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Diss Factsheets

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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1983
Report date:
1983
Reference Type:
publication
Title:
Unnamed
Year:
1991
Reference Type:
secondary source
Title:
Chemical Hazards of the Workplace, Second Edition.
Author:
Proctor NH et al.
Year:
1988
Bibliographic source:
Science Information Resource Center, J. B. Lippincott Compagny

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Acrylic acid
EC Number:
201-177-9
EC Name:
Acrylic acid
Cas Number:
79-10-7
Molecular formula:
C3H4O2
IUPAC Name:
prop-2-enoic acid
Specific details on test material used for the study:
- Name of test material (as cited in study report): Acrylic acid, pure
- Analytical purity: 99.74%
- Impurities (identity and concentrations): Diacrylic acid 0.22%, Acetic acid 0.12%, Propionic acid 0.12%, the concentrations of other imputies were < 0.02%
- Test substance No.: 80/386

Test animals

Species:
rat
Strain:
Sprague-Dawley
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River, Wiga GmbH, D-Sulzfeld
- Age at study initiation: 10 weeks old
- Weight at study initiation: mean weight 215 g
- Housing: Single in Makrolon/wire cages (type MD III supplied by Becker & Co., Castrop-Rauxel)
- Diet (ad libitum): SSNIFF R meal, Ssniff Versuchstierdiaeten GmbH, CH-Soest
- Water (ad libitum): Tap water

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 ± 2
- Humidity (%): 55 ± 5
- Photoperiod (hrs dark / hrs light): 12/12


Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
Exposures were conducted using a continuous infusion pump (type Infu 362). Acrylic acid was metered into the inner coil of a glass evaporator heated by hot water. The acrylic acid vapours were diluted with a flow of fresh conditioned air with a flow meter. This mixture of acrylic acid vapour and air was passed through a glass cooler, thermostated cold water at 8-10°C being passed through its inner coil. The mixture of acrylic acid vapour and air was thus cooled to 23°C and passed to the exposure chambers (made of glass and steel, volume about 500 liters). The following amounts of test substance were used: 1.15 ml/h (study group 1, 40 ppm), 3.4 ml/h (study group 2, 120 ppm), 10.2 ml/h (study group 3, 360 ppm). The temperature in all exposure chambers was continuously monitored using NTC sensors and the measured values were recorded using a 12-channel printer.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentration of acrylic acid in the exposure chambers was determined using a continuously operating total hydrocarbons analyzer equipped with a flame ionization detector.
Nominal concentrations (ppm): 40.7, 120.3, 361
Analytical concentrations (ppm): 39.4, 114.0, 356.2
Details on mating procedure:
- Impregnation procedure: cohoused
- If cohoused:
- M/F ratio per cage: 1/1
- Length of cohabitation: 15.5 hours
- Verification of same strain and source of both sexes: yes
- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy
Duration of treatment / exposure:
from day 6 to day 15 of gestation
Frequency of treatment:
6 hours/day
Duration of test:
until day 20 of gestation
Doses / concentrationsopen allclose all
Dose / conc.:
40 ppm
Remarks:
corresponding to approx. 0.12 mg/L. Recalculation based on the equation c(mg/m3) = molar mass (g) / molar volume (L) x c(mL/m3) with molecular weight (72.06 g/mol) and molar volume (24.1 L at 20 °C and 1013 hPa) [DFG, 2005]
Dose / conc.:
120 ppm
Remarks:
corresponding to approx. 0.36 mg/L. Recalculation based on the equation c(mg/m3) = molar mass (g) / molar volume (L) x c(mL/m3) with molecular weight (72.06 g/mol) and molar volume (24.1 L at 20 °C and 1013 hPa) [DFG, 2005]
Dose / conc.:
360 ppm
Remarks:
corresponding to approx. 1.08 mg/L. Recalculation based on the equation c(mg/m3) = molar mass (g) / molar volume (L) x c(mL/m3) with molecular weight (72.06 g/mol) and molar volume (24.1 L at 20 °C and 1013 hPa) [DFG, 2005]
No. of animals per sex per dose:
30
Control animals:
yes, sham-exposed

Examinations

Maternal examinations:
CAGE SIDE OBSERVATIONS: not specified

DETAILED CLINICAL OBSERVATIONS: Yes
Prior to the exposure period, animals were observed for clinical signs once daily. Preceding and following each exposure, individual does were observed for clinical signs of toxicity.

