Oleic acid, monoester with oxybis(propanediol)

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Intravenous (OECD 414), rat: NOAEL= 4280 mg/kg bw/day;
Intravenous (OECD 414), rabbit: NOAEL= 1000 mg/kg bw/day

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Quality of whole database:

The available information comprises an adequate, reliable study (Klimisch score 2 due to read across) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common origin, common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (refer to endpoint discussion for further details). The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VII, 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 for toxicity to reproduction of Oleic acid, monoester with oxybis(propanediol) (CAS# 49553-76-6). In order to fulfil the standard information requirements set out in Annex VIII, 8.7.1, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was 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 substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.

Overview for toxicity to reproduction

CAS	NOAEL [mg/kg bw/day]
49553-76-6 (a)	RA: 111-03-5 RA: 24800-44-0 RA: decaglycerol decaoleate
111-03-5 (b)	≥1000
24800-44-0	≥ 1000
decaglycerol decaoleate	10%

(a) Substances subject to the REACh  Phase-in registration deadline of 31 May 2013 are indicated in bold font. Only for this substance 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.

The above mentioned substances are considered to be similar on the basis of structural similarity resulting in similar properties and/or activities. The available endpoint information is used to predict the same endpoints for oleic acid, monoester with oxybis(propanediol) (CAS# 49553-76-6).

 

A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Discussion

No data are available on the toxicity to reproduction of oleic acid, monoester with oxybis(propanediol) (CAS# 49553-76-6). In order to fulfil the standard information requirements set out in Annex VIII, 8.7.1, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006 read-across from the source substances, 2,3-dihydroxypropyl oleate (CAS# 111-03-5) and [methyethylene]bis[oxy]dipropanol) (CAS# 24800-44-0) were considered for read-across and assessment was conducted based on an analogue approach.

 

2,3-dihydroxypropyl oleate (CAS# 111-03-5) was tested for toxicity to reproduction in a screening study according to OECD Guideline 422 under GLP conditions (Yamaguchi, 2005).

Prior to the main study, two dose range finding studies were performed. Based on the results of the preliminary studies, 1000 mg/kg bw/day was selected as the highest dose level for the main study. Groups of 12 Sprague-Dawley rats per sex were given the test substance by gavage at dose levels of 100, 300 and 1000 mg/kg bw/day including 5 males of the control and high-dose group which were allowed 14 days of recovery. For the assessment of reproduction and developmental toxicity 5 females were added to a satellite control and high-dose group. A concurrent negative control group receiving the vehicle corn oil only was included in the testing as well.

Examinations revealed no clinical signs or mortality in relation to the test substance. No changes in body weight (gain) and food consumption were observed during the treatment period. Furthermore, findings in haematology and clinical chemistry in single groups were considered to be of no toxicological relevance. No toxicological relevant changes were noted neurobehavioural parameters (for further details refer to “Repeated dose toxicity”). In low-dose males, a significant decrease in absolute weight of seminal vesicles and in the low-dose female group a significant decrease in the relative weight of spleen was observed. These changes were considered not to be treatment-related as no corresponding findings were apparent in the histopathological examination and no dose-relationship was observed. Moreover, gross pathology and histopathology showed no treatment-related changes in any animal. Furthermore, no differences were found regarding spermatogenic cycle and no abnormalities were found in the uterus and ovaries in the non-pregnant females and the unsuccessful copulation females of the control and high-dose groups, respectively. In addition, no treatment-related effects on oestrous cycle and reproductive performance were observed within the study.

Moreover, viability index and sex ratio of the offspring was not affected by treatment. There were no toxicologically relevant clinical signs in the offspring. At pathology no treatment-related macroscopic findings were observed in the offspring. Several visceral variations were found with low incidence in the control and test groups. However, the variations were considered to be not treatment-related effects.

Based on the lack of toxicological relevant effects, a NOAEL of 1000 mg/kg bw/day (m/f) for reproduction toxicity was identified in this study. Furthermore, no adverse effects in the offspring were observed and a NOAEL of 1000 mg/kg bw/day for developmental toxicity was considered.

