Hydroxy(2-methylprop-2-enoato-O)zinc

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:

weight of evidence

Study period:

1999

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Study was conducted in accordance with a recognized scientific procedure for determining the developmental toxicity of a test substance when administered repeatedly via inhalation. The study meets national and international scientific standards (OECD 414) and provides sufficient information to support the conclusions regarding the NOAEL demonstrated from the study data.

Cross-reference

Cross-reference 1

Reason / purpose for cross-reference:

reference to same study

Cross-reference 2

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

1999

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

yes

Remarks:

clinical observations not followed; individual animal data not reported

Principles of method if other than guideline:

Not applicable

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

IUPAC Name:

methacrylic acid

Test material form:

not specified

Details on test material:

- Name of test material (as cited in study report): Methacrylic acid
- Source: Fluka Chemie AG, Buchs, Switzerland.
- Analytical purity: 98 %

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: Sexually mature females; age not specified.
- Weight at study initiation: 180-200 g
- Housing: Mated females were housed singly in clear polycarbonate cages with stainless-steel wire lids and hardwood shavings as bedding. For exposures, the females were transferred to stainless steel wire mesh exposure cages, and the cages were moved into the chambers.
- Diet: Food pellets (UAR Alimentation Villemoisson, France), ad libitum except during exposures
- Water: Filtered tap water, ad libitum except during exposures
- Acclimation period: 2 weeks

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

Administration / exposure

Route of administration:

inhalation

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Details on exposure:

Exposures were conducted in 200 L glass/stainless-steel inhalation chambers with dynamic and adjustable laminar air Now (6-20 m^3/h). In order to prevent any leakage of the test atmospheres, the chambers were maintained at a negative pressure of no more than 3-mm water. The chamber temperature was set at 23 ± 2 °C and the relative humidity at 50 ± 5 %. Vapor generation systems consisted in delivering a constant rate of liquid chemical with an infusion pump at 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.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

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

Details on mating procedure:

- Impregnation procedure: Cohoused
- M/F ratio per cage: 1:2-3
- Verification of same strain and source of both sexes: Yes
- Proof of pregnancy: Sperm in vaginal smear referred to as Day 0 of gestation
- After confirmation of mating, females were returned to an individual cage.

Duration of treatment / exposure:

Days 6-20 of gestation

Frequency of treatment:

6 h/day

Duration of test:

Mated females were exposed 6 h/day on Days 6 through 20 of gestation.

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 50, 100, 200 and 300 ppm
Basis:
nominal conc.

No. of animals per sex per dose:

22 pregnant females per dose for 50, 100 and 200 ppm; 23 pregnant females per dose for control and high dose (300 ppm)

Control animals:

other: exposed concurrently to filtered room air

Details on study design:

- Rationale for animal assignment: Mated females were randomly assigned to treatment groups using a randomization system stratified by body weight on GD 0.

Examinations

Maternal examinations:

BODY WEIGHT: Yes
- Time schedule for examinations: GDs 0, 6, 13 and 21

FOOD CONSUMPTION
- Food consumption was measured for the intervals GDs 6-13 and 13-21.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation Day 21; the females were killed with an intrapulmonary injection of T61 (Hoechst, Frankfurt, Germany)

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 resorptions: Yes

Fetal examinations:

- Live fetuses were weighed and sexed.
- External examinations: Yes: [all per litter]
- Soft tissue examinations: Yes: [half per litter]; 50 % of the live fetuses were preserved in Bouin's solution and examined for internal soft-tissue changes.
- Skeletal examinations: Yes: [half per litter]; 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 one way ANOVA, followed by Dunnett's-test. The percentage of non-live implant, resorptions, and males and the proportion of fetuses with alterations in each litter were evaluated by Kruskal-Wallis test followed by Dixon-Massey test. Rates of pregnancy and percentage of litters with any malformations or external, visceral, or skeletal variations were analyzed using Fisher's test. Where appropriate, least squares analysis was performed. The level of significance was p < 0.05.

Indices:

None

Historical control data:

Not applicable

Results and discussion

Results: maternal animals

Maternal developmental toxicity

Details on maternal toxic effects:

Maternal toxic effects:yes

Details on maternal toxic effects:
All animals survived the exposure. Exposure to 300 ppm led to significant decreases in maternal weight gain and food consumption throughout exposure. Absolute weight gain was significantly reduced at 300 ppm.

Effect levels (maternal animals)

1

Dose descriptor:

NOAEL

Effect level:

200 ppm

Based on:

test mat.

Basis for effect level:

other: maternal toxicity

2

Dose descriptor:

NOAEL

Effect level:

>= 300 ppm

Based on:

test mat.

Basis for effect level:

other: developmental toxicity

Results (fetuses)

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

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 resorptions, 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 incidences 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 were observed after exposure to methacrylic acid. While maternal toxicity was observed, methacrylic acid caused no evidence of developmental toxicity up to 300 ppm.

Fetal abnormalities

Abnormalities:

not specified

Overall developmental toxicity

Developmental effects observed:

not specified

Any other information on results incl. tables

See the attached document for information on tables of results

Applicant's summary and conclusion

Conclusions:

Under the test conditions, the No Observed Adverse Effect Level (NOAEL) of Methacrylic acid was considered to be 200 ppm for maternal toxicity and ≥ 300 ppm for developmental toxicity in Sprague-Dawley rats.

Executive summary:

In a prenatal developmental toxicity study performed similarly to OECD Guideline 414, Methacrylic acid was administered via whole body inhalation to groups of mated female Sprague-Dawley rats (22-23/dose) at the dose levels of 0, 50, 100, 200 and 300 ppm from Days 6 to 20 of gestation. Maternal body weight and food consumption were recorded approximately once a week. On Day 21 of gestation, the dams were sacrificed and the gravid uterine weight, no. of corpora lutea, implantations, resorptions and dead and live fetus were recorded. Fetuses were sexed, weighed and examined for external, soft tissue and skeletal malformations.

All animals survived the exposure. Exposure to 300 ppm led to significant decreases in maternal weight gain and food consumption throughout exposure. Absolute weight gain was significantly reduced at 300 ppm. There were no significant changes in the number of implantations and live fetuses, in the incidence of non-live implants and resorptions, or in fetal body weights across groups. One fetus of the 200 ppm and two of the 300 ppm treated groups showed different types of malformations. There was no consistent pattern of change to suggest any treatment-related effects. The incidences of fetuses with external, visceral, and skeletal variations did not differ between the control and the treated groups.

 

Under the test conditions, the No Observed Adverse Effect Level (NOAEL) of Methacrylic acid was considered to be 200 ppm for maternal toxicity and ≥ 300 ppm for developmental toxicity in Sprague-Dawley rats.