BODY WEIGHT: Yes
- Time schedule for examinations: On gestation day 0, 3, 6 9 12, 15, 18 and 20

FOOD CONSUMPTION: Yes
- The feed consumption by each animal was determined on gestation day 0, 3, 6 9 12, 15, 18 and 20

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: The uteri and ovaries were removed. The uteri were weighed. The number of corpora lutea, implantation sites for each hern of the uterus, dead and live implatations and fetuses were determined.

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:
Living fetuses were weighed, sexed, and examined for externally detectable changes. In addition, attention was paid to the viability of the fetuses, the length of the umbilical cord and the condition of the fetal membranes and amniotic fluid. One-third of the fetuses of each dam were fixed in Bouin's solution and examined for internal soft tissue changes. In order to assess the skeletal system, two-thirds of the living fetuses of each dam were initially fixed in 96% alcohol, then clarified with potassium hydroxide solution and stained with Alizarin red S. The fetuses were stored in 100% glycerol.

- External examinations: Yes: all per dam
- Soft tissue examinations: Yes: one-third per dam
- Skeletal examinations: Yes: two-thirds per dam
Statistics:
Quantitative continuous random variables, eg. body weight data or food consumption data, were examined with the Williams test. Discrete random variables, eg. number of corpora lutea, number of implantations, or percentage values, such as live fetuses as a percentage of total implantations, fetuses with anomalies (or variations, retardations) as a percentage of total fetuses investigated, were examined with a linear rank test of Krauth. The Fisher test was used for the comparison of frequencies, eg. number of litters with anomalies (or variations, retardations) in relation to the number of litters investigated. All tests were performed with type I error of = 0.05 and = 0.01. The linear rank test and the Fisher test were carried out with a Bonferroni correction, but including additional information. If the Bonferroni corrected test did not show any significance for = 0.05, the comparison was calculated with uncorrected = 0.05. The linear rank test and the Fisher test were calculated by counting all possible permutations.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Clinical signs:
effects observed, non-treatment-related
Description (incidence and severity):
The animals in groups 0, 1 and 2 showed no signs of behavior differing from normal during the period of exposure. Starting with the 1st exposure, the animals in group 3 showed pronounced watery discharge from the eyes and nose, and there was occasional wiping of their snouts and restless behavior. The signs disappeared rapidly after each exposure so that the animals were normal again after 1 - 2 hours.
Mortality:
no mortality observed
Description (incidence):
No animal died in any group.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The body weights and the body weight gains of the pregnant animals in groups 1 and 2 (40 ppm and 120 ppm) show, compared to the control group, no relevant differences which could be attributed to an effect of the substance.
An effect of the substance of the nature of a significantly (99% significance) Lower body weight, and an appropriate adverse effect on the body weight gain, was noticeable in group 3 (360 ppm) during the exposure period (6th - 15th day of gestation). After the end of the period of exposure to acrylic acid, the pregnant animals in all groups increased in weight to the same extent (no adverse effect on the body weight gain), but the body weights of the animals in group 3 (360 ppm) remained significantly (99% significance) Lower than in the control group up to the Last day of the observation period (20th day of gestation). Thus, a marked toxic effect on the dams due to inhalation of acrylic acid was demonstrated in the group at the highest concentration (360 ppm).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
The feed consumption of the animals in groups 1 and 2 (40 ppm and 120 ppm) did not differ from the control group over the entire period of the study. A marked effect of exposure to acrylic acid was detected at the highest concentration (360 ppm) in group 3. The feed consumption was lower, with 99% significance, during the exposure period (6th - 15th day of gestation), but no effect of this type was detectable in the follow up observation period.
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
At the highest dose group smaller difference between body weight and uterus weight was reported.
Gross pathological findings:
no effects observed
Description (incidence and severity):
No pathological changes which could be attributed to the inhaled substance were found on macroscopic examination of the internal organs of the animals.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined

Maternal developmental toxicity

Number of abortions:
no effects observed
Pre- and post-implantation loss:
no effects observed
Total litter losses by resorption:
no effects observed
Early or late resorptions:
no effects observed
Dead fetuses:
no effects observed
Changes in pregnancy duration:
not examined
Changes in number of pregnant:
no effects observed
Details on maternal toxic effects:
Indications of a toxic effect on the dams emerged at 120 ppm (decreased consumption of feed during the exposure phase and a smaller difference between the body weight and uterus weight after necropsy). A marked toxicity on the pregnant animals was detected at 360 ppm (lower body weight, body weight gain slowed down, decreased consumption of feed, smaller difference between body weight and uterus weight, and clinical signs of an irritant effect caused by acrylic acid vapours).

