Developmental Toxicity of Mono(2-ethylhexyl)phthalate (CAS No. 4376-20-9) in CD-1 Swiss Mice
Report Date: Jan. 15, 1991
Mono(2-ethylhexyl)phthalate and 2-ethylhexanol are metabolites of di(2-ethylhexyl)phthalate, a widely used phthalate ester plasticizer. In order to determine their contribution to DEHP's developmental toxicity, MEHP (this study) and 2-EH (study in progress) were evaluated under conditions comparable to those in a previous study of DEHP (Tyl et al., 1988).
MEHP (0%, 0.017%, 0.035%, 0.070% or 0.140% in feed) was provided on gestational days 0 to 17 to timed-pregnant Swiss (CD-1) mice (25-27/group). Average doses were 0, 35, 73, 134 or 269 mg MEHP/kg/day, respectively. At sacrifice (gd 17), the number of resorptions, and dead or live fetuses were recorded. Live or dead fetuses were weighed. Live fetuses were sexed and examined for external, visceral and skeletal malformations.
MEHP-exposed females exhibited no clinical signs of toxicity, and food and water intakes (g/kg/day) were comparable to controls. Maternal relative (but not absolute) liver weight was increased at greater than or equal to 0.070%. Since other phthalate esters induce increased relative liver weight even at doses which fail to produce microscopic or gross lesions, this response was interpreted to be physiologic, but not necessarily toxic, in nature. Reduction of maternal weight gain (gd 0 to 17) at greater than or equal to 0.035% MEHP was secondary to reduced gravid uterine weight except at the high dose which also exhibited a 22% reduction in corrected gestational weight gain. Thus, 0.035% MEHP was the maternal no-observed-effect level, 0.070% MEHP was the maternal no-observed-adverse-effect level and 0.140% MEHP was the maternal lowest-observed-adverse-effect level.
The % litters with one or more resorptions or nonlive implants was increased at greater than or equal to 0.017% MEHP (28, 63, 74, 76, and 93% with resorptions; 40, 74, 82, 76 and 93 with nonlive implants). Comparison of MEHP groups to historical control data for these parameters also supported the conclusion that 0.017% MEHP was a LOAEL for developmental toxicity. The % nonlive implants/litter was increased at greater than or equal to 0.035% MEHP (6, 9, 18, 24 and 78%, for control through high-dose groups). The % dams with no live fetuses was elevated at 0.140% MEHP (63% vs 0% for controls). Male fetal weight was not affected; female fetal weight was 93-94% of control weight at 0.070% MEHP (significant) and 0.140% MEHP (nonsignificant). The % litters with one or more malformed fetuses was increased at greater than or equal to 0.035% MEHP (12, 26, 46, 79 and 80%, respectively); the % malformed fetuses/litter was increased at greater than or equal to 0.070% MEHP (3, 4, 7, 25 and 42%, respectively). MEHP exposure was associated with altered cardiovascular (CV) development at greater than or equal to 0.035% MEHP. The % litters with CV malformations was 0, 0, 38, 54 and 70%, and the % fetuses with CV malformations/litter was 0, 0, 5, 16 and 27%, respectively.
In conclusion, maternal and developmental effects of MEHP exposure throughout gestation were qualitatively similar to those previously reported for DEHP at approximately equimolar doses administered under comparable exper-imental conditions (Tyl et al., 1988). These data indicate that MEHP plays a significant role in the expression of DEHP-induced maternal and developmental toxicity. Evaluation of 2-EH, the corresponding alcohol produced by DEHP hydrolysis, is currently in progress in this laboratory.
Summary Table of Maternal and Embryo/Fetal Responses to Mono(2-Ethylhexyl) Phthalate Exposure on Gestational Days 0 to 17
|Dose (% MEHP in Feed)|
|Body weight (gd 12, 15 and 17)[b]||⇓|
|Body weight gain (gestation)||⇓||⇓||⇓|
|No. corpora lutea/dam||⇓|
|Gravid uterine weight||⇓||⇓||⇓|
|Relative liver weight||⇑||⇑|
|% litters with resorptions||⇑||⇑||⇑||⇑|
|% litters with 100% prenatal|
|Average female body wt/litter[d]|
|% malformed fetuses/litter||⇑||⇑|
|% litters with malformations|
|% fetuses with variations/ litter||⇑|
[a] Pregnancy rates were 93-100% per group on gd 17. Thus, each group contained 25-27 confirmed-pregnant females. No maternal deaths, clinical signs or alterations in food/water intake were observed.
[b] Maternal weight was comparable among experimental groups on gd 0, 3, 6 and 9.
[c] Litters with 100% prenatal mortality occurred with the following incidence: 0/25 (0%), 0/27 (0%), 1/27 (4%), 1/25 (4%), and 17/27 (63%) in the control through high dose groups, respectively.
[d] Body weight for male fetuses was not affected.
⇑ indicates significantly greater than control (p<0.05).
⇓ indicates significantly less than control (p<0.05).