Fatty acids, C5-9, hexaesters with dipentaerythritol

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

There are no specific reproductive toxicity studies available for Fatty acids, C5-9, hexaesters with dipentaerythritol (CAS# 67762-52-1) to assess the potential 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, pentaerythritol ester of pentanoic acids and isononanoic acid (CAS# 146289-36-3) reproductive organs were examined.

 

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.

 

In addition, developmental toxicity studies with structural similar substances including Decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate (CAS# 11138-60-6) and Fatty acids C8-10, mixed esters with diPE, isooctanoic acid, PE and triPE (CAS# 189200-42-8) 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 the test substance exhibit no or only low toxicological potency. As determined in the toxicokinetic assessment, only a low potential for absorption is considered for the test substance.

In conclusion, regarding the available studies on source substance, Fatty acids, C5-9, hexaesters with dipentaerythritol (CAS# 67762-52-1) is 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

No reproductive toxicity studies are available for Fatty acids, C5-9, hexaesters with dipentaerythritol (CAS# 67762-52-1). However in one 90-day study with structural related analogue substance pentaerythritol ester of pentanoic acids and isononanoic acid (CAS# 146289-36-3)showed no indications for effects on reproductive organs were examined. As no indications for effects on reproductive organs were found (NOAEL > 1000 mg/kg bw/day Fatty acids, C5-9, hexaesters with dipentaerythritol (CAS# 67762-52-1) were not considered to have toxic effects on reproductive organs.

 

Effects on developmental toxicity

Description of key information

Oral (OECD 414), rat: NOAEL >= 1000 mg/kg bw/day;
Dermal (OECD 414), rat: NOAEL = 2000 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)

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: maternal toxicity

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.

Sex:

male/female

Basis for effect level:

other: developmental toxicity

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; few details on test substance given, no analysis of the test compound

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

few details on test substance given, no analysis of the test compound

GLP compliance:

not specified

Limit test:

no

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Laboratories, Kingston, NY
- Age at study initiation: young adult
- Weight at study initiation: Mean of the maternal body weight: 226 g (Vehicle), 225 g (200 mg/kg bw/day), 227 g (600 mg/kg bw/day), 226 g (2000 mg/kg bw/day)
- Fasting period before study: No
- Housing: Virgin females were cohabitated with singly-housed male rats, one male per female rat for a maximum of 5 days and returned to individual housing in stainless steel wire-bottomed cages after mating.
- Diet: Certified Rodent Diet No. 5002 (PMI Feeds Inc. St.Louis, MO), ad libitum
- Water: water passaged through a reverse osmosis membrane with chlorine added as a bacteriostat, ad libitum
- Acclimation period: yes, period not mentioned


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 30 - 70
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

dermal

Vehicle:

corn oil

Details on exposure:

TEST SITE
- Area of exposure: The back of the animals from the shoulders to the hip joints and extended ventrolaterally from the dorsal midline on each side (5x7 cm)
- % coverage: approx. 10% of the body surface
- Type of wrap if used: occlusive, gauze pad secured with Vetrap or Micropore tape
- Time intervals for shavings or clipplings: during acclimatization period


REMOVAL OF TEST SUBSTANCE
- Washing (if done): exposed area was wiped with a dermal wipe pad dampened with aqueous 1% solution of soap and then patted dry with a second clean pad
- Time after start of exposure: 6 h


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2 mL/kg
- Concentration (if solution): 200, 600, and 2000 mg/kg/day
- Constant volume or concentration used: yes

VEHICLE
- Amount(s) applied (volume or weight with unit): 2 mL/kg
- Concentration (if solution): up to 100% (vehicle control)

USE OF RESTRAINERS FOR PREVENTING INGESTION: yes, Elizabethan collar

Analytical verification of doses or concentrations:

no

Details on mating procedure:

- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: maximum 5 days
- Further matings after two unsuccessful attempts: Not applicable
- Verification of same strain and source of both sexes: No Data
- Proof of pregnancy: Both, vaginal plug and/or sperm in vaginal smear were referred to as Day 0 of pregnancy

Duration of treatment / exposure:

Treatment on Gestation Days (GD) 6 - 15

Frequency of treatment:

Daily

Duration of test:

Termination of the study by CO2 inhalation on GD 20.

