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Toxicological information

Developmental toxicity / teratogenicity

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Administrative data

Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Study period:
3 June to 25 September 2015
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted at an accredited GLP compliant laboratory according to current OECD test guidelines
Cross-reference
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
developmental toxicity
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Justification for type of information:
1. HYPOTHESIS FOR THE ANALOGUE APPROACH
A read-across approach has been suggested based on the metabolism of the common structure of propylene glycol fatty acid esters. Read-across is implemented from already existing data from testing on Dapro FX511, on metabolism products (fatty acid and propylene glycol) and on propylene glycol monolaurate.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)

Source chemical:

Dapro FX 511
EC Number: 285-503-5
CAS Number: 85114-00-7

Target chemical:

RM1004755:
Einecs No. 248-315-4
CAS No. 27194-74-7

See read-across justification report in section 13

3. ANALOGUE APPROACH JUSTIFICATION
A matrix of data has been created using the Dapro FX511 REACH dossier, read-across document for aquatic tox from Dapro FX510 (source) to Dapro FX511 (target), a HPV test plan for the glycol esters of the aliphatic esters chemicals (including Propylene glycol, monostearate (CAS 1323-39-3)) and a Petition to include propylene glycol monolaurate into 7 CFR 205 (constituent of RM1004755).
See read-across justification report in section 13

