Reproductive & Developmental Effects

Technical Summary:

Short chain alkyl-methacrylate esters (MMA, EMA, nBMA, iBMA and 2-EHMA) are high production volume chemicals and have been reviewed extensively by government regulatory agencies. None of these reviews have identified these materials as reproductive or developmental toxicants. Reviews were completed by European Union and OECD Existing Chemicals Risk Assessment programs. MMA has been the subject of an EU Risk Assessment (2002) and OECD review (2007). EMA, nBMA, iBMA and 2-EHMA underwent review as a category in the OECD CICAD program (2009). Data on MAA, a metabolite common to all of the methacrylate esters, has also been reviewed in the EU Risk Assessment (2002).

Definitive reproductive and developmental toxicity tests are available for MMA while screening studies are available for other methacrylate esters. MMA was least harmful to maternal animals and also was not harmful to the fetus. As chain length increases, maternal toxicity accompanied by fetal toxicity increases. However, no selective effect on reproduction or fetal development was observed for any ester or for methacrylic acid.

IIn a 2-generation reproduction toxicity study, MMA was administered to groups of Wistar rats at doses of 0, 50, 150 and 400 mg/kg body weight/day. The NOAEL for maternal, systemic toxicity was 50 mg/kg bw/day while the NOAEL for fertility and reproductive performance and effects on development was 400 mg/kg MMA, i.e. the highest dose tested (Schneider et al 2010a).

MMA did not cause developmental effects in rats even at inhalation exposure levels that caused maternal toxicity. High inhalation exposures to n-BMA and EMA in rats reduced fetal body weight, but were not teratogenic even at concentrations producing overt maternal toxicity. (Saillenfait et al., 1999) Developmental toxicity studies on MMA and nBMA were also conducted in rabbits. MMA was administered to pregnant rabbits orally at doses of 50; 150 and 450 mg/kg body weight/day and nBMA at doses of 100, 300 and 1000 mg/kg body weight/day. No selective effect of either compound on development was found; no fetal effects occurred in the absence of maternal toxicity. (MRTF Studies). Based on these studies, MMA, EMA and nBMA are not selective developmental toxins in rabbits or rats.

Methacrylic acid (MAA), the common metabolite for all the esters, has been tested in groups of pregnant female rats (whole-body inhalation exposure for 6 hr/day, during days 6 to 20 of gestation), at 0, 50, 100, 200, and 300 ppm. No adverse effects on development were found even at exposure levels causing overt maternal toxicity. (Schneider et al 2010b and Schneider et al 2010c)

For the higher methacrylate esters, 1,3-BDDMA was administered at doses 200, 400 or 800 mg/kg bw/day orally to rats. No effects on male fertility were observed. Female fertility was impacted only at doses in which significant maternal toxicity was also observed. Furthermore, no effects on development were noted.

For 1,4-BDDMA, administration at doses up to 1000mg/kg bw/day resulted in fertility effects at the highest dose tested. These effects coincided with significant systemic toxicity in the parental animals and are considered secondary to the overall poor general health of the animals. No effects on development were observed.

For MADAME, administration of doses orally to rats at doses up to 1000 mg/kg bw/day (limit dose) did not show any effects on fertility or development. However, the litters of 3 high dose females were lost during lactation and was considered due to the inability of the mothers to adequately nurse their offspring due to marked systemic toxicity that included but was not limited to twitching, chronic convulsions and nerve fibre degeneration in the brain and spinal cord.

For Allyl methacrylate, Lauryl methacrylate, EGDMA, IBOMA and TRGDMA, administration did not result in any effects on fertility or development up to the highest dose levels tested i.e. the maximum tolerable dose.

In conclusion, extensive guideline compliant reproductive and developmental toxicity studies of the lower and higher methacrylate esters a including methacrylic acid itself, as described above, indicate that these substances are not reproductive or developmental toxicants.

References:

Saillenfait AM, Bonnet P, Gallissot F, Peltier A and Fabries JF. Developmental Toxicities of Methacrylic Acid, Ethyl Methacrylate, n-Butyl Methacrylate, and Allyl Methacrylate in Rats following Inhalation Exposure. Toxicological Sciences 50, 136-145 (1999).

Schneider, S., Fabian, E., and Ravenzwaay, B. (a) n-Butyl Methacrylate Prenatal Developmental Toxicity Study in Himalayan Rabbits Oral Administration (Gavage). November 19, 2010. Lab: BASF Corporation, Project 40R0538/07099. Study Sponsor: Methacrylate REACH Task Force.

Schneider, S., Fabian, E., and Ravenzwaay, B. (b) Methyl Methacrylate Prenatal Developmental Toxicity Study in Himalayan Rabbits Oral Administration (Gavage). November 19, 2010. Lab: BASF Corporation, Project 40R0751/07093. Study Sponsor: Methacrylate REACH Task Force.

Schneider, S., Strauss, V, Treumann, S., and Ravenzwaay, B. (c) Methyl Methacrylate Two-Generation Reproduction Toxicity Study in Wistar Rats Oral Administration (Gavage). October 15, 2010. Lab: BASF Corporation, Project 73R0751/07101. Study Sponsor: Methacrylate REACH Task Force.