2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route

Endpoint conclusion:

no study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Effect on fertility

There are no studies available to assess the potential of the substance 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate (CAS 25811-35-2) to induce effects on reproduction In accordance with Regulation (EC) No 1907/2006, Annex IX, 8.7.3, column 1, a two-Generation Reproduction Toxicity Study does not need to be conducted as the results of a 28-day or 90-day repeated dose toxicity study do not demonstrate any adverse effects on reproductive organs or tissues.

In the 13-week oral repeated-dose toxicity study in rats with Pentaerythritol ester of pentanoic acids and isononanoic acid (CAS 146289-36-3) reproductive organs were examined. Likewise, reproductive organs and sperm morphology/count were assessed in the 90-day dermal and inhalation toxicity studies with Fatty acids, C5-9 tetraesters with pentaerythritol (CAS 67762-53-2).

CAS 146289-36-3

In a 13-week oral repeated-dose toxicity study performed comparable to OECD Guideline 408 with Pentaerythritol ester of pentanoic acids and isononanoic acid in rats (CAS 146289-36-3) reproductive organs were examined as well (Müller, 1998). Groups of 10 male and female Wistar rats each were once daily (7 days/week) exposed to the substance by gavage at 100, 300 and 1000 mg/kg bw for 90 days. Overall, there were no adverse effects found after oral application of the test substance for 90 days. With special regard to the reproductive organs (ovaries, epididymides, prostate, testes and uterus), the examination of organ weights as well as gross and histo-pathology revealed to substance-related findings. Based on the absence of effects up to the highest dose tested, the 90-day oral reproductive NOAEL was found to exceed 1000 mg/kg bw/day for Fatty acids, C16-18 and C18-unsatd., branched and linear ester with trimethylolpropane in Sprague-Dawley rats.

CAS 67762-53-2

A 90-day dermal toxicity study with Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) was performed comparable to OECD Guideline 411 (Cruzan, 1988).Groups of 10 male and female Sprague-Dawley rats each were once daily (5 days/week) exposed to the substance (purity not specified) at concentrations of 800 and 2000 mg/kg bw for 90 days (65 applications in total). Application to the skin was done open without coverage. Reproductive endpoints examined were sperm morphology and weights of reproductive organs. Overall, there were no adverse effects found after dermal application of the test substance for 90 days. Examination of reproductive organs (ovaries, epididymides, prostate and seminal vesicles, testes, uterus and vagina) revealed no substance-related findings. Additionally, cauda epididymal sperm of the control and high dose groups, examined at the end of the treatment period, did not show changes in morphology. Based on the absence of effects concerning weight of reproductive organs and sperm morphology up to the highest dose tested, the 90-day dermal reproductive NOAEL was found to exceed 2000 mg/kg bw/day for Fatty acids, C5-9, tetraesters with pentaerythritol in Sprague-Dawley rats.

A 90-day subchronic inhalation toxicity study was performed with Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) comparable to OECD guideline 413 in Sprague-Dawley rats (Dulbey, 1992). 15 males and 15 females per group were whole body exposed to the test substance for 6 hours/day, 5 days/week at concentrations of 0.05, 0.15 and 0.5 mg/L. The respective controls inhaled clean air under the same conditions. Reproductive parameters examined included reproductive organs and testicular spermatid count as well as epididymal sperm count and morphology. No changes in reproductive organs or effects on sperm count and morphology could be detected in the high dose group compared to the control animals. The NOAEC for reproductive effects was therefore found to exceed 0.5 mg/L.

In addition, a developmental toxicity study with structural similar substances including Fatty acids C8-10, mixed esters with dipentaerythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200-42-8), and Fatty acids, C5-9 tetraesters with pentaerythritol (CAS 67762-53-2)  did not show an influence on the observed fertility parameters.

