Docosyl methacrylate

Developmental toxicity / teratogenicity

Administrative data

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

weight of evidence

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Data source

Reference

Reference Type:

publication

Title:

Developmental Toxicities of Methacrylic Acid, Ethyl Methacrylate, n-Butyl Methacrylate, and Allyl Methacrylate in Rats following Inhalation Exposure.

Author:

Saillenfait AM, Bonnet P, Gallissot F, Peltier A, Fabriès

Year:

1999

Bibliographic source:

Toxicological Sciences 50: 136-145

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

GLP compliance:

not specified

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Methacrylic acid

EC Number:

201-204-4

EC Name:

Methacrylic acid

Cas Number:

79-41-4

Molecular formula:

C4H6O2

IUPAC Name:

2-methylprop-2-enoic acid

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: IFFA Credo Breeding Laboratories, France
- Age at study initiation: not specified
- Weight at study initiation: 180-200  grams
- Housing: mated females were housed in clear polycarbonate cages with stainless steel wire lids and hardwood shavings for bedding
- Diet: food pellets, ad libitum, except during exposure
- Water: tap water, ad libitum, except during exposure
- Acclimation period: 2 weeks

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

Administration / exposure

Route of administration:

inhalation

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Details on exposure:

Exposures were whole body and conducted in a 200 L glass/stainless-steel inhalation chamber with dynamic and adjustable laminar air flow (6-20 m3/h). Chamber temperature was 23°C, and the relative humidity was 50%. Air was passed through a heated bubbler containing test material. The vaporized material was then introduced into the exposure chambers.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Concentrations were monitored continuously with a GC, and were determined once during each 6 hr exposure by collecting the material and analyzing against a standard using GC.   

Details on mating procedure:

Mating: 2-3 females were caged with one male rat 
The onset of gestation was based upon the presence of sperm in the vaginal  smear and this was designated gestation day 0. After confirmation of mating, females werereturned to an individual cage. 

Duration of treatment / exposure:

6 hours per day

Frequency of treatment:

day 6 to 20 of gestation

Duration of test:

mated females were exposed 6 hr/day on days 6 through 20 of gestation

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

50 ppm

Remarks:

55.3 ± 8.1 ppm analytical concentration

Doses / concentrations 2

Dose / conc.:

100 ppm

Remarks:

101.5 ± 16.9 ppm analytical concentration

Doses / concentrations 3

Dose / conc.:

200 ppm

Remarks:

207.3 ± 24.7 ppm analytical concentration

Doses / concentrations 4

Dose / conc.:

300 ppm

Remarks:

316.0 ± 36.7 ppm analytical concentration

No. of animals per sex per dose:

19-25 pregnant females per dose

Control animals:

other: yes, concurrently to filtered room air

Examinations

Maternal examinations:

CAGE SIDE OBSERVATIONS: No data

DETAILED CLINICAL OBSERVATIONS: / No data

BODY WEIGHT: Yes

FOOD CONSUMPTION Yes
for the intervals GDs 6-13 and 13-21

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 21
- Organs examined: uterus

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:

Live fetuses were weighed, sexed, and examined for external anomalies. 50% of the live fetuses were preserved in Bouin's solutionand  examined for internal soft-tissue changes. The remaining fetuses were fixed in ethanol (70%), eviscerated and then processed for skeletal  staining with alizarin red S.

Statistics:

The number of CL, implantation sites,and live fetuses, maternal food consumption and various body weights were analyzed  by ANOVA, followed by Dunnett'st-test. the percentage of non-live  implant, resorptions,and males and the proportion of fetuses with  alterations ineach litter were evaluated by Kruskal-Walles test followed  by Dixon-Massey test. Rates of pregnancy and percentage of litters with  any malformations or external, visceral, or skeletal variations were  analyzedusing Fisher's test. Where appropriate, least squares analysis  was performed. The level of significance was p < 0.05.

Results and discussion

Results: maternal animals

General toxicity (maternal animals)

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Exposure to 300 ppm led to significant decreases in maternal weight gain. Absolute weight gain was significantly reduced at 300 ppm.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Exposure to 300 ppm led to significant decreases in maternal food consumption.

Maternal developmental toxicity

Pre- and post-implantation loss:

no effects observed

Early or late resorptions:

no effects observed

Dead fetuses:

no effects observed

Effect levels (maternal animals)

Key result

Dose descriptor:

NOAEC

Effect level:

200 ppm

Basis for effect level:

other: maternal toxicity

Maternal abnormalities

Abnormalities:

not specified

Results (fetuses)

Fetal body weight changes:

no effects observed

Reduction in number of live offspring:

no effects observed

Details on embryotoxic / teratogenic effects:

There were no significant changes in number of implantations and live fetuses, in the incidence of non-live implants and sorptions, or in fetal weights across groups. One fetus of 200 ppm and two of the 300 ppm group showed different types of malformations. There was no consistent pattern of changes to suggest any treatment-related effects. The difference of fetuses with external, visceral, and skeletal variations did not differ between the control and the treated groups. No significant increase in embryo/fetal lethality or fetal malformations was observed after exposure. While maternal toxicity was observed, methacrylic acid caused no evidence of developmental toxicity up to 300 ppm.

Effect levels (fetuses)

Key result

Dose descriptor:

NOAEC

Effect level:

>= 300 ppm

Sex:

male/female

Basis for effect level:

other: teratogenicity

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

no

Any other information on results incl. tables

 Table 1: Reproductive parameters in Sprague-Dawley Rats Inhaling Methacrylic acid on Days 6 to 20 of Gestation and Euthanized on Day 21

Concentration ppm/6h/day	% of females pregnant at euthanization	No. of litters	No. of corpora lutea per dam	No. of implantation sides per litter	% of nonlive implants per litter(a)	% of resorption sites per litter	No. of live fetuses per litter	% of males per litter
0	92	23	17.05 ± 1.7(b)	14.91 ± 5.06	8.96 ± 20.73	8.96 ± 20.73	14.73 ± 3.92	56.37 ± 17.76
50	88	22	16.10 ± 1.76	15.36 ± 1.97	3.22 ± 3.34	3.22 ± 3.34	14.86 ± 1.93	49.70 ± 14.90
100	84.6	22	16.23 ± 1.74	15.00 ± 2.93	6.76 ± 8.14	6.76 ± 8.14	14.05 ± 3.17	58.70 ± 13.10
200	88	22	16.32 ± 2.12	14.36 ± 3.74	5.67 ± 12.77	5.67 ± 12.77	13.77 ± 3.99	53.91 ± 17.15
300	88.5	23	16.00 ± 2.73	14.43 ± 4.63	10.61 ± 21.45	10.61 ± 21.45	14.05 ± 3.76	50.40 ± 16.30

Concentration ppm/6h/day	Average fetal body weight (g) all	Average fetal body weight (g) males	Average fetal body weight (g) females
0	5.71± 0.56	5.86± 0.57	5.42± 0.37
50	5.66± 0.27	5.82± 0.32	5.49± 0.27
100	5.79± 0.30	5.92± 0.32	5.62± 0.32
200	5.76± 0.47	5.92± 0.47	5.54± 0.45
300	5.67± 0.49	5.71± 0.34	5.54± 0.52

(a)  resorptions plus dead fetuses

(b)  values are expressed as means ± SD