2-methylbutyl acrylate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

14 Feb 1979 - 13 Mar 1979

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Read-across of data for an analogous chemical. The target chemical and the source chemical are very closely related alkyl acrylate compounds. They differ only by the addition of a methyl group in the butyl portion of the molecule. Both molecules are expected to be metabolized via the same hydrolysis and enzymatic pathways. The data from the source chemical are experimental results from well documented studies which meet basic scientific principles and are considered to be acceptable with restrictions.

Data source

Reference

Reference 1

Reference Type:

study report

Title:

Unnamed

Year:

1979

Report date:

1979

Reference 2

Reference Type:

publication

Title:

n-Butyl Acrylate: Prenatal Inhalation Toxicity in the Rat.

Author:

Merkle J and Klimisch H-J

Year:

1983

Bibliographic source:

Fund. Appl. Toxicol. 3: 443-447

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

other: Guidelines for reproduction studies for safety evaluation of drugs for human use, FDA, Jan. 1966 and Guidance on reproduction studies from the Association of the British Pharmaceutical Industry, 1975.

GLP compliance:

no

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

n-Butyl acrylate

IUPAC Name:

n-Butyl acrylate

Constituent 2

Reference substance name:

Butyl acrylate

EC Number:

205-480-7

EC Name:

Butyl acrylate

Cas Number:

141-32-2

IUPAC Name:

butyl acrylate

Details on test material:

- Name of test material (as cited in study report): n-Butyl acrylate
- Analytical purity: 99.91%
- Impurities: water-0.01%, acrylic acid-0.0036%, di-n-butyl ether-0.01%, isobutyl acrylate-0.03%, methyl butyl acrylate-0.04%, hydroquinone monomethyl ether-17 ppm.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Iffa Credo, Lyon, France
- Body weight at study initiation:
The mean body weight ± SD in dose groups 0, 25, 135 and 250 ppm were 209±12, 214±14, 214±9 and 219±16, respectively.
- Age at study initiation: 9-11 week
- Diet (e.g. ad libitum): Herilan Mrh-Zucht, H. Eggermann KG, Rinteln.
- Water: ad libitum


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:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
By means of a continuous infusion apparatus (UNITA I, B. Braun, Melsungen, Federal Republic Germany) constant amounts of the liquid product were supplied to a heated (about 80°C) evaporator. The n-butyl acrylate vapors were diluted with dust-free, conditioned fresh air and passed through 200 L inhalation chambers (all-glass construction with steel frame) under dynamic airflow conditions at a flow rate of 20 changes of air per hour (4000 L/h; 200 L chamber). A mean temperature of 24.5°C and a mean relative humidity of 53% were measured during exposure.


TEST ATMOSPHERE
- Brief description of analytical method used: The n-butyl acrylate test atmosphere concentrations were monitored analytically by means of a total
hydrocarbon analyzer (R 5 of RATFISCH, Munich). The total hydrocarbon analyzer was calibrated using an infrared analyzer Miran I (WILKS) calibrated with standards of known concentrations of n-butyl acrylate.
- Samples taken from breathing zone: yes

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

The analytical concentrations (Mean ± SD) of the dose groups 25, 135 and 250 ppm were 25 ± 1, 137 ± 4 and 251 ± 3 ppm, respectively.

Details on mating procedure:

- Proof of pregnancy: sperm in vaginal smear referred to as day 0 of pregnancy

Duration of treatment / exposure:

days 6-15 of gestation

Frequency of treatment:

6 hours per day

Duration of test:

21 days

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 25, 135 and 250 ppm (corresponding to 0, 0.13, 0.71 and 1.31 mg/L) Calculation of concentrations (mg/L) based on Derelanko MJ (2000). Toxicologist's Pocket Handbook, CRC Press, conversion table, p. 57.
Basis:
nominal conc.

No. of animals per sex per dose:

30

Control animals:

yes, sham-exposed

Examinations

Maternal examinations:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily


BODY WEIGHT: Yes
- Time schedule for examinations: day on which sperm had been detected (day 0) and on the 6th, 16th and 20th days post coitum.



POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on the 20th day post coitum.

Ovaries and uterine content:

Examinations included:
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of resorptions: Yes

Fetal examinations:

The weights and the length of fetuses were determined. After fixation in Bouin's solution, 1/3 of the fetuses were examined for organ changes according to the method of Wilson and Warkany (1965), and after staining of the skeleton (Dawson, 1926) 2/3 of the fetuses were investigated for skeletal changes.
Wilson, J.G. and Warkany, J. (1965). Teratology: Principles and Techniques. The University of Chicago Press, Chicago and London.
Dawson, A.B. (1926). Stain Technol. 1:123.