Effect levels (maternal animals)

open allclose all
Key result
Dose descriptor:
NOAEC
Effect level:
0.12 mg/L air (nominal)
Basis for effect level:
other: maternal toxicity
Key result
Dose descriptor:
LOAEC
Effect level:
0.36 mg/L air (nominal)
Basis for effect level:
other: maternal toxicity

Maternal abnormalities

Key result
Abnormalities:
no effects observed

Results (fetuses)

Fetal body weight changes:
effects observed, non-treatment-related
Description (incidence and severity):
Although the dams lost weight, no negative effect on the fetal weight was seen. In fact, the fetuses in the 120 ppm and 360 ppm groups were heavier, but this is very probably an incidental finding.
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:
not examined
External malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No significant difference between the groups was found.
Skeletal malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No significant difference between the groups was found.
Visceral malformations:
effects observed, non-treatment-related
Description (incidence and severity):
No significant difference between the groups was found.

Effect levels (fetuses)

Key result
Dose descriptor:
NOAEC
Remarks:
teratogenicity
Effect level:
>= 1.08 mg/L air (nominal)
Basis for effect level:
other: highest dose tested

Fetal abnormalities

Key result
Abnormalities:
no effects observed

Overall developmental toxicity

Key result
Developmental effects observed:
no

Any other information on results incl. tables

ANlMALS WITH CESAREAN SECTION

 

Group 0

0 PPM

Group 1

40 PPM

Group 2

120 PPM

Group 3

360 PPM

Number of Animals

25

27

26

25

CORPORA LUTEA

Total

424

430

437

410

M

16.96

15.93

16.81

16.40

ME

16.00

16.00

16.00

17.00

QD

2.00

2.00

1.63

1.50

K (A)

 

 

 

 

IMPLANTATIONS

Total

324

337

324

310

M

12.96

12.48

12.46

12.40

ME

14.00

14.00

13.50

14.00

QD

3.00

2.00

2.63

2.50

K (A)

 

 

 

 

LIVE FETUSES

Total

298

319

309

292

M

11.92

11.81

11.88

11.68

% IMPLANTATIONS/P.ANIMAL

M

93.10

93.21

95.66

90.70

ME

100.00

100.00

100.00

93.33

QD

6.97

3.85

3.39

4.55

K (A)

 

 

 

 

DEAD IMPLANTATIONS

 

 

 

 

Total

26

18

15

18

M

1.04

0.67

0.58

0.72

% IMPLANTATIONS/P.ANIMAL

M

6.90

6.79

4.34

9.30

ME

0.0

0.0

0.0

6.67

QD

6.97

3.85

3.39

4.55

K (A)

 

 

 

 

 

Resorptions Early (Salewski)

0

0

0

0

Resorptions Early

24

14

13

17

Resorptions Intermediate

1

3

2

0

Resorptions Late

1

1

0

0

Dead Fetuses

0

0

0

0

 Symbols

+/++ = Level of Significance 5%/1% in Relation to group 0

Uterus an Body weight of Pregnant Animals

 

 

Test Group 0

0 PPM

Test Group 1

40 PPM

Test Group 2

120 PPM

Test Group 3

360 PPM

Uterus

N

25.00

27.00

26.00

25.00

MV

64.40

65.74

67.54

65.32

SD

18.76

25.51

23.61

21.14

SE

3.75

4.91

4.63

4.23

BWS

N

25.00

27.00

26.00

25.00

MV

216.38

216.00

213.82

215.24

SD

9.36

11.34

7.70

9.85

SE

1.87

2.18

1.51

1.97

BWE

N

25.00

27.00

26.00

25.00

MV

354.33

348.90

345.93

332.61

 

 

 

 

**

SD

19.94

33.27

26.98

26.08

SE

3.99

6.40

5.29

5.22

BWE-Uterus

N

25.00

27.00

26.00

25.00

MV

289.93

283.15

278.39

267.30

 

 

 

**

**

SD

12.03

17.77

16.57

13.36

SE

2.41

3.42

3.25

2.67

BWE-BWS-Uterus

N

25.00

27.00

26.00

25.00

MV

73.56

67.15

64.57

52.06

 

 

*

**

**

SD

11.45

11.18

13.06

9.54

SE

2.29

2.15

2.56

1.91

 Key                             Test Group      Significance 95 %        Significance 99%

Analysis of Trend                    0                                 *                                 **

Uterus an Body weight of Non-Pregnant Animals

 

 

