Identity Identification of the substance CAS Number: 117-81-7 Chemical Name: 1,2-Benzenedicarboxylic acid, bis(2-ethylhexyl) ester Common Name: Diethylhexyl phthalate (DEHP) Molecular Formula: C24H38O4 Structural Formula: R = Molecular Weight: 390.56 Synonyms: 1,2-Benzenedicarboxylic acid, bis(2-ethylhexylester); Phthalic acid, bis(2-ethylhexyl)ester; Bis(2- ethylhexyl) 1,2-benzenedicarboxylate; Bis(2- ethylhexyl) o-phthalate; Bis(2-ethylhexyl)phthalate; Di-2-ethylhexyl-phthalate; Ethylhexyl phthalate; Dioctyl Phthalate; Di(isooctyl) phthalate; Octyl phthalate; DOP Purity/Impurities/Additives: Purity: ≥ 99.7% w/w Impurities: other phthalates Additives: none Physico-chemical properties Table 1: Summary of physico-chemical properties d 3 (20˚C) 8 kPa (25˚C) g/L (25˚C) -5 atm.m3/mole (25˚C) Source: ATSDR (2002)
Conclusion DEHP causes minimal skin irritation in rabbits. Limited data suggest no irritant effects in humans. Eye irritation Previous evaluations Two eye irritation studies in rabbits were performed according to OECD guideline 404 (BASF, 1986*; Hüls, 1987*) and another eye irritation study in rabbits was performed according to FDA recommended methods (Hüls, 1981*). No reaction was observed in the cornea or iris in any of the studies. All three studies reported mild conjuctival redness after one hour. In the earlier study, mild conjunctival redness was observed in five eyes, one hour after dosing and in three eyes, 24 hours after application (Huls, 1981*). Where reported, all reactions resolved at later timepoints. Data not reported in previous evaluations No data. Conclusion DEHP causes minimal eye irritation in rabbits. Respiratory irritation Previous evaluations No studies specifically addressing this issue have been found. One acute toxicity study included examination of the lungs. Exposure to 10 mg/L DEHP for 4 hours induced dark red foci and patches in the lungs of 19/31 rats (Hüls, 1981*; Klimisch et al., 1992*). It is unknown if these effects were reversible. are no adequate human data. In a case report of 3 preterm infants artificially ventilated with PVC respiratory tubes, an unusual lung disorder resembling hyaline membrane disease was observed in two infants, whilst the third died (Roth et al., 1988*). The authors assumed that these findings were causally related to the exposure to high doses of DEHP released from the PVC tubes. Data not reported in previous evaluations No data. Conclusion Data are insufficient to determine the respiratory irritant potential of DEHP.
Species, Study Duration, Route Doses (mg/kg bw/d) NOAEL (mg/kg bw/d) LOAEL (mg/kg bw/d) Effects at LOAEL References Rat, Sprague-Dawley 0, 25, 100, 250, 1000 NE 25 ↑p.enz.act. from 25 mg/kg bw/d Lake et al., 1984a* 5 males/group 14 days, gavage Rat, Wistar 0, 5, 18, 52, 182, 549 5 18 ↑nb peroxisomes from 18 mg/kg RIVM, 1992* 6 males/group bw/d 2 or 4 weeks, diet Rat, Wistar 0, 250, 500, 1000, 2000 250 500 liver: ↑relw from 500 mg/kg bw/d Khaliq & Srivastava, 5 males/group 1993* 14 days, gavage Rat, Wistar 0, 0.01, 0.025, 0.05, 0.1, 0.5, 42 88 liver: ↑relw at 88 mg/kg bw/d Fukuhara & 5-6 males/group 1.0% (0, 8, 22, 42, 88, 500, 900 Takabatake, 1977* 16 days, diet Rat, F344 0, 2% NE NE ↑relw, ↑p.enz.act. & Reddy, 4-5 males/group hypolipidemia 1978* 3 diet Rat, Sprague-Dawley 0, 2% (0, 900) NE 900 ↓bw and bwg General Motors, 4 males 3 diet liver: ↑absw and relw, ↑nb peroxisomes, ↑pSER, ↑p.enz.act. 1982a,b* kidney: ↑absw and relw ↑CHO and TG only) Rat, F344 0, 0.01, 0.1, 0.6, 1.2, 2.5% (0, NE 11 ↑TG at 0.01% CMA, 1984*; 5 11, 105, 667, 1224, 2101 [M]; Barber et al., 1987 21 days, diet 0, 12, 109, 643, 1197, or 1892 [F])
