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Administrative data

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
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

A study investigating the toxicological effects of the test item 1,2,3 -Propanetriol, homopolymer, diidoctadecanoate to rats according to OECD guideline 422 resulting from repeated oral-gavage administration is performed. 1,2,3 -Propanetriol, homopolymer, diidoctadecanoate was administered in corn oil as vehicle at dosages of 100, 300, 1000 mg/kg bw/day, and control received the vehicle control only.

To meet the guideline requirements concerning number of pregnant females per group, male and female rats were added in a second delivery for breeding due to reduced fertility observed in all groups of the first delivery. It is believed, that a disturbance of the light / dark cycle was the reason for the reduced mating rate of the females of the first delivery. The additional animals ran through the whole study as the animals from the first delivery with the exception that the males went to necropsy on day 24 of the after pairing period and not on day 16 of the pairing period as the males of the first delivery (logistical reasons). Therefore, the test item was administered to male rats for up to 28 days (first delivery) and up to 41 days (second delivery) and to female rats for 14 days prior to pairing, through the pairing and gestation periods until the F1 generation reached day 4 post partum.

Because an impact of the light/dark cycle disturbance during the study on these results (a prolonged duration of gestation and an increased post-implantation loss was observed at the high dose) could not be excluded, the study was repeated with a third animal delivery of control and high-dose (1000 mg/kg bw/day) groups under proper light conditions. The test item was administered

to 12 male rats per group for up to 33 days and to 12 female rats per group for 14 days prior to pairing, through the pairing and gestation periods until the F1 generation reached day 4 post partum.

All animals survived until scheduled necropsy. There were no treatment-related clinical signs or effects on fuctional observational battery or locomotor activity. No test-titem related findings were noted during the clinical laboratory investigations.

Liver and kidney weights were slightly increased at 1000 mg/kg bw/day in both sexes of the first and second delivery, which was confirmed in animals of the third delivery except for kidney weights in females. These changes were considered compound-related, but not adverse, since there was no evidence for an impairment of organ function by clinical pathology and histopathology. There were no treatment-related necropsy or microscopic findings.

Overall at 1000 mg/kg bw/day, food consumption and body weight gain was transiently reduced in males at the beginning of the treatment period which was considered to be not adverse. The mean duration of gestation was slightly higher than in controls and the post-implantation loss was increased (up to 16.2% versus 6.6% in controls), which was borderline regarding the historical control data (3.3% - 14.4% as a percentage of total implantations). At 1000 mg/kg bw/d some changes in clinical biochemistry were noted in females. Although these effects were not dose-dependant and within the historical control range, a test item-related effect can´t be excluded. Therefore it is possible that the higher implantation losses and reduced litter size at 1000 mg/kg bw/d were induced by maternal toxicity, even if the observed effects are not regarded as adverse to the parental animals. According to the applicant, the borderline effects on post-implantation losses and litter size, should not be regarded a seperat toxicity to reproduction.

Based on these results, the NOAEL (No Observed Adverse Effect Level) for general parental toxicity was considered to be 1000 mg/kg body weight/day. The NOEL (No Observed Effect Level) for general parental toxicity and for reproduction and development was established at 300 mg/kg bw/day.


Short description of key information:
No adverse effects were observed on fertility in the OECD 422.

Justification for selection of Effect on fertility via oral route:
No adverse effects on fertility were observed. At 1000 mg/kg bw/d some maternal toxicity was observed. Therefore it is possible that the higher implantation losses and reduced litter size at 1000 mg/kg bw/d were induced by maternal toxicity, even if the observed effects are not regarded as adverse to the parental animals. According to the applicant, the borderline effects on post-implantation losses and litter size, should not be regarded a separate toxicity to reproduction. Nevertheless the highest concentration could not be stated as NOAEL, but has to be seen in connection with maternal toxicity. A NOEL of 300 mg/kg was established for parental and developmental toxicity, whereas for fertility a NOAEL of 1000 mg/kg can be deduced.

Effects on developmental toxicity

Description of key information
Oral (OECD 414), rabbit: NOAEL >= 1200 mg/kg bw/day (RA: 25265-71-8)
Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Study duration:
subacute
Species:
rabbit
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 1,2,3-Propanetriol, homopolymer, diisooctadecanoate (CAS# 63705-03-3). 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 substance 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]

63705-03-3 (a)

Target substance

RA: Medium/Long Chain Triglycerides

RA: CAS 25265-71-8

25265-71-8 (b)

≥ 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.

 

 

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 1,2,3-Propanetriol, homopolymer, diisooctadecanoate (CAS# 63705-03-3).

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

 

Discussion

Developmental toxicity

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% (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 gestation. No 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.

Toxicity to reproduction: other studies

Additional information

Developmental toxicity

Since no studies investigating the developmental toxicity of 1,2,3-Propanetriol, homopolymer, diisooctadecanoate (CAS# 63705-03-3) are available, in accordance with Regulation (EC) No. 1907/2006 Annex XI, 1.5 a read-across from the source 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 information on the substance and on read-across from structurally similar substances the available data on toxicity to reproduction 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.