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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:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study conducted in compliance with GLP regulations.

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:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- 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 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 / concentrations
Remarks:
Doses / Concentrations:
40, 120, 360 ppm (corresponding to approx. 0.12, 0.36, 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]
Basis:
nominal conc.
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

Maternal developmental toxicity

Details on maternal toxic effects:
Maternal toxic effects:yes

Details on maternal toxic effects:
Clinical signs:
No animal died in any group. 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
Dose descriptor:
NOAEC
Effect level:
0.12 mg/L air (nominal)
Basis for effect level:
other: maternal toxicity
Dose descriptor:
LOAEC
Effect level:
0.36 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:
There were no signs of embryotoxicity, in particular no teratogenic effects.

Effect levels (fetuses)

open allclose all
Dose descriptor:
NOAEC
Effect level:
>= 1.08 mg/L air (nominal)
Basis for effect level:
other: teratogenicity
Dose descriptor:
NOAEC
Effect level:
>= 1.08 mg/L air (nominal)
Basis for effect level:
other: fetotoxicity

Fetal abnormalities

Abnormalities:
not specified

Overall developmental toxicity

Developmental effects observed:
not specified

Any other information on results incl. tables

EFFECTS OF EXPOSURES ON MATERIAL BODY WEIGHT AND UTERUS WEIGHT (g)

Concentration (ppm)             

 0

40

120

360

Body weight

Day 0

216 (9.4)a

216 (11.4)

214 (7.7)

215 (9.9)

Day 6

243 (10.1)

243 (16.1)

242 (9.5)

242 (12.7)

Day 15

288 (9.6)

284 (19.2)

280 (14.4)

261 (16.3)**

Day 20

354 (19.9)

349 (33.3)

346 (27.0)

333 (26.1)**

Uterus weight (Day 20)

64 (18.8)

66 (25.5)

68 (23.6)

65 (21.1)

BWE-uterusb

290 (12.0)

283 (17.8)

278 (16.6)**

267 (13.4)**

BWE-BWS-uterusc

74 (11.5)

67 (11.2)*

65 (13.1)**

52 (9.2)**

 aFigures in parentheses indicate standard deviations.

bBWE-uterus = body weight on Day 20 minus uterus weight.

cBWE-BWS-uterus = body weight gain between Day 0 and Day 20 minus uterus weight.

* p<0.05.

**p<0.01.

TERMINAL OBSERVATIONS AND GENERAL FETAL DATA

Concentration (ppm)

0

40

120

360

Number of animals

30

30

29

29

Number of dams

25

27

26

25

Implantations

12.96

12.48

12.46

12.40

Live fetuses

11.92

11.81

11.88

11.68

Dead implantations

1.04

0.67

0.58

0.72

Fetal numbers (male:female)

145:153

140:179

149:160

133:159

Mean weight of live fetuses (g)

3.51

3.64

3.73*

3.77*

Mean length of live fetuses (cm)

3.28

3.30

3.36

3.36

Mean weight of placenta (g)

0.50

0.55

0.52

0.48

 * p<0.05.

FETAL FINDINGS

 

Concentration (ppm)

0

40

120

360

Anomalies/Litters

4 (16.0)m

10 (37.04)

3 (11.54)

3 (13.04)

Anomalies/Fetuses

6 (1.69)n

13 (4.76)

3 (0.81)

3 (1.06)

Variations/Litters

12 (48.00)

17 (62.96)

10 (38.46)

8 (34.78)

Variations/Fetuses

20 (8.04)

36 (11.09)

17 (5.27)

10 (4.36)

Retardations/Litters

24 (96.00)

24 (88.89)

23 (88.46)

21 (91.30)

Retardations/fetuses

114 (35.53)

95 (32.10)

104 (30.63)

89 (32.61)

mFigures in parentheses show percentage of fetuses examined that were affected per litter.

nFigures in parentheses show percentage of fetuses examined that were affected.

Applicant's summary and conclusion