test substance administration group, control group and soybean oil administration group.

Key result

Dose descriptor:

NOAEL

Effect level:

2 862 mg/kg bw/day (actual dose received)

Based on:

test mat.

Basis for effect level:

other: no adverse effects

Key result

Abnormalities:

no effects observed

Fetal body weight changes:

no effects observed

Reduction in number of live offspring:

no effects observed

Changes in sex ratio:

no effects observed

Changes in litter size and weights:

no effects observed

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Description (incidence and severity):

No abnormalities in treated animals. Abnormalities were only seen in the soybean and control group.
External abnormalities: hydrocephalus (1 foetus) and absence of the head (1 foetus) was observed in the soybean oil group.
Skeletal abnormalities: Division of the skull was observed in 4 foetuses of the control group and 1 foetus of the soybean oil group. One foetus of the soybean oil group showed assimilation of the ribs.

Visceral malformations:

not specified

Key result

Dose descriptor:

NOAEL

Effect level:

2 862 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: teratogenicity; no adverse effects

Key result

Abnormalities:

no effects observed

Key result

Developmental effects observed:

no

Table 1. Effects on foetuses of parental females treated tricaprylin (3 mL/kg bw), soybean oil and controls

Groups	No of mothers	No. of fetuses (mean per litter)	Live fetuses				Dead
			No.			Mean body weight (g)	No. of resorbed fetuses	No. of dead fetuses	Total (%)
			M.	F.	M.+F.
Control	8	69 (8.6 ± 1.36)	35	23	58	36.2 ± 2.55	7	4	11 (15.9)
Soybean oil	8	65 (8.1 ± 1.26)	34	28	62	38.6 ± 2.21	2	1	3 (4.8)
Tricaprylin 3 mL/kg	8	72 (9.0 ± 0.60)	28	33	61	34.9 ± 1.47	4	7	11 (15.3)

M.: male, F.: female

Mean ± standard error

Table 2. Malformations in foetuses of females treated with the test substance (3 mL/kg) or soybean oil

Group	Malformed
	No. (%)		Type
	Ex	Sk
Control	0	4 (6.9)	4: Division of the skull
Soybean oil	2 (3.2)	2 (3.2)	1: Hydrocephalus 1: Absence of the head 1: Assimilation of the ribs 1: Division of the skull
3 mL/kg	0	0

Ex: external malformation

Sk: skeletal malformation

Conclusions:

No indication for develomental toxicity.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

2 862 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Quality of whole database:

The available information comprised well documented studies with the target substance, meeting generally accepted scientific principles, acceptable for assessment (Klimisch score 2).

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

CAS 538-23-8

An non-guideline teratogenicity study was performed in rabbits (WoE, 1970, rabbit). Eight female animals were administered glycerol trioctanoate (CAS 538-23-8) on days 7-16 of gestation at 3 mL/kg bw once daily by oral gavage, equivalent to 2862 mg/kg bw/day. No treatment-related effects were seen on the incidence of clinical signs, body weight, number of implantations, early resorptions, number of total litter losses by resorption, number of live foetuses, and external and skeletal examination of foetuses.

A non-guideline teratogenicity study was performed in mice (WoE, 1970, mouse). Twenty female animals per dose were administered glycerol trioctanoate (CAS 538-23-8) on days 7-12 of gestation at 2 and 10 mL/kg bw once daily by oral gavage, equivalent to 1908 and 9540 mg/kg bw/day. No treatment-related effects were seen on the incidence of clinical signs, body weight, number of implantations, early resorptions, number of total litter losses by resorption, number of live foetuses, and external and skeletal examination of foetuses.

 

Overall conclusion for developmental toxicity/teratogenicity

No adverse effects on developmental toxicity and no teratogenic effect were seen in the available studies with glycerol trioctanoate (CAS 538-23-8) performed in rabbits and mice. The studies were conducted in 1970, prior to the adoption of OECD testing guidelines, but were acceptable for assessment. The NOAEL values for developmental toxicity/teratogenicity were found to be greater than 1000 mg/kg bw/day. Based on the available data glycerol trioctanoate (CAS 538-23-8) is considered to be not toxic to uterine development.

Mode of Action Analysis / Human Relevance Framework

Not applicable

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 glycerol trioctanoate (CAS 538-23-8), 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 available data from the target and source substances on toxicity to reproduction and development, glycerol trioctanoate (CAS 538-23-8) does not meet the classification criteria according to Regulation (EC) 1272/2008, and is therefore conclusive but not sufficient for classification.