Moreover, according to Regulation (EC) No 1907/2006, Annex IX, 8.7.3, column 2, ”reproductive toxicity studies do not need to be conducted if the substance is of low toxicological activity and it can be proven from toxicokinetic data that no systemic absorption occurs via relevant routes of exposure”. In accordance with the general rules set out in Regulation (EC) No 1907/2006, Annex XI, section 1.2, a weight of evidence approach considering “several independent sources of information”, available toxicity data demonstrate that 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate (CAS 25811-35-2) exhibit no or only low toxicological potency. As determined in the toxicokinetic assessment, only a moderate to low potential for absorption is considered for the 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate (CAS 25811-35-2).

In addition polyol esters have a common metabolic fate that involves stepwise hydrolysis to fatty acids and the respective polyols. This process is catalysed by esterases. Whereas the carboxylic acids are naturally occurring substances with an effective metabolic turnover, the polar polyols (Kow>-2) are rapidly excreted in the urine, either un-metabolised or with hydroxylation. Therefore, no long term exposure with the test material is expected, even if applied in repeated doses.

In conclusion, regarding the available studies on structurally related substances are considered to exhibit low toxicological activity and systemic absorption. Therefore, according to Regulation (EC) No 1907/2006 and with respect to animal welfare, further reproductive toxicity studies would be scientifically unjustified.

Conclusion for reproductive toxicity

There are no specific reproductive toxicity studies available for the 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate (CAS 25811-35-2). However, in three 90-day repeated dose studies performed with PE esters (CAS 146289-36-3 and CAS 67762-53-2) reproductive organs and sperm morphology were examined. As no indications for effects on reproductive parameters were found in all three 90-day studies (NOAEL > 1000 mg/kg bw/day, NOAEL > 2000 mg/kg bw/day and NOAEC > 0.5 mg/L), 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate (CAS 25811-35-2) was not considered to have a potential for reproductive toxicity.

Short description of key information:
No adverse effect are expected

Effects on developmental toxicity

Description of key information

Oral (OECD 414), rat: NOAEL >= 1000  mg/kg bw/day
Dermal (OECD 414), rat: NOAEL < 800 mg/kg bw/day

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restricitions (Lack of data on test substance).

Qualifier:

according to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

- lack of data on test substance

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: Crl:CD BR VAF/Plus

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Inc., Stone Ridge, NY, USA
- Age at study initiation: approximately 9 - 10 weeks
- Weight at study initiation: 200 - 274 g (female)
- Housing: The animals were housed in suspended stainless steel and wire mesh cages with absorbent paper below the cages. The females were housed separately during the study period except during mating.
- Diet: Purina Certified Rodent Chow No. 5002, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 13 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20.0 - 24.4
- Humidity (%): 40 - 70
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES:
From: 03 Oct 1994
To: 08 Nov 1994

Route of administration:

oral: gavage

Vehicle:

other: polyethylene glycol (PEG 400)

Details on exposure:

PREPARATION OF DOSING SOLUTIONS: The undiluted test substance was thoroughly mixed in vehicle prior to dispensing. The dosing solutions were prepared weekly.

VEHICLE
- Lot/batch no. (if required): 122H1109
- Physical state: colorless liquid

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Analysis for homogenity of the test substance dilutions were performed on the lowest and the highest concentrations expected during the course of the study. The relative standard deviation ranged from 0.72 to 3.19%. Concentrations were analysed in the first and the third dosing mixture preparation. The analytical results for all test solutions were within 7% of the nominal concentrations for weeks 1 and 3.

Details on mating procedure:

- Impregnation procedure: cohoused
- M/F ratio per cage: 1/1
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as day 0 of pregnancy
After confirmation of pregnancy, each mated female was returned to its cage and new females were placed into the males' cages until a required number of pregnant females was obtained.