Statistics:

A trend analysis based on the generalization of the t-test according to Williams (1971, 1972) was carried out for the variables of maternal body weight and body weight gain, fetal weight and length, and placental weight in each case. The U-test (Krauth, 1971; Stucky and Vollmar, 1976) was carried out for the parameters of implantations per pregnant animal, live and dead embryos as percent per pregnant animal, and anomalies, variations and retardations as percent of live fetuses per litter.
Williams, D.A. (1971). Biometrics 27:103-117.
Williams, D.A. (1972). Biometrics 28:519-531.
Krauth, J. (1971). Ann. Math. Statist. 42:1949-1956.
Stucky, W. and Vollmar, J. (1976). J. Statist. Comput. Simul. 5:73-81.

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
25 ppm were tolerated without any impairment of body weight. The body weight gain was significantly reduced after inhalation of 135 and 250 ppm during the period of treatment. In the period after the end of treatment (gd 16 - 20) the steepness of the body weight curve obtained after 135 and 250 ppm was similar to that of the control group. During the exposure 135 ppm led to distinct discharge from the eyes and noses and to ruffled fur. After inhalation of 250 ppm these symptoms were even more pronounced. No mortality occurred.

Effect levels (maternal animals)

Dose descriptor:

NOAEC

Effect level:

ca. 0.13 mg/L air (nominal)

Basis for effect level:

other: maternal toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:yes

Details on embryotoxic / teratogenic effects:
The necropsy of the animals did not reveal any gross-pathological changes of the internal organs which could be attributed to the test substance. The number of corpora lutea and the number of implantations did not show any differences between the individual groups. After inhalation of 135 and 250 ppm the percentage of live implanations per pregnant animal was dose-dependent reduced. In the 135 and 250 ppm groups, the percentage of dead resorptions were significantly increased. No adverse effect on the weight and length of the fetuses was observed. No treatment related malformations and no signs of organ changes or skeletal abnormalities were observed in the fetuses at any concentration.

Effect levels (fetuses)

1

Dose descriptor:

NOAEC

Effect level:

ca. 0.13 mg/L air (nominal)

Basis for effect level:

other: embryotoxicity

2

Dose descriptor:

NOAEC

Effect level:

ca. 1.31 mg/L air (nominal)

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

Maternal body weight development (mean values ± standard deviation):

 

Concentration [ppm]	Maternal body weight GD 0 [g]	Maternal body weight GD 20 [g]	Maternal body weight gain GD 0-20 [g]
0	209.38 ± 11.83	354.01 ± 36.66	144.64 ± 33.08
25	213.96 ± 13.94	359.62 ± 36.81	145.66 ± 29.87
135	213.68 ± 9.30	335.54 ± 43.00	121.87 ± 37.62*
250	218.64 ± 16.19	318.11 ± 42.79**	99.47± 33.68**

*  p < 0.05

** p < 0.01

Reproductive parameters:

 

Conc.  (ppm)	no. pregnant/  total animals	live fetuses/ animal	resorptions (%)	weight of fetuses (g)
0	22/30	11.5 ± 5.34	11.6	3.85 ± 0.41
25	23/30	10.6 ± 4.94	13.8	4.08 ± 0.39
135	18/30	8.8 ± 5.14	23.6*	4.09 ± 0.23
250	19/30	8.4 ± 5.68	31.6*	4.08 ± 0.47

*: p<0.05

Conc.  (ppm)	% fetuses per litter with anomalies	% litters with fetuses showing anomalies	% fetuses per litter with variations/ retardations	% litters with fetuses showing variations/ retardations
0	2.7	23.8	19.7	81.0
25	0.9	9.1	11.2	59.1
135	1.9	18.8	10.2	43.8
250	0	0	8.2	43.8

	0 ppm	25 ppm	135 ppm	250 ppm
Skeletal findings
Anomalies:
- Cleft vertebral centra	7/170	2/162	4/105	0/107
Variations/retardations:
- incomplete ossification of skull bone	0/170	0/162	1/105	0/107
- aplasia of sternebrae	16/170	11/162	3/105	3/107
-incomplete ossification of sternebrae	30/170	18/162	14/105	9/107
- asymmetric sternebrae	4/170	1/162	0/105	0/107
-accessory rib, bilateral	2/170	3/162	0/105	0/107
-accessory rib, bilateral and rudimentary	1/170	0/162	0/105	0/107
-accessory rib, unilateral and rudimentary	1/170	0/162	0/105	0/107
-general incomplete ossification of bones	1/170	2/162	1/105	1/107
Organ findings
Variations/retardations:
-dilatation of pelvis, unilateral	2/82	0/81	1/54	0/53

Units given as number found/number examined

 

Applicant's summary and conclusion

Executive summary:

The results presented in this summary are experimental results for the source chemical n-butyl acrylate. The results are considered to be appropriate for read-across to the target chemical 2-methylbutyl acrylate.