Test Group 0

0 PPM

Test Group 1

40 PPM

Test Group 2

120 PPM

Test Group 3

360 PPM

Uterus

N

5.00

3.00

3.00

4.00

MV

1.00

1.00

1.00

1.50

SD

0.0

0.0

0.0

0.0

SE

0.0

0.0

0.0

0.5

BWS

N

5.00

3.00

3.00

4.00

MV

214.50

208.57

213.67

217.10

SD

4.25

15.31

6.70

3.52

SE

1.90

8.84

3.87

1.76

BWE

N

5.00

3.00

3.00

4.00

MV

255.88

242.70

247.00

251.02

SD

20.93

10.91

3.96

7.94

SE

9.36

6.30

2.29

3.97

BWE-Uterus

N

5.00

3.00

3.00

4.00

MV

254.88

241.70

246.00

249.52

SD

20.93

10.91

3.96

7.11

SE

9.36

6.30

2.29

3.56

BWE-BWS-Uterus

N

5.00

3.00

3.00

4.00

MV

40.38

33.13

32.33

32.42

SD

18.43

6.95

7.92

7.05

SE

8.24

4.01

4.57

3.52

 Key                             Test Group      Significance 95 %        Significance 99%

Analysis of Trend                    0                                 *                                 **

Findings in Fetuses: Cesarean Section

 

Group 0

0 PPM

Group 1

40 PPM

Group 2

120 PPM

Group 3

360 PPM

Fetuses Investigates

298

319

309

292

Litters Investigated

25

27

26

24

Anomalies

Litters

0

1

0

0

(% Litters)

0.0

3.70

0.0

0.0

F (E)

 

 

 

 

Fetuses

0

1

0

0

(% Fetuses / Litter)

 

 

 

 

M

0.0

0.25

0.0

0.0

ME

0.0

0.0

0.0

0.0

QD

0.0

0.0

0.0

0.0

K (E)

 

 

 

 

Variations

Litters

0

0

0

0

(% Litters)

0.0

0.0

0.0

0.0

F (E)

 

 

 

 

Fetuses

0

0

0

1

(% Fetuses / Litter)

 

 

 

 

M

0.0

0.0

0.0

0.42

ME

0.0

0.0

0.0

0.0

QD

0.0

0.0

0.0

0.0

K (E)

 

 

 

 

Retardations

Litters

0

0

0

0

(% Litters)

0.0

0.0

0.0

0.0

F (E)

 

 

 

 

Fetuses

0

0

0

0

(% Fetuses / Litter)

 

 

 

 

M

0.0

0.0

0.0

0.0

ME

0.0

0.0

0.0

0.0

QD

0.0

0.0

0.0

0.0

K (E)

0.0

0.0

0.0

0.0

 Symbols

+/++ = Level of Significance 5%/1% in Relation to group 0

 

Findings in Fetuses: Cesarean Section

Anomalies

 

 

Test Group 0

0 PPM

Test Group 1

40 PPM

Test Group 2

120 PPM

Test Group 3

360 PPM

Litters

25

27

26

24

Fetus Investigated

298

319

309

292

Head

BI

 

1

 

 

 

Findings in Fetuses: Cesarean Section

Variations

 

 

Test Group 0

0 PPM

Test Group 1

40 PPM

Test Group 2

120 PPM

Test Group 3

360 PPM

Litters

25

27

26

24

Fetus Investigated

298

319

309

292

LIMBS

PAB

 

 

 

1

 

 

Findings in Fetuses: Cesarean Section

Retardations

 

Test Group 0

0 PPM

Test Group 1

40 PPM

Test Group 2

120 PPM

Test Group 3

360 PPM

Litters

25

27

26

24

Fetus Investigated

298

319

309

292

 

Mean Litter Data

 

 

Test Group 0

0 PPM

Test Group 1

40 PPM

Test Group 2

120 PPM

Test Group 3

360 PPM

Fetuses Males

145.00

140.00

149.00

133.00

Fetuses Females

153.00

179.00

160.00

159.00

Fetuses Total

298.00

319.00

309.00

292.00

Weight

Males

N

24.00

26.00

25.00

24.00

MV

3.60

3.77

3.83

3.83

 

 

 

*

*

SD

0.29

0.25

0.45

0.28

SE

0.06

0.05

0.09

0.06

 

Females

N

25.00

27.00

24.00

24.00

MV

3.42

3.51

3.62

3.70

 

 

 

*

**

SD

0.26

0.27

0.30

0.26

SE

0.05

0.05

0.06

0.05

 

Total

N

25.00

27.00

26.00

24.00

MV

3.51

3.63

3.77

3.76

 

 

 

**

**

SD

0.27

0.23

0.46

0.26

SE

0.05

0.04

0.09

0.05

Runts

Total

 

3.00

1.00

2.00

0.0

 Key                             Test Group      Significance 95 %        Significance 99%

Analysis of Trend                    0                                 *                                 **

 

Applicant's summary and conclusion