Duration of treatment / exposure:

gestation days (GD) 6 - 15

Frequency of treatment:

daily, 7 d/week

Duration of test:

21 d (GD 0 - 21)

Remarks:

Doses / Concentrations:
100, 500 and 1000 mg/kg bw/d
Basis:
actual ingested

No. of animals per sex per dose:

25 females per dose, 50 males in total

Control animals:

yes, concurrent vehicle

Details on study design:

- Rationale for animal assignment: Mated females were assigned to dose groups in the order of mating. Accordingly, the first confirmed mated female was assigned to Group 1, the next to Group 2 and so on until all mated animals for a given day were assigned to dose groups. On subsequent days, the next group in sequence was filled by the first confirmed mated female on that day and so on. Assignments were made until all groups were filled with confirmed mated females.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily during the treatment period and once daily at all other times during the study period

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to selection and daily during gestation

BODY WEIGHT: Yes
- Time schedule for examinations: prior to selection and on GD 0, 6, 9, 12, 15, 18 and 21

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Time schedule for examinations: concurrently with body weight examinations

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on GD 21
- all females were examined by gross necropsy

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes

Fetal examinations:

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter

Statistics:

Bartlett's Test was performed to determine if the dose groups had equal variance (1% level of significance). If equal, the testing was done using parametric methods, otherwise nonparametric techniques were used. Parametric procedures: a standard one way ANOVA (F distribution) was used. If significant differences among the means were indicated, Dunnett's Test was used to determine which treatment groups differed significantly from control. In addition to the ANOVA, a standard regression analysis for linear response in the dose groups was performed that also tested for linear lack of fit in the model. Nonparametric procedures: the test of equality of means was performed using the Kruskal-Wallis Test. If significant differences among the means were indicated, Dunn's Summed Rank Test was used to determine which treatment groups differed significantly from the control. In addition, Jonckheere's Test for monotonic trend in the dose response was performed. All tests were conducted at the 5% and 1% level of significance.
Fetal weight was analyzed by a standard nested analysis of covariance (fetuses nested within dams and dams nested within doses and litter size (both sexes combined)). If differences in groups were identified, the Least Significant Difference technique was used to determine which groups differed from the control group. Male and female fetuses were tested separately (the covariate was combined sexes in each analysis). Fetal malformation and variation incidence data were analyzed for statistical significance as follows: a standard chi-square analysis was performed to determine if the proportions of incidences differ between the groups tested. If any one cell had an expected value less than 5, this step was not reported. Next, each treatment group was compared to the control group using a 2x2 Fisher Exact Test. Thirdly, Armitage's test for linear trend in the dosage groups was performed. All tests were reported at the 5% or 1% level of significance.

Indices:

Preimplantation loss = (no. of Corpora Lutea - no. of Implantation Sites) / no. of Corpora Lutea * 100

Postimplantation loss = (no. of Implantation Sites - no. of live foetuses) / no. of Implantation Sites * 100

Details on maternal toxic effects:

Maternal toxic effects:no effects

Details on maternal toxic effects:
Mortality:
No treatment-related mortality occurred. On GD 7, one female of the 500 mg/kg bw/d group was found dead. At necropsy, discolored and consolidated lungs were the only findings. The death of this female was probably a result of an accidental gavage error.

Clinical signs:
No treatment-related clinical signs were observed during the study period. The most frequently observation was soft stool, that occurred in treated and control animals and was therefore considered as a response to the vehicle rather than to the test substance. Other findings were scabs, little sign of stool, rales and alopecia in one or more groups. One female of the high dose group had a subcutis mass in the cervical area on GD 21. In summary, these clinical findings were considered to be incidental and unrelated to treatment with the test substance.

Body weight:
Treatment with the test substance had no statistically significant effect on mean body weight and mean body weight change at any interval.

Food consumption:
There were no statistically significant differences in mean food consumption between treated and control animals at any interval.

Post-mortem examinations:
There were no necropsy findings that were considered to be treatment-related. One high dose female had a subcutaneous mass in the cervical area and one control and one high dose female had dilated renal pelvis. In summary, these necropsy findings were considered to be incidental and unrelated to treatment.

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

other: No adverse effects observed in the highest dose level.

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
Fetal body weight:
There were no statistically significant differences between treated and control mean fetal body weights of either sex (see Table 1).