 

Methyethylene]bis[oxy]dipropanol) (CAS# 24800-44-0) was tested for toxicity to reproduction in a screening study according to OECD 422 under GLP condition (MHW, 1993). 12 Male and female SD rats were administered by gavage at doses of 8, 40, 200 and 1000 mg/kg/day bw. In male rats, the administration period was two weeks prior to mating, 2 weeks of mating and 2 weeks after the completion. In females, the administration period was two weeks prior mating, 2 weeks during mating, during pregnancy and until day 3 post-partum.

In clinical observation, salivation was observed in the 1000 mg/kg bw male group. There were no differences in body weight gain, food consumption, clinical chemistry, or haematological parameters between the treated and control animals of both sexes. Increased absolute and relative liver weights, and increased relative kidney weight occurred in 1000 mg/kg/day bw in males. Increased relative liver weight was observed in 1000 mg/kg/day female group as well. In histopathological examinations, any changes which may have been caused by the test substance were not observed in the heart, kidneys, liver, thymus, testes, ovaries, epididymides, adrenal, brain or spleen in both sexes.

There were no effects on mating, fertility, and oestrus cycle or on dams during the pregnancy and lactation period. No effects on viability were observed in offspring of the treated animals compared to controls. External examination of pups revealed no increase in appearance of abnormal pups.

No effects on the body weight were noted in offspring of the treated animals compared with controls.

Therefore, under the experimental conditions of the study a NOAEL of 1000 mg/kg bw/day (m/f) for toxicity to reproduction based on the lack of toxicological relevant effects was identified in this study. Furthermore, no adverse effects in the offspring were observed and a NOAEL of 1000 mg/kg bw/day for developmental toxicity was considered.

In addition a in 90-day oral feeding study (King, 1971) was performed with the structurally related analogue substance decaglycerol decaoleate according a method equivalent to OECD Guideline 408 effects on reproductive organs and tissues were investigated as well. Test substance was administered via diet to 20 Sprague-Dawley rats per dose group at specified dose levels (2.5, 5, and 10% corresponding to approx. 1900, 3800 and 6000 mg/kg bw/day). Soyabean oil was used as the control fat. All animals appeared to be in excellent health during the duration of the study, and no adverse effects were observed with regard to survival, growth, absolute and relative organ weights, and histopathology. With regard to food consumption, it was found that males fed 10% PGE consumed more food and had a poorer feed efficiency value than male control animals. However despite decreased feed efficiency those animals consumed enough food to maintain normal growth. The available subchronic toxicity study did not show adverse effect on reproductive organs and tissues up the limit dose of respective currently valid test methods. 90-day oral NOAEL was determined to be 10% test substance, which refers to approximately 5500 mg/kg bw/day .

In conclusion, based the overall weight of evidence from data on structurally-related substances, a Two-generation reproductive toxicity study with oleic acid, monoester with oxybis(propanediol (CAS# 49553-76-6) is not required and should be avoided for reasons of animal welfare following Annex XI, 1.2 and 1.5 of Regulation (EC) No 1907/2006.

Short description of key information:
Oral (OECD 422), rat: NOAEL >= 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. All available studies are adequate and reliable based on the identified similarities in structure and intrinsic properties between source and target substances and overall quality assessment (refer to the endpoint discussion for further details).

Effects on developmental toxicity

Description of key information

Oral (OECD 414), rat: NOAEL >= 5000 mg/kg bw/day;
Oral  (OECD 414), rabbit: NOAEL> = 1200 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 an adequate, reliable study (Klimisch score 2) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on common origin, common precursors and breakdown products of hydrolysis and consistent trends in environmental fate, ecotoxicological and toxicological profile (refer to endpoint discussion for further details). The selected study is thus sufficient 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.

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 for developmental toxicity of Oleic acid, monoester with oxybis(propanediol) (CAS# 49553-76-6). In order to fulfil the standard information requirements set out in Annex VIII, 8.7.1 and Annex XI, 8.7.2, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was 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 substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.