No. of animals per sex per dose:

25

Control animals:

yes, concurrent vehicle

Details on study design:

- Dose selection rationale: Dose dependent occurrence of skin irritation. Higher levels than 2000 mg/kg bw/day might be expected to produce marked irritation thereby compromising the interpretaion of developmental results.
- Rationale for animal assignment (if not random): Computer-generated randomization by weight (Barlett´s test for homogeneity) such that the groups were not statistically different (5% significance level) from each other.

Maternal examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: Animals were checked for mortality twice daily during the treatment period and daily thereafter.


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: Animals were checked for signs of reaction to treatment and/or symptoms of illness once daily before treatment, approx. 60 min after treatment during the dosing period. The dosing site was examined daily prior to substance application for signs of skin irritation according to Draize.


BODY WEIGHT: Yes
- Time schedule for examinations: Recorded on GD 0 and daily during the treatment period.


FOOD CONSUMPTION AND COMPOUND INTAKE : Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg b.w./day: Yes
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day # 20
- Organs examined: The uterus, uterine contents, position of the fetuses in the uterus and number of corpora lutea. Number and distribution of intrauterine implantations were classified as live or death fetuses, late intrauterine deaths (resorptions) and early intrauterine resorption sites. Live fetuses were sexed and further examined (see below).

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 (the heads of the animals used for soft tissue examinations)

Statistics:

Clinical observations and other proportion data were analyzed using the Variance Test for Homogeneity of the Binominal Distribution. Quantitative continuous data were analyzed using Barlett´s Test for Homogeneity of Variance and the Analysis of Variance when Barlett´s Test was not significant (p>0.05). If the Analysis of Variance was significant (p>0.05), Dunnett´s Test was used to identify the statistical significance of the individual groups. If the Analysis of Variance was not appropriate, the Kruskal-Wallis Test was used when >75% ties were present. In case of significance (p>0.05), Dunn´s Method of Multiple Comparisons was used for identification of statistical significance of the individual groups.

Historical control data:

No details.
One dam having a litter consisting of seven early resorptions was pointed out as single non-dosage dependent event and to be within the ranges observed historically at the test facility.

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: local irritation

Details on maternal toxic effects:
The two highest dose levels caused some local irritation at the site of application, but no decreases in maternal weight gain or feed consumption. Two animals in the control group and one animal in the high-dose group died within 6 h after first application; these were not considered to be treatment related and the animals were replaced. One dam of the mid-dose goup (1/25) having a litter consisting of seven early resorptions was pointed out as single non-dosage dependent event and to be within the ranges observed historically at the test facility.
Necropsy findings were limited to skin flaking and scabbing first identified in life and observations related to wearing the Elizabethan collar (local alopecia, chromorhinorrhea, and neck lesions).

Dose descriptor:

NOAEL

Remarks:

local

Effect level:

200 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

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:
There were no significant differences from control in any of the developmental parameters measured, including embryo/fetal viability, fetal weight, malformations, or variations. The observed effects in fetuses were dose-independent and regarded to be sporadic.

Dose descriptor:

NOAEL

Effect level:

2 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: developmental toxicity

Abnormalities:

not specified

Developmental effects observed:

not specified

Table 1: Skin reaction observations

	0 mg/kg bw/d	200 mg/kg bw/d	600 mg/kg bw/d	2000 mg/kg bw/d
Maximum possible incidences^a	375/25	375/25	375/25	375/25
Erythema
Total	0/0	2/1	22/4	91/13^b
Grade 1	0/0	2/1	10/4	81/13^b
Grade 2	0/0	0/0	4/1	10/4^b
Flaking
Total	11/3	15/2	55/6	170/17 ^b
Grade 1	11/3	9/2	27/5	61/14 ^b
Grade 2	0/0	6/1	19/4	71/14^b
Grade 3	0/0	0/0	9/1	38/7 ^b
Edema
Total	0/0	0/0	23/4	83/11^b
Grade 1	0/0	0/0	18/4	59/11^b
Grade 2	0/0	0/0	5/1	24/6^b
Scab	0/0	0/0	6/2	19/4

a:       Maximum incidence : Days x rats from first treatment on GD 6 through sacrifice on GD 20 divided by the number of rats examined per group on GD 6-20

b:        Significantly different from vehicle control group value (p≤0.01)

 

Table 2: Maternal reproductive, litter, and fetal alteration observations: Caesarian-Section results on GD 20