Implantation data:
There were no statistically significant differences in the mean live fetuses, mean live male or female fetuses, mean resorptions, mean implantation sites, mean corpora lutea, mean total dead fetuses, mean fetuses per implantation sites, mean dead fetuses per implantation sites, mean resorptions per implantation sites, % pre-implantation loss, % post-implantation loss, mean malformed fetuses, mean fetuses with variations, or mean affected (resorptions + dead + malformed fetuses per litter) fetuses between treated and control groups. (see Table 1)

Fetal observations:
No biologically or statistically significant differences in total or individual variations or malformations were observed between the litters of test substance groups and control group (see Table 2). In the control, 100, 500 and 1000 mg/kg bw/d group, 5, 2, 6 and 1 fetuses, respectively, were stunted.
External observations regarded as malformations were found in one fetus of the 100 mg/kg bw/d group (agnathia, astomia, low set ears, anophthalmia) and single findings of cleft palate, syndactyly and kinked tail in three foetuses of separate litters of the 500 mg/kg bw/d group. External variations were not observed in any group.
Visceral observations regarded as malformations were limited to single occurrences of anophthalmia in one foetus each of the low and mid dose group, cleft palate and dilated brain ventricles in the 100 mg/kg bw/d group and two occurrences of folded retina in the control group. Visceral variations included a single or low incidence of dilated renal pelves, distended ureters and/or convoluted ureter.
Skeletal observations regarded as malformations were limited to multiple skull bones malformed in one foetus of the 100 mg/kg bw/d group, short pubis in one foetus of the 1000 mg/kg bw/d group and one less presacral vertebrae in one foetus of the control, two foetuses in the low dose and one foetus in the high dose groups. Skeletal variations were observed throughout the groups and consisted primarily of hypoplastic, misshapen or unossified stemebrae, hypoplastic skull bones or pubis and rudimentary or misshapen ribs.
In summary and without a clear pattern of response, all malformations were considered incidental and not to be treatment-related. Statistically significant differences in incidences of variations were limited to a decrease in hypoplastic skull bones of the mid dose group and a decrease in unossified stemebrae of the high dose group compared with controls. All variations were of no biological importance.

Skeletal ossification:
There were no statistically significant differences in mean ossification sites between treated and control groups.

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Basis for effect level:

other: No adverse effects observed in the highest dose level.

Abnormalities:

not specified

Developmental effects observed:

not specified

Table 1: Litter data and fetal body weight

 

	Control	dose groups [mg/kg bw/day]
		100	500	1000
No. of dams/litters examined	25	21	23	25
Mean no. of Corpora Lutea	16.8	16.8	17.7	16.8
	± 2.28	± 2.50	± 3.50	± 1.82
	n=25	n=20	n=23	n=25
Mean no. of Implantation Sites	15.76	15.9	16.09	15.52
	± 2.24	± 2.62	± 2.25	± 2.49
	n=25	n=21	n=23	n=25
Mean no. of resorptions	0.88	0.81	0.91	0.56
	± 1.05	± 1.29	± 1.12	± 0.82
	n=25	n=21	n=23	n=25
Pre-implantation loss [%]	5.7	6.7	8	7.7
	± 8.1	± 8.2	± 8.2	± 12.9
	n=25	n=20	n=23	n=25
Post-implantation loss per litter [%]	5.4	4.9	6	4.4
	± 6.4	± 7.7	± 7.3	± 6.4
	n=25	n=21	n=23	n=25
Mean no. of live fetuses	14.88	15.1	15.13	14.88
	± 2.19	± 2.64	± 2.46	± 2.64
	n=25	n=21	n=23	n=25
Mean no. of dead fetuses	0	0	0.04	0.08
			± 0.21	± 0.28
	n=25	n=21	n=23	n=25
Mean no. of female fetuses	7.72	7.48	8.04	7.8
	± 2.28	± 3.11	± 2.29	± 1.78
	n=25	n=21	n=23	n=25
Mean no. of male fetuses	7.16	7.62	7.09	7.08
	± 1.93	± 2.25	± 2.09	± 2.58
	n=25	n=21	n=23	n=25
Mean body weight (female fetuses) (g)	5.04	5.05	5.06	5.2
	± 0.44	± 0.32	± 0.46	± 0.37
	n=188	n=157	n=185	n=195
Mean body weight (male fetuses) (g)	5.33	5.27	5.39	5.44
	± 0.52	± 0.39	± 0.38	± 0.38
	n=175	n=160	n=163	n=177