 

Overview for developmental toxicity

CAS	NOAEL [mg/kg bw/day]
49553-76-6 (a) Target substance	RA: CAS 111-03-5 RA: CAS 24800-44-0 RA: Medium/Long Chain Triglycerides RA: CAS 25265-71-8
111-03-5 (b)	≥1000
24800-44-0	≥ 1000
Medium/Long Chain Triglycerides (MCT/LCT)	≥1000
25265-71-8	≥ 5000 (rat) ≥ 1200 (rabbit)

(a) Substances subject to the REACh Phase-in registration deadline of 31 May 2013 are indicated in bold font. Only for this substance 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 “--“.

The above mentioned substances are considered to be similar on the basis of structural similarity resulting in similar properties and/or activities. The available endpoint information is used to predict the same endpoints for oleic acid, monoester with oxybis(propanediol) (CAS# 49553-76-6).

A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Discussion

Developmental toxicity

Since no studies investigating the developmental toxicity of oral Oleic acid, monoester with oxybis(propanediol) (CAS# 49553-76-6) are available, in accordance with Regulation (EC) No. 1907/2006 Annex XI, 1.5 a read-across from the structurally related analogue substances 2,3-dihydroxypropyl oleate (CAS# 111-03-5), [(methylethylene)bis(oxy)]dipropanol (CAS# 24800-44-0) , and oxydipropanol (CAS# 25265-71-8) was conducted.

CAS 111-03-5

The read across substance 2,3-dihydroxypropyl oleate (CAS# 111-03-5) was tested for oral toxicity in rats in an OECD 422 combined repeated dose and reproductive toxicity screening test under GLP conditions (Yamaguchi, 2005). Male and female Sprague-Dawley rats (12 per sex) per dose were given the test substance by gavage at dose levels of 100, 300 and 1000 mg/kg/day. Two range findings studies were performed to select the highest dose level for the main study. The test material was administered to females from 14 days before mating until day 4 of lactation and to males for 14 days prior mating and 28 days thereafter. The test item showed no general toxicological effects in either sex. There were no clinical observations attributable to the administration of test substance and there was no mortality in any of the groups. No treatment related effects were observed in terms of body weights, food consumption, urinalysis, hematology, blood chemistry, organ weight, necropsy or histopathological findings. Therefore, under the experimental conditions of the study and on the basic on the lack of toxicological relevant effects a of NOAEL for 2,3-dihydroxypropyl oleate for repeated dose toxicity after oral administration is 1000 mg/kg bw/day in both sexes was derived.

In low-dose males and in the low-dose females, a significant decrease in absolute weight of seminal vesicles and a significant decrease in the relative weight of spleen were observed respectively. These changes were considered not to be compound-related as no corresponding findings were apparent in the histopathological examination and no dose-relationship was observed. Moreover, gross pathology and histopathology showed no substance-related changes in any animal. No differences were found regarding spermatogenic cycle and no abnormalities were found in the uterus and ovaries in the non-pregnant females and the unsuccessful copulation females of the control and high-dose groups, respectively. In addition, no treatment-related effects on oestrous cycle and reproductive performance were observed within the study.

The viability of the offspring was not affected by treatment. Viability index and sex ratio remained unaffected by the treatment as well. There were no toxicologically relevant clinical signs in the offspring as well. At pathology no treatment-related macroscopic findings were observed in the offspring. Several visceral variations were found with low incidence in the control and test groups. However, the variations were considered to be not treatment-related effects.

Based on the lack of toxicological relevant effects, a NOAEL for reproduction toxicity of 1000 mg/kg bw/day in male and females was identified in this study. Furthermore, as no adverse effects in the offspring were observed a NOAEL of 1000 mg/kg bw/day for developmental toxicity was considered.

 

CAS 24800-44-0

The read across substance methyethylene]bis[oxy]dipropanol (CAS# 24800-44-0) was tested for oral toxicity in rats in an OECD 422 combined repeated dose and reproductive toxicity screening test under GLP conditions (MHW, 1993). Groups of 12 male and female rats per dose were administered with 8, 40, 200 and 1000 mg/kg/day via gavage. The test material was administered to females two weeks prior to mating, 2 weeks during mating, during pregnancy and until Day 3 post-partum (54 days) and to males two weeks prior to mating, 2 weeks during mating and 2 weeks after the completion of mating period (49 days). The test substance showed no general toxicological effects in either sex. No mortality was observed in any of the groups. However increased in salivation was observed in males treated with 1000 mg/kg bw/day.There were no differences in body weight gain, food consumption, clinical chemistry, or haematological parameters between the treated and control animals of both sexes. Increased absolute and relative liver weights, and increased relative kidney weight occurred in 1000 mg/kg/day bw in males. Also, increased relative liver weight was observed in 1000 mg/kg/day female group. In histopathological examinations, any changes which may have been caused by the test substance were not observed in the heart, kidneys, liver, thymus, testes, ovaries, epididymides, adrenal, brain or spleen in both sexes.