4. DATA MATRIX
Data matrix is given in read-across justification report in section 13

Reason / purpose for cross-reference:
read-across source
Species:
rat
Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Description (incidence and severity):
See Tables 2 and 3 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the
rat Tables 2-10", attached in the background data section below, for data
Number of abortions:
no effects observed
Description (incidence and severity):
See Table 6 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat
Tables 2-10", attached in the background data section below, for data. Rats do not abort foetuses but
resorb them
Pre- and post-implantation loss:
no effects observed
Description (incidence and severity):
Early and late implantation losses were not statistically significant compared to control animal group
See Table 6 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat Table
s 2-10", attached in the background data section below, for data
Total litter losses by resorption:
no effects observed
Description (incidence and severity):
Early and late resorption values not statistically significant compared to control animal group
See Table 6 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat Tab
les 2-10", attached in the background data section below, for data
Early or late resorptions:
no effects observed
Description (incidence and severity):
See Table 6 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat
Tables 2-10", attached in the background data section below, for data
Dead fetuses:
no effects observed
Description (incidence and severity):
No dead foetuses were noted on termination at day 20 of gestation in either the control group or any
of the treatment groups.
See Table 6 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat
Tables 2-10", attached in the background data section below, for data
Changes in pregnancy duration:
no effects observed
Description (incidence and severity):
No rat gave birth prior to termination at day 20.
See Table 6 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat Tab
les 2-10", attached in the background data section below, for data
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): It is stated in the results section 3.3.1 (Reproductive assessment) of the report that -
"All females were pregnant. The following assessment is based on the 20, 20, 20 and 20 females
with live young at termination on Day 20 of gestation in the Control group, and at 100, 300 and 1000
mg/kg/day, respectively. "
From this information it is also apparant that there were no early deliveries or still births.
This shown in Table 6 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the
rat Tables 2-10", attached in the background data section below, for data
Changes in number of pregnant:
no effects observed
Description (incidence and severity):
It is stated in the results section 3.3.1 (Reproductive assessment) of the report that -
"All females were pregnant. The following assessment is based on the 20, 20, 20 and 20 females
with live young at termination on Day 20 of gestation in the Control group, and at 100, 300 and 1000
mg/kg/day, respectively. "
See Table 6 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat
Tables 2-10", attached in the background data section below, for data
Details on maternal toxic effects:
Maternal toxic effects:no effects
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other: No effects
Remarks on result:
not determinable due to absence of adverse toxic effects
Remarks:
There were no signs at routine examination that could be associated to treatment and no signs were observed in association with dose administration. Bodyweight, gravid uterine weight, food consumption and macroscopic evaluation were not adversely affected by treatment with RD 15134 up to 1000 mg/kg/day when compared with Control animals. At 1000 mg/kg/day, slight mean body weight loss was recorded during Days 6-7 of gestation and mean food consumption was slightly low during Days 6-9.
Abnormalities:
no effects observed
Description (incidence and severity):
There were no signs at routine examination that could be associated to treatment and no signs were observed in association with dose administration. Bodyweight, gravid uterine weight, food consumption and macroscopic evaluation were not adversely affected by treatment with RD 15134 up to 1000 mg/kg/day when compared with Control animals. At 1000 mg/kg/day, slight mean body weight loss was recorded during Days 6-7 of gestation and mean food consumption was slightly low during Days 6-9.
Fetal body weight changes:
effects observed, treatment-related
Description (incidence and severity):
Male, female and overall fetal weights were statistically significantly lower for females receiving 1000
mg/kg/day, when compared with Controls.
At 1000 mg/kg/day, mean fetal weight was lower than in Controls (11% lower) reflecting the fact that
the mean fetal weight in the majority of litters in this group was less than 3.40 grams whereas in the
Control group most litters had a mean fetal weight above 3.70 grams. This difference was considered
to reflect an effect of treatment on fetal growth and not to be due to the slightly higher mean litter size
in the 1000 mg/kg/day group.
See Table 7 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat
Tables 2-10", attached in the background data section below, for data
Reduction in number of live offspring:
effects observed, non-treatment-related
Description (incidence and severity):
Among females allocated to the 100, 300 or 1000 mg/kg/day groups, the mean numbers of corpora lutea were slightly higher than in Controls; as the number of corpora lutea reflect the number of
eggs shed and treatment did not start until Day 6 after mating these differences were due to chance as they were established before the start of treatment. Principally as a result of these differences
which were due to chance, the mean numbers of implantations and live fetuses in all treated groups were slightly higher than in Controls and the difference for live fetuses in the 1000 mg/kg/day group a
ttained statistical significance.
See Table 6 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat Tables 2-10", attached in the background data section below, for data
Changes in sex ratio:
effects observed, non-treatment-related
Description (incidence and severity):
The sex ratio was 45.6% males for the 300 mg/kg/day group compared to 57.1% for the control group
and 52.7% and 52.8% for the 100 mg/kg/day and 1000 mg/kg/day, respectively.
See Table 6 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat
Tables 2-10", attached in the background data section below, for data
Changes in litter size and weights:
no effects observed
Description (incidence and severity):
Gravid uterine weights, embryo-fetal survival and litter and placental weights were unaffected by treatment up to 1000 mg/kg/day. Intergroup differences in gravid uterine weight reflected intergroup
differences in litter size which were due to chance.
See Table 7 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat Tables 2-10", attached in the background data section below, for data
External malformations:
effects observed, treatment-related
Description (incidence and severity):
At 1000 mg/kg/day there were two fetuses in two litters with the major abnormality short/threadlike tail.
See Table 8 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat Tables 2-10", attached in the background data section below, for data
