Registration Dossier

Administrative data

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

Effects on developmental toxicity

Description of key information

Prenatal developmental toxicity study in the rat by the dermal route: NOAEL for systemic maternal toxicity is 2000 mg/kg body weight/day and the NOAEL for local maternal toxicity is 200 mg/kg body weight/day.

Link to relevant study records

Referenceopen allclose all

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
2004
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
Justification for type of information:
Comparable to guideline study with acceptable restrictions; few details on test substance given, no analysis of the test compound. Read across.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Version / remarks:
See below
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 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 mentionedENVIRONMENTAL 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 periodREMOVAL 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 hTEST 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: yesVEHICLE- 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.
Clinical signs:
no effects observed
Dermal irritation (if dermal study):
effects observed, non-treatment-related
Description (incidence and severity):
The two highest dose levels caused some local irritation at the site of application, but no decreases in maternal weight gain or feed consumption. 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).
Mortality:
mortality observed, non-treatment-related
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
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Other effects:
not specified
Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
effects observed, non-treatment-related
Description (incidence and severity):
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.
Early or late resorptions:
effects observed, non-treatment-related
Description (incidence and severity):
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.
Dead fetuses:
no effects observed
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Changes in number of pregnant:
no effects observed
Other effects:
no effects observed
Details on maternal toxic effects:
Maternal toxic effects:yes. Remark: local irritationDetails 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).
Key result
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
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
Key result
Abnormalities:
no effects observed
Fetal body weight changes:
no effects observed
Description (incidence and severity):
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Reduction in number of live offspring:
no effects observed
Changes in sex ratio:
no effects observed
Changes in litter size and weights:
no effects observed
Changes in postnatal survival:
no effects observed
External malformations:
no effects observed
Skeletal malformations:
no effects observed
Visceral malformations:
no effects observed
Other effects:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effectsDetails 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.
Key result
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day
Based on:
test mat.
Sex:
male/female
Remarks on result:
not determinable due to absence of adverse toxic effects
Key result
Abnormalities:
no effects observed
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 incidencesa

375/25

375/25

375/25

375/25

Erythema

Total

0/0

2/1

22/4

91/13b

Grade 1

0/0

2/1

10/4

81/13b

Grade 2

0/0

0/0

4/1

10/4b

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

71/14b

Grade 3

0/0

0/0

9/1

38/7 b

Edema

Total

0/0

0/0

23/4

83/11b

Grade 1

0/0

0/0

18/4

59/11b

Grade 2

0/0

0/0

5/1

24/6b

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

22b

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

6.8c

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

22b

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)

Conclusions:
Only local irritation effects were noted. Minor maternal toxicity effects only were noted. The substance is not considered to cause teratogenicity.
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:
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 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:
effects observed, non-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).
Dermal irritation (if dermal study):
effects observed, treatment-related
Description (incidence and severity):
Local effects: mild dermal irritation including erythema and flaking of the skin in the treatment groups.
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
Body weight: similar to controls in both treatment groups.
Body weight gain: 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:
no effects observed
Description (incidence and severity):
Uterine and net body weights: similar to controls in both treatment groups
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 adversly affected
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
no parameter evaluated appeared to be adversly affected
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
no parameter evaluated appeared to be adversly affected
Early or late resorptions:
no effects observed
Description (incidence and severity):
no parameter evaluated appeared to be adversly affected
Dead fetuses:
no effects observed
Description (incidence and severity):
no parameter evaluated appeared to be adversly affected
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
no parameter evaluated appeared to be adversly affected
Migrated Data from removed field(s)
Field "Effects on pregnancy duration" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.EffectsOnPregnancyDuration): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsMaternalAnimals.MaternalDevelopmentalToxicity.DescriptionIncidenceAndSeverityEffectsOnPregnancyDuration): no parameter evaluated appeared to be adversly affected
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
no parameter evaluated appeared to be adversly affected
Other effects:
no effects observed
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
Key result
Dose descriptor:
LOAEL
Effect level:
800 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Dose descriptor:
NOAEL
Effect level:
< 800 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental 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.
Migrated Data from removed field(s)
Field "Fetal/pup body weight changes" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.FetalPupBodyWeightChanges): no effects observed
Field "Description (incidence and severity)" (Path: ENDPOINT_STUDY_RECORD.DevelopmentalToxicityTeratogenicity.ResultsAndDiscussion.ResultsFetuses.DescriptionIncidenceAndSeverityFetalPupBodyWeightChanges): 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:
no effects observed
Description (incidence and severity):
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
Changes in sex ratio:
not specified
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
Litters: control: 0 (0%); 800 mg/kg bw/day: 2 (14.3%); 2000 mg/kg bw/day: 7 (50%); 14 litters per group examined
Changes in postnatal survival:
no effects observed
Description (incidence and severity):
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
External malformations:
no effects observed
Description (incidence and severity):
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.
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: Microphthalmia, anophtalmia and "apparent" hydronephrosis were also observed. Variant visceral development was observed in control and treated fetuses.
Other effects:
not specified
Key result
Dose descriptor:
NOEL
Effect level:
< 800 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
visceral malformations
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
2 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
Klimisch 2 study.
Additional information

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.

The prenatal developmental toxicity study with Fatty acids, C5-9, tetraesters with pentaerythritol (CAS 67762-53-2) using Sprague-Dawley rats resulted in a NOAEL lower than 800 mg/kg bw/day since levocardia was found in the pups of both treated groups, although not internal heart malformation was detected. 

CAS 11138 -60 -6

A prenatal developmental toxicity study in the rat by the dermal route was conducted with read-across substance, decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate (CAS 11138-60-6). The doses administered were 0 (control), 200, 600 and 2000 mg/kg body weight on each gestation day 6 to 15. Dermal application of 600 and 2000 mg/kg/day dosages of the test article caused local irritation at the site of application (statistically significant compared with control at 2000 mg/kg bw), but no decrease in material weight gain. There appeared to be no systemic effects. No adverse effects on embryo-fetal number, viability, sex ratio, body weight or morphology were observed at the highest dosage tested. Based on these results, the NOAEL for systemic maternal toxicity is 2000 mg/kg body weight/day and the NOAEL for local maternal toxicity is 200 mg/kg body weight/day.

Justification for classification or non-classification