Therefore, under the experimental conditions and on the basis of the lack of toxicological relevant effects, a NOAEL of 1000 mg/kg bw/day (m/f) for reproduction toxicity was identified in this study. Furthermore, no adverse effects in the offspring were observed and a NOAEL of 1000 mg/kg bw/day for developmental toxicity was considered.

 

CAS 25265-71-8

Oxydipropanol (CAS# 25265-71-8) was administered to groups of 26 or 27 pregnant Crl: CD rats by gavage at doses of 800, 2000 or 5000 mg/kg/day on days 6-15 of gestation according to a method similar to OECD 414 and under GLP conditions (Bates, 1992a).

Treatment with 2000 mg/kg/day produced maternal lethality in 1 out of 25 pregnant animals, while administration of 5000 mg/kg/day caused the death of 2 out of 22 pregnant animals. Since necropsy of these animals failed to determine the exact cause of death (i.e. no evidence was found for gavage error, accidental injury or disease), mortalities were considered to be related to test substance exposure. Further clinical signs observed in confirmed-pregnant animals during and after exposure to 2000 and 5000 mg/kg/day included ataxia, weight loss, lethargy, unstable gait, piloerection and morbidity. Maternal body weights were significantly decreased at 5000 mg/kg/day from GD 9 through GD 20. In addition, maternal body weight gain of the animals exposed to 5000 mg/kg/day was significantly reduced during the period of treatment and gestation compared to controls. The corrected maternal weight gain (gestation gain minus gravid uterine weight) was also significantly reduced in animals receiving 5000 mg/kg bw/day. The reduction in body weight was accompanied by a significant decrease in absolute (g/day) and relative (g/kg body weight/day) food consumption in the 5000 mg/kg bw/day group for the intervals from GD 6 to 9 and GD 9 to 12 when compared to controls. Food consumption was also decreased during treatment (GD 6 to 15) and across gestation (GD 0 to 20). In the 2000 mg/kg bw/day group, absolute food consumption was decreased from GD 6 to 9. Relative water consumption by the animals in the 5000 mg/kg/day group was increased for all measurement periods between GD 9 and GD 18. Relative liver weight of the maternal animals was significantly increased in the animals exposed to 2000 and 5000 mg/kg/day. At necropsy on GD 20, 74% (20/27) of the mated animals in the controls and 74% (20/27), 96% (24/26), and 83.0% (20/26) of animals treated with 800, 2000 and 5000 mg/kg bw/day, respectively, were confirmed to be pregnant after uterine examination, and thus did not reveal any treatment-related changes.

No treatment-related effects on pre- or post-implantation loss were observed. The mean male and female body weights per litter of treated animals were associated with a significant decreasing linear trend, but did not significantly different from control. However, the male and female body weights in treated groups were not significantly different from control. External, visceral and skeletal examinations of the foetuses did not reveal any significant incidences of malformations and variations. The percentage of malformed foetuses per litter was somewhat higher in the exposed groups than in the control (10.49, 9.01, and 11.61% in the 800, 2000 and 5000 mg/kg bw/day group compared to 6.61% in the control group). This effect was due to the visceral finding of enlarged lateral ventricles of the brain in approximately 8, 15, 14, and 16% of the foetuses examined in the control, 800, 2000 and 5000 mg/kg bw/day group, respectively.

Based on these results the developmental NOAEL for oxydipropanol was found to be ≥ 5000 mg/kg bw/day, while the maternal toxicity NOAEL for oxydipropanol was found to be 800 mg/kg bw/day.

