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Diss Factsheets

Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
other: data sharing dispute
Adequacy of study:
key 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
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
assessment report
Reference
Endpoint:
developmental toxicity
Type of 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:
guideline study
Justification for type of information:
Guidance on registration Reference: ECHA-16-G-06-EN Publ.date:November 2016
Read-Across Assessment Framework (RAAF) Reference: ECHA-15-R-07-EN Date: May 2015
Practical guide 2: How to report weight of evidence - Reference: ECHA-10-B-05-EN Publ.date: 24/03/2010
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
assessment report
Reason / purpose for cross-reference:
assessment report
Qualifier:
according to guideline
Guideline:
other: European Communities L133, Methods for Determination of Toxicity, "Teratogenicity" (Annex V, adopted November 18, 1987)
Species:
rat
Strain:
other: Crl:CD BR vaf/plus rats
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Frequency of treatment:
Daily on each gestation days 6-15
Duration of test:
10 days

Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
100 mg/kg bw/day
Dose / conc.:
500 mg/kg bw/day
Dose / conc.:
1 000 mg/kg bw/day
No. of animals per sex per dose:
25/group
Control animals:
yes
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
clinical signs
Remarks on result:
other: highest dose tested
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
Changes in sex ratio:
no effects observed
External malformations:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
changes in sex ratio
fetal/pup body weight changes
external malformations
Key result
Developmental effects observed:
no
Conclusions:
There was no evidence of maternal toxicity observed at any dose level tested. There
were no statistically significant differences in mean body weight, body weight change,
uterine weight, corrected body weight, food consumption, or uterine implantation data
Between treated and control animals. Additionally, there was no mortality or adverse
clinical/postmortem signs which were considered treatment-related. In the fetuses, there
was no evidence of growth retardation or increased fetal death in the treated groups
compared with controls. Additionally, there were no biologically significant differences
in total or individual variations or malformations (external, visceral, or skeletal) in the
treated groups when compared with controls on either a per fetus or per litter basis. Thtest material
was not considered embryotoxic nor teratogenic under the conditions of this study.
Reason / purpose for cross-reference:
assessment report
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
weight of evidence
Study period:
1997
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study
Justification for type of information:
Guidance on registration Reference: ECHA-16-G-06-EN Publ.date:November 2016
Read-Across Assessment Framework (RAAF) Reference: ECHA-15-R-07-EN Date: May 2015
Practical guide 2: How to report weight of evidence - Reference: ECHA-10-B-05-EN Publ.date: 24/03/2010
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
assessment report
Reason / purpose for cross-reference:
assessment report
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Species:
rat
Strain:
Sprague-Dawley
Route of administration:
dermal
Vehicle:
corn oil
Duration of treatment / exposure:
6 hours/day
Frequency of treatment:
Daily
Duration of test:
10 days - days 6-15 gestation post coitum

Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
200 mg/kg bw/day
Dose / conc.:
600 mg/kg bw/day
Dose / conc.:
2 000 mg/kg bw/day
No. of animals per sex per dose:
25/group
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
>= 2 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
clinical signs
Remarks on result:
other: highest dose tested
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
Changes in sex ratio:
no effects observed
External malformations:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
>= 2 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
changes in sex ratio
fetal/pup body weight changes
external malformations
Key result
Developmental effects observed:
no
Conclusions:
Maternal data: Dermal application of 600 and 2000 mg/kg/day dosages of the test article caused local irritation (erythema, flaking, edema, and scabbing). The NOAEL of 200 mg/kg for maternal toxicity.
Developmental data: The developmental NOAEL is greater than 2000 mg/kg/day (no adverse effects on embryo-fetal number, viability, sex ratio, body weight or morphology were observed at the highest dosage tested). As evaluated for the embryo/fetotoxicity and teratogenicity, the NOAEL was >2000 mg/kg b.w.
Conclusion: As evaluated in this study, dermal application of this test article at a dosage of 2000 mg/kg/day was not selectively toxic to female reproductive performance or development of the offspring.
Reason / purpose for cross-reference:
assessment report
Reference
Endpoint:
developmental toxicity
Type of 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:
guideline study
Justification for type of information:
Guidance on registration Reference: ECHA-16-G-06-EN Publ.date:November 2016
Read-Across Assessment Framework (RAAF) Reference: ECHA-15-R-07-EN Date: May 2015
Practical guide 2: How to report weight of evidence - Reference: ECHA-10-B-05-EN Publ.date: 24/03/2010
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
assessment report
Reason / purpose for cross-reference:
assessment report
Qualifier:
according to guideline
Guideline:
other: Developmental Toxicity Screen in Rats - US EPA
Species:
rat
Strain:
Sprague-Dawley
Route of administration:
dermal
Vehicle:
unchanged (no vehicle)
Frequency of treatment:
Daily
Duration of test:
10 days