Table 2: Fetal variations and malformations

 

	Control	dose groups [mg/kg bw/day]
		100	500	1000
No. of fetuses with external variations	0	0	0	0
	n=372	n=317	n=347	n=358
No. of fetuses with external malformations	0	1	3	0
	n=372	n=317	n=347	n=358
No. of fetuses with visceral or head variations	0	0	1	2
	n=187	n=161	n=173	n=186/187*
No. of fetuses with visceral or head malformations	2	2	1	0
	n=187	n=161	n=173	n=186/187*
No. of fetuses with skeletal variations	45	39	29	35
	n=185	n=156	n=176	n=185
No. of fetuses with skeletal malformations	1	3	0	2
	n=185	n=156	n=176	n=185

  

*186 visceral examinations performed, 187 head examinations performed

Conclusions:

The test substance was not considered embryotoxic under the conditions of this study. Accordingly, the maternal and developmental NOAELs were established at 1000 mg/kg bw/d under the conditions of this study. The results indicate that test substance was not a selective developmental toxicant and was not embryotoxic or teratogenic under the conditions of this study.

Reference 2

Endpoint:

developmental toxicity

Type of information:

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

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions (15 dams per group instead of 20, administration on day 0-19 of gestation, limited details on study design)

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

(only 15 presumed pregnant females per group, exposure on day 0-19 of gestation, only 2 dose levels, nonstandard dermal exposure, limited details on exposure)

GLP compliance:

no

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Kingston, N.Y.
- Age at study initiation: approx. 9 weeks
- Mean weight at study initiation: 248 g
- Diet: Purina Certified Rodent Chow #5002 (Meal), ad libitum
- Water: tap water, ad libitum
- Acclimation period: 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 - 22
- Humidity (%): 40 - 60
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

dermal

Vehicle:

unchanged (no vehicle)

Details on exposure:

TEST SITE
- Type of wrap if used: open exposure, no wrap
- Time intervals for shavings or clipplings: no data on frequency; clipped, intact skin
- Site: dorsal
Controls: The rats of the control group were clipped and collared. The intact dorsal skin of each rat was stroked with the tip of a syringe, but no test material was applied.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): no

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): The amount of the test material applied with a syringe was calculated based on the body weight of the animals and the density of the test substance.

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes. To minimize ingestion of the test material, the rats were fitted with cardboard Elizabethan-style collars.

Analytical verification of doses or concentrations:

no

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused: M/F ratio per cage: 1/1
- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

gestation days 0 - 19

Frequency of treatment:

daily

Duration of test:

The animals were sacrificed on day 20 of gestation.

Remarks:

Doses / Concentrations:
800 and 2000 mg/kg bw/day
Basis:
nominal conc.

No. of animals per sex per dose:

15 presumed-pregnant females

Control animals:

yes, concurrent no treatment

Details on study design:

- Dose selection rationale: based on results of a 13-week dermal study previously conducted with the same material

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: at least once daily
- Cage side observations checked: signs of pathosis, abortion, premature delivery, and death

DETAILED CLINICAL OBSERVATIONS: No data

BODY WEIGHT: Yes
- Time schedule for examinations: day 0, 3, 6, 10, 13, 16, and 20 of gestation

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: Yes
- Time schedule for calculation: days 0-3, 3-6, 6-10, 10-13, 13-16, and 16-20

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: The thoracic and abdominal cavities were exposed and all organs were examined grossly for evidence of pathosis.