In the same study the test substance was administered to groups of 24 pregnant New Zealand White rabbits via gavage at doses of 200, 400, 800, or 1200 mg/kg bw/day on 6-19 days of gestation. Dams were sacrificed and necropsied on day 30 of gestationNo maternal mortality and no dose-related clinical signs of toxicity occurred during the study. Pregnancy rates were 95% in the controls and 83, 91, 92, and 82% in animals treated with 200, 400, 800 and 1200 mg/kg bw/day, respectively. No treatment-related effects on maternal body weights and food consumption compared to controls were noted during the study. Kidney and liver weights were not altered in exposed animals. One control animal and one animal treated with 1200 mg/kg bw/day aborted prior to GD 30. All of the remaining pregnant animals had one or more live foetuses on GD 30. Examination of the ovaries from pregnant animals revealed a significant decrease in the number of corpora lutea at 1200 mg/kg bw/day compared to controls. This observation was not treatment-related, since exposure of the maternal animals did not begin until approximately six days after ovulation. Although the number of ova produced by the animals in the high dose group was less than control, the fertility rate among these animals was high. Consequently, the mean number of implantation sites in exposed groups was equivalent to control. These two factors (low corpora lutea and normal implantation rate) caused a decrease in the preimplantation loss rate. No alterations in the frequency of post-implantation loss and mean foetal body weight per litter were observed. External, visceral, or skeletal examination did not reveal any statistically significant, treatment-related malformations, except for a significant linear trend associated with the number of litters showing visceral malformations Based on these results the maternal and developmental toxicity NOAELs were determined to be ≥ 1200 mg/kg bw.

In summary, based on a weight of evidence approach, all reliable studies showed no treatment-related effects on maternal and developmental toxicity.

Justification for selection of Effect on developmental toxicity: via oral route:
Hazard assessment is conducted by means of read-across from a structural analogue. All available studies are adequate and reliable based on the identified similarities in structure and intrinsic properties between source and target substances and overall quality assessment (refer to the endpoint discussion for further details).

Toxicity to reproduction: other studies

Additional information

Justification for grouping of substances and read-across

There are no data available for developmental toxicity of Oleic acid, monoester with oxybis(propanediol) (CAS# 49553-76-6). In order to fulfil the standard information requirements set out in Annex VIII, 8.7.1 and Annex XI, 8.7.2, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006, read-across from structurally related substances was 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 substances may be predicted as similar provided that their physicochemical, toxicological and ecotoxicological properties are likely to be similar or follow a regular pattern as a result of structural similarity.

 

Overview for developmental toxicity

CAS	NOAEL [mg/kg bw/day]
49553-76-6 (a) Target substance	RA: CAS 111-03-5 RA: CAS 24800-44-0 RA: Medium/Long Chain Triglycerides RA: CAS 25265-71-8
111-03-5 (b)	≥1000
24800-44-0	≥ 1000
Medium/Long Chain Triglycerides (MCT/LCT)	≥1000
25265-71-8	≥ 5000 (rat) ≥ 1200 (rabbit)

(a) Substances subject to the REACh  Phase-in registration deadline of 31 May 2013 are indicated in bold font. Only for this substance 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 “--“.

The above mentioned substances are considered to be similar on the basis of structural similarity resulting in similar properties and/or activities. The available endpoint information is used to predict the same endpoints for oleic acid, monoester with oxybis(propanediol) (CAS# 49553-76-6).

A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

 

Discussion

Developmental toxicity

Since no studies investigating the developmental toxicity of oral oleic acid, monoester with oxybis(propanediol) (CAS# 49553-76-6) are available, in accordance with Regulation (EC) No. 1907/2006 Annex XI, 1.5 a read-across from the structurally related analogue substance Medium/Long Chain Triglycerides (MCT/LCT) was conducted.

Medium/Long Chain Triglycerides (MCT/LCT)

In a prenatal developmental toxicity study 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 the increased incidence of necropsy findings on the tail, which were 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 exposed foetuses. 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 5h intravenous infusion via a marginal ear vein at doses of 1000 and 4280 mg/kg bw/day from gestation day 6 through 19 (Henwood, 1997). A similar constituted control group was injected with 0.9% saline. In dams, 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.

 

Justification for classification or non-classification

Based on read-across from structurally similar substances, the available data on developmental toxicity 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.