	0 mg/kg bw/d	200 mg/kg bw/d	600 mg/kg bw/d	2000 mg/kg bw/d
Rats pregnant and sectioned on Day 20 of gestation (n)	25	23	22^b	24
Corpora lutea/dam	16.4	16.6	16.9	16.5
Implantation sites/litter	15.0	15.4	14.9	14.2
Litter size
Live fetuses/litter	14.6	14.6	14.0	13.3
Live fetuses (n)	364	335	308	320
Dead fetuses (n)	0	0	0	0
Resorptions	0.4	0.9	0.9	0.9
Early (n)	10	20	19	21
Late (n)	1	0	0	0
Dams with any resorptions n(%)	9 (36)	11 (48)	15 (68)	11 (46)
% resorbed/litter	2.9	5.4	5.8	5.0
% male/litter	51.3	50.8	48.1	47.7
Live fetal body weight (g/litter)	3.68	3.62	3.69	3.75
Male	3.77	3.68	3.82	3.85
Female	3.58	3.56	3.58	3.65
Fetuses evaluated (n)	364	335	308	320
Litters with any alterations observed n(%)	10 (40)	8 (35)	14 (64)	7 (25)
Fetuses with any alterations observed n(%)	13 (3.5)	10 (3.0)	20 (6.5)	9 (2.0)
% fetuses/litter with any alterations observed	3.5	2.9	6.8^c	2.7

b:       Excludes values for one dam, which had a litter consisting of seven early resorptions.

c:       Significantly different from vehicle control group value (p≤0.05)

Table 3: Fetal evaluations

	0 mg/kg bw/d	200 mg/kg bw/d	600 mg/kg bw/d	2000 mg/kg bw/d
Litters evaluated	25	23	22^b	24
Fetuses evaluated	364	335	308	320
Live	364	335	308	320
Fetal gross external alterations	364	335	308	320
Tail: kinked
Litter incidence, n (%)	0(0)	1 (4.3)	0(0)	0(0)
Fetal incidence, n (%)	0(0)	1(0.3)	0(0)	0(0)
Body: hematoma
Litter incidence, n (%)	1(4.0)	0(0)	0(0)	0(0)
Fetal incidence, n (%)	1 (0.3)	0(0)	0(0)	0(0)
Fetal soft tissue alterations, evaluations	174	162	149	155
Vessels: umbilical artery descended to the left of urinary bladder
Litter incidence, n (%)	2(8.0)	3(13.0)	2(9.1)	2(8.3)
Fetal incidence, n (%)	2(1.1)	3(1.8)	3(2.0)	2(1.3)
Vessels: apparent additional umbilical artery descended left of the bladder
Litter incidence, n (%)	0(0)	0(0)	1(4.5)	0(0)
Fetal incidence, n (%)	0(0)	0(0)	1(0.7)	0(0)
Fetal skeletal alterations, evaluations	190	173	159	165
Cervical vertebrae: cervical rib present at 7th cervical vertebrae
Litter incidence, n (%)	2(8.0)	1(4.3)	1(4.8)	0(0)
Fetal incidence, n (%)	2(1.0)	2(1.2)	1(1.2)	0(0)
Thoracic vertebrae: centrum, bifid
Litter incidence, n (%)	1(4.0)	1(4.3)	5(22.7)	0(0)
Fetal incidence, n (%)	1(0.5)	1(0.6)	5(3.1)^a	0(0)
Lumbar vertebrae: centrum, bifid
Litter incidence, n (%)	0(0)	1(4.3)	0(0)	0(0)
Fetal incidence, n (%)	0(0)	1(0.6)	0(0)	0(0)
Ribs: wavy
Litter incidence, n (%)	0(0)	0(0)	2(9.1)	1(4.2)
Fetal incidence, n (%)	0(0)	0(0)	2(1.2)	1(0.5
Sternal centra: 1st, not ossified
Litter incidence, n (%)	1(4.0)	0(0)	0(0)	2(8.3)
Fetal incidence, n (%)	1(0.5)	0(0)	0(0)	2(1.3)
Sternal centra: 1st, incompletely ossified
Litter incidence, n (%)	3(12.0)	3(13.0)	2(5.1)	1(4.2)
Fetal incidence, n (%)	4(2.1)	4(2.3)	2(1.2)	1(0.6)
Pelvis: pubis, incompletely ossified
Litter incidence, n (%)	3(12.0)	0(0)	4(18.2)	3(12.5)
Fetal incidence, n (%)	3(1.6)	0(0)	5(3.1)	3(1.8)
Pelvis: ischium, incompletely ossified
Litter incidence, n (%)	0(0)	0(0)	2(9.1)	0(0)
Fetal incidence, n (%)	0(0)	0(0)	2(1.2)	0(0)

a: Significantly different from vehicle control group (p≤0.01)

