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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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented publication, comparable to current guidelines

Data source

Reference
Reference Type:
publication
Title:
Relative Developmental Toxicities of Acrylates in Rats following Inhalation Exposure.
Author:
Saillenfait AM, Bonnet P, Gallissot F, et al.,
Year:
1999
Bibliographic source:
Toxicol. Sciences 48: 240-254

Materials and methods

Principles of method if other than guideline:
Groups of 20-29 bred female rats (17-25 pregnant) were exposed to the compound 6h/day on days 6 through 20 of gestation by inhalation. Control animals were exposed concurrently to filtered room air. The test concentrations were 1, 5, and 10 ppm (corresponding to approx. 5.4, 27.0, and 54.0 µg/L)*.
GLP compliance:
not specified
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Acrylic acid, monoester with propane-1,2-diol
EC Number:
247-118-0
EC Name:
Acrylic acid, monoester with propane-1,2-diol
Cas Number:
25584-83-2
Molecular formula:
C6H10O3
IUPAC Name:
Reaction mass of 2-hydroxy-1-methylethyl acrylate and 2-hydroxypropyl acrylate
Details on test material:
- Name of test material (as cited in study report): Hydroxypropyl acrylate
- Analytical purity: 97.5 % (determined by GC)
- Source: Roehm, Germany

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: IFFA CREDO Breeding Laboratories (Saint-Germain-sur-l' Arbresle, France)
- Age at study initiation: Young, nulliparous females
- Weight at study initiation: 200-220 g
- Housing: Single in clear polycarbonate cages with stainless-steel wire lids and hardwood shaving as bedding.
- Diet: Food pellets (UAR Alimentation Villemoisson, France), ad libitum
- Water: Filtered tap water, ad libitum


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21 ± 2
- Humidity (%): 50 ± 5
- Photoperiod (hrs dark / hrs light): 12 hrs dark/12 hrs light

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
EXPOSURE
Exposures were conducted in 200-L glass/stainless-steel inhalation chambers with dynamic and adjustable laminar air flow (6-20 m3/h). The chamber temperature was set at 23 ± 2°C, and the relative humidity at 50 ± 5 %. The exposure system delivered, with an infusion pump, a constant rate of liquid chemical from the top of a heated glass column filled with glass beads. Compressed air heated by a glass heater was introduced at the bottom of the glass column in a countercurrent fashion to the liquid flow. The vapourized compound was introduced into the main air inlet pipe of the exposure chambers.
Concentrations of acrylate ester were monitored continuously with a gas-chromatograph equipped with a flame ionization detector and an automatic gas-sampling valve. In addition, exposure levels were determined once during each 6-h exposure period by collecting atmosphere samples through glass tubes packed with activated charcoal. The charcoal samples were then desorbed with dichloromethane. The resulting samples were analyzed by gas chromatography using appropriate internal standards. Since 2-HPA has a rather low vapour pressure (0.07 mm Hg at 20 °C), the presence of liquid particles was evaluated at the highest concentration generated (i.e. 25 ppm). Airborn particles were measured with an Aerodynamic Particle Sizer.
No differences in particle counts were observed between the clean filtered air (control) and the vapour-laden air in the exposure chambers.


GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: Glass/stainless-steel inhalation chambers
- Source and rate of air: Test atmospheres were generated through an additional air-flow  rate passed through the fritted disk of a heated bubbler containing 2-hydroxypropyl acrylate.  The vapourized compound was introduced into the main air inlet pipe of the exposure chamber.
- Air flow rate: 6-20 m3/h


TEST ATMOSPHERE
- Brief description of analytical method used: GC/FID
- Samples taken from breathing zone: yes
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analytical concentrations (mean ± SD):
1.0 ± 0.1 ppm (nominal: 1 ppm)
5.1 ± 0.3 ppm (nominal: 5 ppm)
10.3 ± 0.8 ppm (nominal: 10 ppm)
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/2-3
- Length of cohabitation: Overnight
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
day 6 to 20 of gestation
Frequency of treatment:
daily, 6h/d
Duration of test:
until gestation day 21
Doses / concentrations
Remarks:
Doses / Concentrations:
1, 5, and 10 ppm (corresponding to approx. 5.4, 27.0, and 54.0 µg/L)
Basis:
nominal conc.
No. of animals per sex per dose:
20
Control animals:
yes, sham-exposed
Details on study design:
- Dose selection rationale:
Exposure concentrations were based on preliminary studies in which severe maternal toxicity (i.e. weight loss during GD 6-13 and pronounced reduction in weight gain during GD 13-21) was observed at 25 ppm hydroxypropyl acrylate.