Skeletal malformations:
effects observed, treatment-related
Description (incidence and severity):
There was evidence of a slight disturbance of fetal development at 1000 mg/kg/day characterized by the increased incidence of large nasofrontal suture; thoracic vertebral abnormality; short supernumerary cervical rib and 14th rib; delayed/incomplete ossification/unossified cranial centres, cervical, thoracic and sacral caudal vertebrae, sternebrae, pelvic bones, metacarpals/metatarsals and a decrease in ossified cervical vertebral centra; variation in lens shape; small/absent lobe of thyroid; partial
ly undescended lobe of thymus; small/absent renal papilla and dilated ureter when compared to concurrent control and the incidences were outside of the Historical Control Data with the exception of
delayed/incomplete ossification/unossified cervical vertebrae.
Although not adverse in isolation, many of these findings would usually be associated with a significant decrease in body weight signifying a delay in fetal development. However, this was not the case on this study with some abnormalities present in fetuses with weights at the upper end of the Control range. There was a very high incidence (107 fetuses in 20 litters) of large nasofrontal suture (an abnormality not seen in the Control group or in the Control groups on the 11 studies included in the
HCD) and high incidences of delayed/incomplete ossification/unossified cranial centres, sacrocaudalvertebrae, sternebrae other than 5th/6th, pelvic bones, meta tarsals/carpals compared with the HCD range. The wide range of abnormalities involved, the occurrence in fetuses with a high fetal weight and the high incidences indicate a treatment related disturbance of development which is potentially adverse.
Sixteen fetuses (7 litters) at 300 mg/kg/day, and 5 fetuses (3 litters) at 100 mg/kg/day, had a large nasofrontal suture, and in view of the very high incidence of this unusual abnormality at 1000 mg/kg/day, these finding were considered to be related to treatment at doses which did not elicit any maternal toxicity. In isolation, this finding was not considered to represent an adverse effect on fetal development.
See Tables 8-10 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat Tables 2-10", attached in the background data section below, for data
Visceral malformations:
no effects observed
Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:yes
Details on embryotoxic / teratogenic effects:
Placental and litter weights were similar to Controls, and were not affected by the administration of RD 15134.
Male, female and overall fetal weights were statistically significantly lower for females receiving 1000mg/kg/day, when compared with Controls. This difference was considered to reflect an effect of treatment on fetal growth and not to be due to the sli
ghtly higher mean litter size in the 1000 mg/kg/day group.
There was evidence of a slight disturbance of fetal development at 1000 mg/kg/day characterize d by the increased incidence of large nasofrontal suture; thoracic vertebral abnormality; short supernumerary cervical rib and 14th rib; delayed/incomplete ossification/unossified cranial centres, cervical, thoracic and sacral caudal vertebrae, sternebrae, pelvic bones, metacarpals/metatarsals and a decrease in ossified cervical vertebral centra; variation in lens shape; small/absent lobe of thyroid;
partially undescended lobe of thymus; small/absent renal papilla and dilated ureter when compared to concurrent control and the incidences were outside of the Historical Control Data with the exception of delayed/incomplete ossification/unossified cervical vertebrae.
There was a very high incidence (107 fetuses in 20 litters) of large nasofrontal suture (an abnormality not seen in the Control group or in the Control groups on the 11 studies included in the HCD) and high incidences of delayed/incomplete ossification/unossified cranial centres, sacrocaudal vertebrae, sternebrae other than 5th/6th, pelvic bones, meta tarsals/carpals compared with the HCD range. The wide range of abnormalities involved, the occurrence in fetuses with a high fetal weight and the high incidences indicate a treatment related disturbance of development which is potentially adverse.
Sixteen fetuses (7 litters) at 300 mg/kg/day, and 5 fetuses (3 litters) at 100 mg/kg/day, had a large nasofrontal suture, and in view of the very high incidence of this unusual abnormality at 1000 mg/kg/day, these finding were considered to be related to treatment at doses which did not elicit any maternal toxicity. In isolation, this finding was not considered to represent an adverse effect on fetal development.
See Tables 8-10 in the document "2016-06-07 RD 15134 Embryo-fetal development study in the rat Tables 2-10", attached in the background data section below, for data
Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: embryotoxicity - overall effects
Remarks on result:
other:
Remarks:
Male, female and overall fetal weights were statistically significantly lower for dams receiving 1000 mg/kg/day, when compared with Controls this reflected an effect of treatment on fetal growth, not due to the slightly higher mean litter size in the 1000 mg/kg/day group. There was evidence of a slight disturbance of fetal development at 1000 mg/kg/day characterized by the increased incidence of large nasofrontal suture; thoracic vertebral abnormality; short supernumerary cervical rib and 14th rib; delayed/incomplete ossification/unossified cranial centres, cervical, thoracic and sacral caudal vertebrae, sternebrae, pelvic bones, metacarpals/metatarsals and a decrease in ossified cervical vertebral centra; variation in lens shape; small/absent or partially undescended lobe of thyroid; small/absent renal papilla and dilated ureter compared to concurrent control, these incidences were outside of the Historical Control Data except the delayed/incomplete ossification/unossified cervical vertebrae. There was a very high incidence (107 fetuses in 20 litters) of large nasofrontal suture (an abnormality not seen in the Control group or in the Control groups on the 11 studies included in the HCD) and high incidences of delayed/incomplete ossification/unossified cranial centres, sacrocaudal verte brae, sternebrae other than 5th/6th, pelvic bones, meta tarsals/carpals compared with the HCD range. The wide range of abnormalities involved, the occurrence in fetuses with a high fetal weight and the high incidences indicate a treatment related disturbance of development which is potentially adverse. 16 fetuses (7 litters) at 300 mg/kg/day, and 5 fetuses (3 litters) at 100 mg/kg/day, had a large nasofrontal suture, and in view of the very high incidence of this unusual abnormality at 1000 mg/ kg/day, these finding were considered to be related to treatment at doses which did not elicit any maternal toxicity. This finding did not represent an adverse effect on fetal development.
Abnormalities:
not specified
Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects in the absence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
not specified
Conclusions:
It was concluded from this study that the dosage of 1000 mg/kg/day was the maternal no-observed-adverse-effect-level (NOAEL) and 300 mg/kg/day was the no-observed-adverse-effect-level (NOAEL) for embryo-fetal survival, growth and development.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2016
Report date:
2016