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 due to read-across) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on similar functional groups and similar precursors/breakdown products (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

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 similar functional groups and similar precursors/breakdown products (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

Justification for grouping of substances and read-across

There are no data available for developmental toxicity of the substance Fatty acids, C5-9, hexaesters with dipentaerythritol (CAS# 67762-52-1). In order 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, 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 toxicological properties may be predicted from data for the reference substance(s) on the basis of structural similarity, the substances listed below are selected as reference substances for assessment of toxicological endpoints, for which information gaps are identified.

 

Overview for developmental toxicity

CAS	Toxicity
70983-72-1 (a) Target substance	RA: CAS 11138-60-6 RA: CAS 189200-42-8
11138 -60-6 (b)	NOAEL = 2000 mg/kg bw
189200-42-8	NOAEL ≥ 1000 mg/kg bw

 (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 the structural and similar properties and/or activities.The available endpoint information is used to predict the same endpoints for Fatty acids, C5-9, hexaesters with dipentaerythritol (CAS# 67762-52-1).

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

 

Discussion

Developmental toxcity

Since no studies investigating the developmental toxicity of Fatty acids, C5-9, hexaesters with dipentaerythritol (CAS# 67762-52-1)are available, in accordance to Regulation (EC) No. 1907/2006 Annex XI, 1.5 a read-across from thesource substances fatty acids, C8-10, mixed esters with dipenaterythritol, isooctanoic acid, pentaerythritol and tripentaerythritol (CAS# 189200-42-8), and decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate (CAS# 11138-60-6) was conducted.

 

CAS 189200-42-8

The developmental toxicity of Fatty acids C8-10, mixed esters with diPE, isooctanoic acid, PE and triPE (CAS# 189200-42-8) was investigated according to OECD Guideline 414 (prenatal developmental toxicity study) and under GLP (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. 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, the highest dose tested. 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. The NOAEL for embryo-/fetotoxicity and teratogenicity in rats for Fatty acids C8-10, mixed esters with diPE, isooctanoic acid, PE and triPE was found to be 1000 mg/kg bw/day.

 

CAS 11138-60-6

Decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate (CAS# 11138-60-6) was tested in a prenatal developmental toxicity study comparable to OECD Guideline 414 (Azuka and Daston, 2004). The test substance was percutaneously applied to Sprague-Dawley rats for 6 h/day under occlusive conditions. 25 animals per dose were treated with 200, 600 or 2000 mg/kg/day in corn oil on days 6-15 after gestation.

The two highest dose levels caused some local irritation at the site of application, but no decreases in maternal weight gain or food consumption. There were no differences from control in any of the developmental parameters measured, including embryo/fetal viability, fetal weight, malformations, or variations. Therefore, a NOAEL of 2000 mg/kg/day was derived for prenatal development and for systemic maternal toxicity. Due to the irritation effects on skin, the local maternal NOAEL was found to be 200 mg/kg bw/day.

In summary, based on a weight of evidence approach, all reliable studies consistently showed no treatment-related effects on maternal and developmental toxicity and the overall NOAEL was found to exceed 1000 mg/kg bw/day for maternal systemic and developmental toxicity.

 

Conclusion for developmental toxicity

No prenatal developmental toxicity studies are available for Fatty acids, C5-9, hexaesters with dipentaerythritol (CAS 67762-52-1) but a read-across from decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate (CAS# 11138-60-6), and Fatty acids C8-10, mixed esters with diPE, isooctanoic acid, PE and triPE (CAS# 189200-42-8) was applied to assess developmental toxicity.All studies were conducted with Sprague-Dawley rats and did not show any developmental toxic effects. The NOAELs are 2000 and 1000 mg/kg bw/day, respectively.Therefore, Fatty acids, C5-9, hexaesters with dipentaerythritol (CAS 67762-52-1) was not considered to have a potential for 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. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance 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 selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall quality assessment (refer to the endpoint discussion for further details).

Justification for classification or non-classification

Based on read-across from the 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.