OTHER:
- Clinical chemistry: alanine aminotransferase (ALT), albumin, albumin/globulin ration, alkaline phosphatase (ALP), aspartate aminotransferase (AST), bilirubin, calcium, chloride, cholesterol, creatinine, globuline, glucose, iron, lactate dehydrogenase (LDH), phosphorus, potassium, sodium, sorbitol dehydrogenase (SDH), total protein, triglycerides, urea nitrogen, and uric acid

Ovaries and uterine content:

The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Number of live and dead fetuses: Yes
- Other: The ovaries of non-pregnant females were grossly examined and then discarded.

Fetal examinations:

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

Statistics:

- Analysis of variances and group comparison using Fisher's Exact or Dunnett's test (maternal biophase and cesarean section data, and fetal data)
- ANOVA and Fisher's Exact test (fetal skeletal data)
- Fisher's Exact test (fetal visceral data)
- SAS procdures, Student-Newman-Keul's multiple comparison test (clinical chemistry data)
P < 0.05

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: slight local effects

Details on maternal toxic effects:
- General observations: neck lesions, red nasal exudate, and chromodacryorrhea in all groups (considered not to be test substance-related as these signs are common in animals that are collared)
- Local effects: mild dermal irritation including erythema and flaking of the skin in the treatment groups
- Body weight: similar to controls in both treatment groups
- Body weight gain: similar to controls in both treatment groups
- Uterine and net body weights: similar to controls in both treatment groups
- Food consumption: similar to control in both treatment groups; only difference (statistically significant) in high dose group on day 13-16: 31.5 g vs. 29.5 g (corresponding control data)
- Necropsy: no remarkable findings were observed
- Fetal status and uterine position: no parameter evaluated appeared to be adversly affected
- Clinical chemistry: no differences between treated and non-treated rats were observed

Dose descriptor:

NOAEL

Remarks:

systemic

Effect level:

2 000 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
- Fetal body measurements: Mean fetal body weights and crown-rump lengths, parameters of body growth and development were normal compared to controls.
- Fetal examination: No malformations or variations were observeed. Bruises were observed on the skin of 4 fetuses from the control group and 2 fetuses form the 800 mg/kg bw/day group (considered to be incidental). One fetus from one dam exposed to 800 mg/kg bw/day was pale in colour. No other remarkable findings were observed during external examination.
- Malformations (lumbar and sacral vertebrae, tail, sternebrae, and ribs) were observed. The incidence was low and there was no apparent dose-response relationship, these effects were considered to be not treatment-related. Comparable incidences of variant skeletal development were observed in both cotnrol and trated fetuses.
- Visceral examinations: A statistically significant (high dose) increase in the number of fetuses with levocardia was observed. The response appeared to be dose-related
Levocardia:
Litters: control: 0 (0%); 800 mg/kg bw/day: 2 (14.3%); 2000 mg/kg bw/day: 7 (50%); 14 litters per group examined
Fetuses: control: 0 (0%); 800 mg/kg bw/day: 3 (3.2%); 2000 mg/kg bw/day: 7 (10.1%); 94, 93, and 99 fetuses examined, respectively
Microphthalmia, anophtalmia and "apparent" hydronephrosis were also observed. Variant visceral development was observed in control and treated fetuses.

Dose descriptor:

LOAEL

Effect level:

800 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

visceral malformations

Dose descriptor:

NOAEL

Effect level:

< 800 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: No adverse effects observed in the highest dose level.

Abnormalities:

not specified

Developmental effects observed:

not specified

Levocardia was the only parameter affected in fetuses of dams treated with the test substance during gestation. In other studies, levocardia was observed in control fetuses, too. However, the effect of the test substance on heart development should be focused on in further studies as well as the impact, this effect has on postnatal survival.