Dose / conc.:
0 mg/kg bw/day
Dose / conc.:
800 mg/kg bw/day
Dose / conc.:
2 000 mg/kg bw/day
No. of animals per sex per dose:
15/group
Control animals:
yes
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
>= 2 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
clinical signs
Remarks on result:
other: highest dose tested
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
Changes in sex ratio:
no effects observed
External malformations:
no effects observed
Key result
Dose descriptor:
NOAEL
Effect level:
>= 2 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
changes in sex ratio
fetal/pup body weight changes
external malformations
Key result
Developmental effects observed:
no
Conclusions:
Administration of test article to the uncovered skin of collared rats at doses of 800 or 2000 mg/kg/day produced slight skin irritation (erythema and flaking) at the site of application. Neither maternal parameters (food consumption, body weight gain: monitored throughout gestation (days O-19) nor reproductive parameters (number ol implants, resorptions, or viable fetuses) were adversely affected at either of the dose levels tested. No evidence of teratogenicity (abnormal development) was observec during external examination of fetuses from pregnant dams exposed to test article. Mean fetal body weights and crown-rump distances were similar in all of the experimental groups.
Reason / purpose for cross-reference:
assessment report
Reference
Endpoint:
developmental toxicity
Type of information:
(Q)SAR
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
accepted calculation method
Justification for type of information:
Guidance on registration Reference: ECHA-16-G-06-EN Publ.date:November 2016
Practical guide 2: How to report weight of evidence - Reference: ECHA-10-B-05-EN Publ.date: 24/03/2010
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
read-across source
Reason / purpose for cross-reference:
assessment report
Reason / purpose for cross-reference:
assessment report
Qualifier:
according to guideline
Guideline:
other: FDA METHOD by T.E.S.T software 4.2.1
Principles of method if other than guideline:
FDA METHOD by T.E.S.T software 4.2.1
Specific details on test material used for the study:
SMILES Descriptors of test material : CCCCCCCC\C=C/CCCCCCCC(=O)OCC(COC(=O)CCCCCCC\C=C/CCCCCCCC)(COC(=O)CCCCCCC\C=C/CCCCCCCC)COC(=O)CCCCCCC\C=C/CCCCCCCC
Species:
other: QSAR estimation
Key result
Remarks on result:
other: qualitative QSAR estimation
Key result
Remarks on result:
other: qualitative QSAR estimation
Key result
Developmental effects observed:
no
Conclusions:
Based on the prediction for developmental toxicity it was estimated that the substance is NOT a Developmental Toxicant
Reason / purpose for cross-reference:
assessment report
Reference
Endpoint:
developmental toxicity
Type of information:
other: data sharing dispute
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Reason / purpose for cross-reference:
assessment report
Reason / purpose for cross-reference:
assessment report
Reason / purpose for cross-reference:
assessment report
Reason / purpose for cross-reference:
assessment report
Reason / purpose for cross-reference:
assessment report
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
yes
Remarks:
- lack of data on test substance
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
other: Crl:CD BR VAF/Plus
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Inc., Stone Ridge, NY, USA
- Age at study initiation: approximately 9 - 10 weeks
- Weight at study initiation: 200 - 274 g (female)
- Housing: The animals were housed in suspended stainless steel and wire mesh cages with absorbent paper below the cages. The females were housed separately during the study period except during mating.
- Diet: Purina Certified Rodent Chow No. 5002, ad libitum
- Water: tap water, ad libitum
- Acclimation period: 13 d

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

IN-LIFE DATES:
From: 03 Oct 1994
To: 08 Nov 1994
Route of administration:
oral: gavage
Vehicle:
other: polyethylene glycol (PEG 400)
Details on exposure:
PREPARATION OF DOSING SOLUTIONS: The undiluted test substance was thoroughly mixed in vehicle prior to dispensing. The dosing solutions were prepared weekly.

VEHICLE
- Lot/batch no. (if required): 122H1109
- Physical state: colorless liquid
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysis for homogenity of the test substance dilutions were performed on the lowest and the highest concentrations expected during the course of the study. The relative standard deviation ranged from 0.72 to 3.19%. Concentrations were analysed in the first and the third dosing mixture preparation. The analytical results for all test solutions were within 7% of the nominal concentrations for weeks 1 and 3.
Details on mating procedure:
- Impregnation procedure: cohoused
- M/F ratio per cage: 1/1
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: vaginal plug and/or sperm in vaginal smear referred to as day 0 of pregnancy
After confirmation of pregnancy, each mated female was returned to its cage and new females were placed into the males' cages until a required number of pregnant females was obtained.
Duration of treatment / exposure:
gestation days (GD) 6 - 15
Frequency of treatment:
daily, 7 d/week
Duration of test:
21 d (GD 0 - 21)
Remarks:
Doses / Concentrations:
100, 500 and 1000 mg/kg bw/d
Basis:
actual ingested
No. of animals per sex per dose:
25 females per dose, 50 males in total
Control animals:
yes, concurrent vehicle
Details on study design:
- Rationale for animal assignment: Mated females were assigned to dose groups in the order of mating. Accordingly, the first confirmed mated female was assigned to Group 1, the next to Group 2 and so on until all mated animals for a given day were assigned to dose groups. On subsequent days, the next group in sequence was filled by the first confirmed mated female on that day and so on. Assignments were made until all groups were filled with confirmed mated females.
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily during the treatment period and once daily at all other times during the study period