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Deviations:
no
Qualifier:
according to guideline
Guideline:
other: Japanese Ministry of Agriculture, Forestry and Fisheries, Test Data for Registration of Agric ultural Chemicals, 12 Nohsan No. 8147, Agricultural Production Bureau, November 24, 2000
Deviations:
no
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
2-hydroxypropyl 2-ethylhexanoate
EC Number:
261-499-0
EC Name:
2-hydroxypropyl 2-ethylhexanoate
Cas Number:
58921-10-1
Molecular formula:
C11H22O3
IUPAC Name:
2-hydroxypropyl 2-ethylhexanoate
Constituent 2
Chemical structure
Reference substance name:
1-hydroxypropan-2-yl 2-ethylhexanoate
Molecular formula:
C11H22O3
IUPAC Name:
1-hydroxypropan-2-yl 2-ethylhexanoate
impurity 1
Chemical structure
Reference substance name:
Monoesters of 2-ethylhexanoic acid and dipropyleneglycol
IUPAC Name:
Monoesters of 2-ethylhexanoic acid and dipropyleneglycol
impurity 2
Chemical structure
Reference substance name:
1-methylethylene 2-ethylhexanoate
EC Number:
301-185-3
EC Name:
1-methylethylene 2-ethylhexanoate
Cas Number:
93981-97-6
Molecular formula:
C19H36O4
IUPAC Name:
propane-1,2-diyl bis(2-ethylhexanoate)
impurity 3
Chemical structure
Reference substance name:
2-ethylhexanoic acid
EC Number:
205-743-6
EC Name:
2-ethylhexanoic acid
Cas Number:
149-57-5
Molecular formula:
C8H16O2
IUPAC Name:
2-ethylhexanoic acid
impurity 4
Reference substance name:
Propane-1,2-diol, propoxylated
EC Number:
500-039-8
EC Name:
Propane-1,2-diol, propoxylated
Cas Number:
25322-69-4
IUPAC Name:
Propane-1,2-diol, propoxylated
impurity 5
Chemical structure
Reference substance name:
Water
EC Number:
231-791-2
EC Name:
Water
Cas Number:
7732-18-5
Molecular formula:
H2O
IUPAC Name:
Water
Test material form:
liquid: viscous
Specific details on test material used for the study:
- Name of test material (as cited in study report): rd 15134
- Physical state: liquid
- Analytical purity: 95.8%
- Lot/batch No.: 1023R12118
- Expiration date of the lot/batch: 01 May 2018
- Storage condition of test material: room temperature
Test animals