Conclusions:

In a developmental toxicity study, pregnant rats were dermally exposed to the test substance. No adverse effects were observed in any maternal or reproductive parameter nor on external and skeletal development of fetuses. Levocardia was observed in 3.2% and 10.1% of the fetuses exposed in utero to 800 and 2000 mg/kg bw /day, respectively. Thus, the developmental NOAEL was determined to be < 800 mg/kg bw.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Species:

rat

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 adverse effect observed

Species:

rat

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.

Additional information

Effect on developmental toxicity

Justification for grouping of substances and read-across

There are no data available for developmental toxicity of 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate (CAS 25811-35-2). 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]
25811-35-2 Target substance	RA: CAS 189200-42-8 RA: CAS 67762-53-2
189200-42-8	> = 1000 (rat)
67762-53-2	< 800 (rat)

 

The above mentioned substance is 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 2,2-bis[[(1-oxoheptyl)oxy]methyl]propane-1,3-diyl bisheptanoate (CAS 25811-35-2).

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

CAS 67762-53-2

The developmental toxicity of Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) was investigated comparable to OECD Guideline 414 (prenatal developmental toxicity study) (Feusten, 1988). Groups of 15 presumed pregnant female Sprague-Dawley rats received daily dermal doses of the test substance at concentrations of 800 and 2000 mg/kg bw/day during gestational days 0 to 19. Control animals remained untreated. On day 20 of gestation the animals were euthanized and examined for maternal and fetal parameters. There were no adverse effects found for all parameters examined in maternal animals. Based on the number of implantations, number of total litter losses by resorption, mortality, clinical signs, body weight, gross pathology and organ weights of maternal animals the NOAEL for maternal toxicity was found to be 2000 mg/kg bw/day. Examination of fetus litter size and weights, offspring viability (number alive and number dead), sex ratio, grossly visible abnormalities, external, head, soft tissue and skeletal abnormalities revealed no differences to controls and thus no indication for teratogenic effects. The only effect found was a dose-dependently increased number of fetuses with levocardia, although no hearth malformations have been detected. Furthermore levocardia was observed in vehicle control foetuses (Smith et al. 1988) and in the control foetuses conducted in the test laboratory. Since levocardia was observed in both treated groups, the NOAEL for embryo-/fetotoxicity and teratogenicity in rats Fatty acids, C5-9, tetraesters with pentaerythritol was found to be < 800 mg/kg bw/day and the LOAEL = 800 mg/kg bw/day.

CAS 189200-42-8

The developmental toxicity of Fatty acids C8-10, mixed esters with dipentaerythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS 189200-42-8) was investigated according to OECD Guideline 414 (prenatal developmental toxicity study) and under GLP conditions (Trimmer, 1995). 50 male Sprague-Dawley rats were mated with females to achieve groups of 25 pregnant Sprague-Dawley rats which then received daily oral gavage doses of the test substance at concentrations of 100, 500 and 1000 mg/kg bw/day during gestational days 6 to 15. Control animals received the vehicle polyethylene glycol (PEG 400). On day 21 of gestation the animals were euthanized and examined for maternal and fetal parameters. There were no adverse effects found for all parameters examined in maternal animals. Based on the number of implantations, number of total litter losses by resorption, mortality, clinical signs, body weight, gross pathology and organ weights of maternal animals the NOAEL for maternal toxicity was found to be 1000 mg/kg bw/day. Examination of fetus litter size and weights, offspring viability (number alive and number dead), sex ratio, grossly visible abnormalities, external, head, soft tissue and skeletal abnormalities showed only incidental malformations in two high dose females. The NOAEL for embryo-/fetotoxicity and teratogenicity in rats for Fatty acids C8-10, mixed esteres with dipentaerythritol, isooctanoic acid, pentaerythritol and tridipentaerythritol was found to be 1000 mg/kg bw/day.

Justification for selection of Effect on developmental toxicity: via oral route:
Hazard assessment is conducted by means of read-across from a structural analogue. The available studiy is 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).

Justification for selection of Effect on developmental toxicity: via dermal route:
Hazard assessment is conducted by means of read-across from a structural analogue. The available studiy is 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).

Justification for classification or non-classification

Based 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.