Examinations

Maternal examinations:
BODY WEIGHT: Yes
- Time schedule for examinations: On gestation day (GD) 0, 6, 13 and 21.


FOOD CONSUMPTION: YES
Food consumption was measured for the intervals GD 6-13 and 13-21.


POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: The uteri were removed and weighed. The number of implantation sites, resorptions, and dead and live fetuses were recorded.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
The number of implantation sites, resorptions, and dead and live fetuses were recorded. Uteri which had no visible implantation sites were stained with ammonium sulfide (10 %) to detect very early resorptions.

Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: No data
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
Fetal examinations:
Live fetuses were weighed, sexed, and examined for external anomalies including those of the oral cavity. Half of the live fetuses from each litter were preserved in Bouin's solution and examined for internal soft tissue changes. The other half were fixed in ethanol (70 %), eviscerated, and then processed for skeletal staining with alizarin red S for subsequent skeletal examination.

- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
- Head examinations: Yes: all per litter
Statistics:
Data were presented as mean ± SD. The number of  implantation sites and live fetuses and the various body weights were analyzed by one-way analysis of variance (ANOVA), followed by Dunnett's test if differences were found. The percentages of non-live  implants and  resorptions and the proportions of fetuses with alterations in each litter were evaluated by using the Kruskal-Wallis test, followed by the Dixon-Massey test where appropriate. Rates of pregnancy, fetal sex ratio, and percentage of litters with malformations or external, visceral, or skeletal variations were analyzed by using Fisher's test. Where applicable, least-squares analysis was carried out. For all statistical tests, the level of significance was set a priori at alpha = 0.05.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
No maternal deaths were observed. Maternal weight gain was significantly less than control during the first half of exposure at 10 ppm and absolute weight gain at 5 and 10 ppm. Food consumption was slightly reduced during treatment at 10 ppm.

Effect levels (maternal animals)

Dose descriptor:
NOAEC
Effect level:
ca. 0.005 mg/L air (nominal)
Basis for effect level:
other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:
Embryotoxic / teratogenic effects:no effects

Details on embryotoxic / teratogenic effects:
The number of implantation sites and live fetuses, and the incidence of non-live implants and resorptions were comparable among groups. There was no effect on fetal weights at any exposure level. Visceral malformations were observed in single fetuses in the control and the 5 ppm groups. Several visceral and skeletal variations were observed, with no significant differences between treated and control groups.

Effect levels (fetuses)

Dose descriptor:
NOAEC
Effect level:
ca. 0.054 mg/L air (nominal)
Basis for effect level:
other: developmental toxicity
Remarks on result:
other: no adverse effects observed up to and including the highest tested dose

Fetal abnormalities

Abnormalities:
no effects observed

Overall developmental toxicity

Developmental effects observed:
no

Any other information on results incl. tables

Maternal body weights:

 

Concentration [ppm/6h/d]

Maternal body weight GD 6 [g]

Absolute weight gain [g]

0

266 ± 16

27 ± 13

1

272 ± 15

27 ± 9

5

271 ± 13

19 ± 11*

10

272 ± 15

16 ± 12**

 

 

Reproductive parameters:

 

Conc. [ppm/6h/d]

No. of litters

No. of implantation sites/litter

% of non-live implants/litter

% of resorption sites/litter

No. of live fetuses/litter

Average fetal body weight/litter [g]

0

21

14.48 ± 3.06

6.10 ± 8.37

6.10 ± 8.37

13.62 ± 3.29

5.48 ± 0.21

1

20

14.40 ± 2.23

9.76 ± 15.58

9.76 ± 15.58

13.00 ± 2.90

5.61 ± 0.29

5

22

14.27 ± 4.09

10.83 ± 21.79

10.83 ± 21.79

14.00 ± 3.22

5.58 ± 0.33

10

21

14.52 ± 3.74

6.70 ± 5.90

6.70 ± 5.90

13.57 ± 3.70

5.48 ± 0.27

 

 

Concentration [ppm/6h/d]

0

1

5

10

Mean % of fetuses with:

 

 

 

 

- any malformations/litter

0.43 ± 1.98

0

0.26 ± 1.21

0

- external variations/litter

0

0

0

0

- visceral variations/litter

5.05 ± 12.39

7.45 ± 13.11

7.66 ± 13.08

4.65 ± 6.82

- skeletal variations/litter

10.40 ± 11.37

11.70 ± 19.45

23.76 ± 28.69

7.37 ± 9.35

- any variations/litter

7.68 ± 8.51

9.56 ± 10.87

15.67 ± 18.03

5.92 ± 5.70

 

* ,** Significant differences from the control (0 ppm) value, p< 0.05, and p< 0.01, respectively.

 

Applicant's summary and conclusion