Decanoic acid, mixed esters with dipentaerythritol, heptanoic acid and octanoic acid.

Endpoint summary

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Effects on fertility

Description of key information

No study available.

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

Effects on developmental toxicity

Description of key information

Two prenatal developmental toxicity (dermal) studies are available. One study result  in NOAEL of 2000 mg/kg bw and the second one in a NOAEL < 800 mg/kg bw.

One prenatal developmental toxicity (oral) is available, which results in NOAEL of 1000 mg/kg bw.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

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

Remarks:

2 substances are available for read across

Adequacy of study:

weight of evidence

Justification for type of information:

see the attached justification in section 13 for details.

Reason / purpose for cross-reference:

read-across source

Reason / purpose for cross-reference:

read-across source

Key result

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

Remarks on result:

other: Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2)

Key result

Dose descriptor:

NOAEL

Remarks:

local

Effect level:

200 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Remarks on result:

other: 2,2-bis[(octanoyloxy)methyl]butyl decanoate (CAS 11138-60-6)

Key result

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

Remarks on result:

other: 2,2-bis[(octanoyloxy)methyl]butyl decanoate (CAS 11138-60-6)

Key result

Dose descriptor:

LOAEL

Remarks:

developmental

Effect level:

800 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: developmental toxicity

Remarks on result:

other: Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2)

Key result

Dose descriptor:

NOAEL

Effect level:

< 800 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: developmental toxicity

Remarks on result:

other: Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2)

Key result

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

Remarks on result:

other: 2,2-bis[(octanoyloxy)methyl]butyl decanoate (CAS 11138-60-6)

Key result

Abnormalities:

not specified

Key result

Developmental effects observed:

not specified

Conclusions:

The substance, CAS: 70851-04-6; EC: 453-480-2, is analogous to the substances to be read across to, in terms of basic form, and the degree of substitution of functional groups is not considered to effect the proposed read across for the endpoint of developmental toxicity/teratogenicity. Based on the available information to read across to, the substance is not expected to cause developmental toxcitiy / teratogenicity.

Reference 2

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

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.

Remarks:

Doses / Concentrations:
200, 600 and 2000 mg/kg bw/day
Basis:
nominal conc.

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.

Clinical signs:

not specified

Dermal irritation (if dermal study):

effects observed, treatment-related

Description (incidence and severity):

The two highest dose levels caused some local irritation at the site of application.

Mortality:

no mortality observed

Description (incidence):

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.

Body weight and weight changes:

no effects observed

Description (incidence and severity):

No decreases in maternal weight gain.

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

No decreases in feed consumption

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Description (incidence and severity):

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).

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Number of abortions:

not specified

Pre- and post-implantation loss:

not specified

Total litter losses by resorption:

not specified

Early or late resorptions:

not specified

Dead fetuses:

not specified

Changes in pregnancy duration:

not specified

Changes in number of pregnant:

not specified

Other effects:

not specified

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: local irritation

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.

Key result

Dose descriptor:

NOAEL

Remarks:

local

Effect level:

200 mg/kg bw/day (nominal)

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

Key result

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

Fetal body weight changes:

no effects observed

Description (incidence and severity):

There were no significant differences from control in fetal weight.

Reduction in number of live offspring:

no effects observed

Description (incidence and severity):

There were no significant differences from control in embryo/fetal viability.

Changes in sex ratio:

no effects observed

Description (incidence and severity):

There were no significant differences from control in variations. The observed effects in fetuses were dose-independent and regarded to be sporadic.

Changes in litter size and weights:

no effects observed

Description (incidence and severity):

There were no significant differences from control invariations. The observed effects in fetuses were dose-independent and regarded to be sporadic.

Changes in postnatal survival:

not examined

External malformations:

no effects observed

Description (incidence and severity):

There were no significant differences from control in malformations, or variations. The observed effects in fetuses were dose-independent and regarded to be sporadic.

Skeletal malformations:

no effects observed

Description (incidence and severity):

There were no significant differences from control in malformations, or variations. The observed effects in fetuses were dose-independent and regarded to be sporadic.

Description (incidence and severity):

There were no significant differences from control in malformations, or variations. The observed effects in fetuses were dose-independent and regarded to be sporadic.

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects: The observed effects in fetuses were dose-independent and regarded to be sporadic.

Key result

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

Key result

Abnormalities:

not specified

Key result

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)

Reference 3

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

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

Clinical signs:

not specified

Dermal irritation (if dermal study):

effects observed, treatment-related

Description (incidence and severity):

- 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

Mortality:

not specified

Body weight and weight changes:

no effects observed

Description (incidence and severity):

similar to controls in both treatment groups

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

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)

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

no effects observed

Description (incidence and severity):

no differences between treated and non-treated rats were observed

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Description (incidence and severity):

no remarkable findings were observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not specified

Number of abortions:

no effects observed

Description (incidence and severity):

no parameter evaluated appeared to be adversely affected

Pre- and post-implantation loss:

no effects observed

Description (incidence and severity):

no parameter evaluated appeared to be adversely affected

Total litter losses by resorption:

no effects observed

Description (incidence and severity):

no parameter evaluated appeared to be adversely affected

Early or late resorptions:

no effects observed

Description (incidence and severity):

no parameter evaluated appeared to be adversely affected

Dead fetuses:

no effects observed

Description (incidence and severity):

no parameter evaluated appeared to be adversely affected

Changes in pregnancy duration:

no effects observed

Description (incidence and severity):

no parameter evaluated appeared to be adversely affected

Changes in number of pregnant:

no effects observed

Description (incidence and severity):

no parameter evaluated appeared to be adversely affected

Other effects:

not specified

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: slight local effects

Key result

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

Fetal body weight changes:

no effects observed

Description (incidence and severity):

Mean fetal body weights and crown-rump lengths, parameters of body growth and development were normal compared to controls.

Reduction in number of live offspring:

not specified

Changes in sex ratio:

not specified

Changes in litter size and weights:

not specified

Changes in postnatal survival:

not specified

External malformations:

no effects observed

Description (incidence and severity):

No malformations or variations were observed. 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.

Skeletal malformations:

effects observed, non-treatment-related

Description (incidence and severity):

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 malformations:

effects observed, treatment-related

Description (incidence and severity):

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.

Other effects:

not specified

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Key result

Dose descriptor:

LOAEL

Remarks:

developmental

Effect level:

800 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: developmental toxicity

Key result

Dose descriptor:

NOAEL

Effect level:

< 800 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: developmental toxicity

Key result

Abnormalities:

not specified

Key result

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 study available

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

Dose descriptor:

NOAEL

800 mg/kg bw/day

Study duration:

subacute

Species:

rabbit

Quality of whole database:

K2

Toxicity to reproduction: other studies

Additional information

Developmental toxicity

CAS 11138-60-6

Fatty acids, 8-10 (even numbered), di- and triesters with propylidynetrimethanol (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 sex per dose were treated with 200, 600 or 2000 mg/kg bw/day in corn oil on Days 6-15 of gestation. Control animals (25 per sex per dose) received the vehicle. The middle and the high 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 bw/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.

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.

 

A waiver for the requirement to perform a prenatal developmental toxicity study in a 2nd species was included, as this requirement is considered not to add new information for hazard assessment and therefore is scientifically and, considering concerns regarding the use of vertebrate animals for experimental purposes, unjustified.

 

 

Justification for classification or non-classification

Based on the information present from the read-across substances, the substance is not anticipated to induce effects that would affect the reproductive and developmental parameters, therefore in accordance with Regulation 1272/2008, the substance is not classified for reproduction or development toxicity.