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

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

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

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on GD 21
- all females were examined by gross necropsy
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: half per litter
Statistics:
Bartlett's Test was performed to determine if the dose groups had equal variance (1% level of significance). If equal, the testing was done using parametric methods, otherwise nonparametric techniques were used. Parametric procedures: a standard one way ANOVA (F distribution) was used. If significant differences among the means were indicated, Dunnett's Test was used to determine which treatment groups differed significantly from control. In addition to the ANOVA, a standard regression analysis for linear response in the dose groups was performed that also tested for linear lack of fit in the model. Nonparametric procedures: the test of equality of means was performed using the Kruskal-Wallis Test. If significant differences among the means were indicated, Dunn's Summed Rank Test was used to determine which treatment groups differed significantly from the control. In addition, Jonckheere's Test for monotonic trend in the dose response was performed. All tests were conducted at the 5% and 1% level of significance.
Fetal weight was analyzed by a standard nested analysis of covariance (fetuses nested within dams and dams nested within doses and litter size (both sexes combined)). If differences in groups were identified, the Least Significant Difference technique was used to determine which groups differed from the control group. Male and female fetuses were tested separately (the covariate was combined sexes in each analysis). Fetal malformation and variation incidence data were analyzed for statistical significance as follows: a standard chi-square analysis was performed to determine if the proportions of incidences differ between the groups tested. If any one cell had an expected value less than 5, this step was not reported. Next, each treatment group was compared to the control group using a 2x2 Fisher Exact Test. Thirdly, Armitage's test for linear trend in the dosage groups was performed. All tests were reported at the 5% or 1% level of significance.
Indices:
Preimplantation loss = (no. of Corpora Lutea - no. of Implantation Sites) / no. of Corpora Lutea * 100

Postimplantation loss = (no. of Implantation Sites - no. of live foetuses) / no. of Implantation Sites * 100
Details on maternal toxic effects:
Maternal toxic effects:no effects

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

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

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

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

Post-mortem examinations:
There were no necropsy findings that were considered to be treatment-related. One high dose female had a subcutaneous mass in the cervical area and one control and one high dose female had dilated renal pelvis. In summary, these necropsy findings were considered to be incidental and unrelated to treatment.
Dose descriptor:
NOAEL
Effect level:
>= 1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
Remarks on result:
other: developmental toxicity
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
Remarks on result:
other: maternal toxicity
Fetal body weight changes:
no effects observed
Skeletal malformations:
effects observed, non-treatment-related
Visceral malformations:
effects observed, non-treatment-related
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.
Remarks on result:
other: The results indicate that test substance was not a selective developmental toxicant and was not embryotoxic or teratogenic under the conditions of this study.
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.

Data source

Reference
Reference Type:
publication
Title:
Developmental toxicity evaluation of trimethylolpropane caprylate caprate in Sprague-Dawley rats.
Author:
Azuka, C. and Daston, P.
Year:
2004
Bibliographic source:
Birth Defects Res B Dev Reprod Toxicol. 2004 Dec;71(6):374-9.

Materials and methods

Test guideline
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

Test material

Constituent 1
Chemical structure
Reference substance name:
Decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate
EC Number:
234-392-1
EC Name:
Decanoic acid, ester with 2-ethyl-2-(hydroxymethyl)-1,3-propanediol octanoate
Cas Number:
11138-60-6
Molecular formula:
C32H60O6
IUPAC Name:
2,2-bis[(octanoyloxy)methyl]butyl decanoate

Test animals

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

Administration / exposure

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.
Doses / concentrations
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.

Examinations

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.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

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).

Effect levels (maternal animals)

open allclose all
Dose descriptor:
NOAEL
Effect level:
2 000 mg/kg bw/day (nominal)
Based on:
test mat.
Basis for effect level:
other: developmental toxicity
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

Results (fetuses)

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.

Effect levels (fetuses)

Basis for effect level:
other: no effects determined
Remarks on result:
other: no effects determined

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

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

170/17b

Grade 1

11/3

9/2

27/5

61/14b

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)

Applicant's summary and conclusion