Test animals

Species:
rat
Strain:
Sprague-Dawley

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Analytical verification of doses or concentrations:
yes
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1:1 with identified stock males
- Length of cohabitation: until positive evidence of mating
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy:Ejected copulation plugs in cage tray and vaginal smears were checked for the p
resence of sperm referred to as day 0 of pregnancy
Duration of treatment / exposure:
Males were treated once daily, at approximately the same time each day for 14 days.
Females were treated from Day 6 to Day 19 (inclusive) after mating, once daily at approximately the
same time each day.
Frequency of treatment:
Daily at approximately the same time each day
Duration of test:
Females until day 20 of gestation. Males 14 days
Doses / concentrationsopen allclose all
Dose / conc.:
100 mg/kg bw/day (actual dose received)
Dose / conc.:
300 mg/kg bw/day (actual dose received)
Dose / conc.:
1 000 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
6 females per group for phase I and 14 females per group for Phase II. 3 males for the 14-day toxicity
phase
Control animals:
yes, concurrent vehicle

Results and discussion

Results: maternal animals

Effect levels (maternal animals)

Key result
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Basis for effect level:
other:
Remarks on result:
not determinable due to absence of adverse toxic effects

Results (fetuses)

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEL
Effect level:
300 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: overall effects
Remarks on result:
other:
Remarks:
Male, female and overall fetal weights were statistically significantly lower for dams receiving 1000 mg/kg/day, when compared with Controls this reflected an effect of treatment on fetal growth, not due to the slightly higher mean litter size in the 1000 mg/kg/day group. There was evidence of a slight disturbance of fetal development at 1000 mg/kg/day characterized by the increased incidence of large nasofrontal suture; thoracic vertebral abnormality; short supernumerary cervical rib and 14th rib; delayed/incomplete ossification/unossified cranial centres, cervical, thoracic and sacral caudal vertebrae, sternebrae, pelvic bones, metacarpals/metatarsals and a decrease in ossified cervical vertebral centra; variation in lens shape; small/absent or partially undescended lobe of thyroid; small/absent renal papilla and dilated ureter compared to concurrent control, these incidences were outside of the Historical Control Data except the delayed/incomplete ossification/unossified cervical vertebrae. There was a very high incidence (107 fetuses in 20 litters) of large nasofrontal suture (an abnormality not seen in the Control group or in the Control groups on the 11 studies included in the HCD) and high incidences of delayed/incomplete ossification/unossified cranial centres, sacrocaudal verte brae, sternebrae other than 5th/6th, pelvic bones, meta tarsals/carpals compared with the HCD range. The wide range of abnormalities involved, the occurrence in fetuses with a high fetal weight and the high incidences indicate a treatment related disturbance of development which is potentially adverse. 16 fetuses (7 litters) at 300 mg/kg/day, and 5 fetuses (3 litters) at 100 mg/kg/day, had a large nasofrontal suture, and in view of the very high incidence of this unusual abnormality at 1000 mg/ kg/day, these finding were considered to be related to treatment at doses which did not elicit any maternal toxicity. This finding did not represent an adverse effect on fetal development.

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Key result
Developmental effects observed:
yes
Lowest effective dose / conc.:
1 000 mg/kg bw/day (actual dose received)
Treatment related:
yes
Relation to maternal toxicity:
developmental effects in the absence of maternal toxicity effects
Dose response relationship:
yes
Relevant for humans:
not specified

Applicant's summary and conclusion

Conclusions:
It was concluded from this study that the dosage of 1000 mg/kg/day was the maternal no-observed-adverse-
effect-level (NOAEL) and 300 mg/kg/day was the no-observed-adverse-effect-level (NOAEL)
for embryo-fetal survival, growth and development.