Species, Study Duration, Route (mg/kg bw/d) (mg/kg bw/d) LOAEL (mg/kg bw/d) Effects at References Rat, F344, 0, 100, 1000, 6000, 12000, 11 105 liver: ↑p.enz.act. from 1000 ppm Short et al., 1987* 5 males/group ppm (0, 11, 105, 667, 21 days, diet 1223, 2100) Rat, Wistar 0, 2% (4 w) or NE NE liver: ↑ wt during treatment period, ↓ Miyazawa et al., 3 males/group 2-4 weeks, diet 2 w, 2% +2 w control diet during withdrawal period; ↑ p.enz.act. during treatment, ↓ during withdrawal 1980* Rat, F344 0, 0.2, 0.67, 2.0% (M: 0, 150, NE 150 liver: ↑absw and relw from 0.2%, Nuodex, 1981c* 5 rats/sex/group 28 days, diet 504, 1563); (F: 0, 147, 490, 1416) ↑p.enz.act., ↓ total lipids Rat, F344 0, 1000 NE 1000 liver: ↑absw and relw Tenneco, 1981* 5 males/group 28 days, gavage Rat, F344 0, 0.67% (0, 350) NE 350 liver: ↑relw, ↑nb peroxisomes, and Hodgson, 1987* 5 28 days, diet ↑p.enz.act. at 0.67% Rat, F344 0 700 NE 700 liver: ↑relw, ↑nb peroxisomes, and Hodgson, 1987* 5 21 days, gavage ↑p.enz.act. at 700 mg/kg bw/d Rat, F344 0, 0.02, 0.05, 0.1, 0.5, 1.0, NE 24 liver: ↑relw from 0.02% BIBRA, 1990* 5 males/group 2.5% (0, 24, 52, 115, 559, 10 group 1093, 2496) 28 days, diet
Appendix 3 – Key Reproduction Studies with DEHP in Laboratory Animals (Adapted from FDA, 2002; ECB, 2006) Study Design/ Species Route (mg/kg bw/d) NOAEL (mg/kg bw/d) LOAEL (mg/kg bw/d) & Endpoint References ORAL Two-generation studies Rat, Sprague-Dawley Diet 1.5, 10, 30, 100, 300, Sys: 14-23 Sys: 46, ↑ kidney wt (Wolfe & Layton, 17 males/group 1000, 7500, 10000 ppm (F0/F1/F2: 0.1, 0.5-0.8, 1.4-2.4, 4.8- Fert: 46 Devp: 4.8 Fert: 592, ↓ nb live pups (F1); Devp: 14, testes, epididymis atrophy (F1,2) 2003) 7.9, 14-23, 46-77, 359- 592, 543-775) Rat, Wistar; Diet 0, 1000, 3000, 9000 Mat: 340 Mat: 1088, ↓ bw & food consumption (Schilling et al., 25/group ppm Fert: NE Fert: 113, minimal testes atrophy (F2); 2001) (0, 113, 340, 1088) Devp: NE Devp: 113, testes atrophy (described above) Repeat dose studies Mouse, CD-1 Diet 0, 0.01, 0.1, 0.3 % Sys: 140 Sys: 425 (Lamb et al., 1987) 11-week-old (0, 14, 140, 425) Fert: 14 Fert: 140, reduced fertility; ↓ Live pups per litter 20 pairs of mice 98 days Rat, Long-Evans Gavage 0, 10, 100 Sys: NE Sys: NE (Akingbemi et al., 10/group Fert: NE Fert: 10, ↑ serum LH and testosterone, ↑ nb Leydig 2004) 70 or 100 days cells
design/Species INHALATION Rat, Wistar 25 F/ group GD 6-15 PARENTERAL Doses (mg/kg bw/d) Head-nose 0, 0.01, 0.05, or 0.3 mg/litre (0, 10, 50, or 300 mg/m3) 6h/d NOAEL (mg/kg bw/d) Mat: 300 Fert: 300 Devp: 300 LOAEL (mg/kg bw/d) & Endpoint Mat: NE Fert: NE Devp: NE (↓ nb live foetuses at 50 mg/m3 but not 300 mg/m3; ↑ % of resorptions at 50 mg/m3 but not 300 mg/m3 References (Merkle et al., 1988*) Rat GD 6-15. Rat, Sprague-Dawley 5/group GD 5, 10, and 15 Rat, Sprague-Dawley GD3, 6, and 9 Examined at weaning IV 0, 1.3-1.4, 4.7-5.3 Mat: 4.7-5.3 Fert: 4.7-5.3 Devp: 4.7-5.3 IP 0, 4930 and 9860 Mat: NE Fert: NE Devp: NE IP 0, 1972, Mat: NE Fert: NE Devp: NE Mat: NE Fert: NE Devp: NE Mat: Fert: 4930, ↓ implantations Devp: 4930, ↓ foetal wt Mat: 1972, ↑ dam deaths Fert: 1972, ↓ implantations Devp: 1972, ↓ nb of weaned pups (Lewandowski et al., 1980*) (Singh et al., 1972*) (Peters & Cook, 1973*) M: male; F: female; AGD: anogenital distance; bw: body weight; bwg: body weight gain; nb: number; NE: not established; NR: not reported; Mat: maternal; Fert: fertility; Devp: development; wt: weight