Developmental toxicity in rats after inhalation exposure of di-2-ethylhexylphthalate (DEHP)

Merkle, J.; Klimisch, H.-J.; Jäckh, Rudolf

doi:10.1016/0378-4274(88)90080-x

Cited by 21 publications

(11 citation statements)

References 10 publications

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“…Although teratogenicity was not clearly demonstrated in Fischer 344 rats, DEHP was associated with embryolethality when administered in the diet throughout gestation (Wolkowski-Tyl et al, 1983b) and with marginal effects (increased resorption rate and decreased pup weight) when administered throughout organogenesis (Morrissey et al, 1989). Inhalation exposure, however, did not cause developmental toxicity in Fischer 344 rats (Merkle et al, 1988). Phenol, used in many medicinal and industrial organic preparations, can cause neurotoxicity and respiratory irritation.…”

mentioning

confidence: 95%

A multidisciplinary approach to toxicological screening: II. Developmental toxicity

Narotsky

Kavlock

1995

Journal of Toxicology and Environmental Health

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As part of the validation of an integrated bioassay for systemic toxicity, neurotoxicity, and developmental toxicity, we evaluated the effects of four pesticides, four chlorinated solvents, and two other industrial chemicals in Fischer 344 rats. The pesticides included carbaryl, triadimefon, chlordane, and heptachlor; the solvents included dichloromethane (DCM), carbon tetrachloride, trichloroethylene (TCE), and tetrachloroethylene (perchloroethylene, PER); and the industrial chemicals were di(2-ethylhexyl)phthalate (DEHP) and phenol. In the developmental toxicity studies, timed-pregnant rats were treated by gavage with vehicle or 1 of 2 dose levels of each compound on gestation d 6-19. The dams were allowed to deliver and their litters were examined on postnatal d 1, 3, and 6. Litter weights were determined on postnatal d 1 and 6. Implants were also counted to determine prenatal loss. Maternal toxicity was evidenced by dose-related alterations in weight gain for all 10 compounds. Clinical signs of maternal toxicity were present for all chemicals except chlordane and heptachlor. DEHP exposure resulted in the most pronounced developmental toxicity (high levels of pre- and postnatal mortality), whereas chlordane induced extensive postnatal loss. Of the solvents, only DCM did not cause a high incidence of full-litter resorption. Phenol, heptachlor, triadimefon, and carbaryl showed only slight potential for developmental toxicity. Malformations suggestive of teratogenicity included kinked tail (phenol), microphthalmia (TCE, PER, DEHP), and cleft palate with renal agenesis (DEHP). Although several findings (eye defects caused by TCE and PER, full-litter resorption and delayed parturition caused by PER, and delayed parturition/dystocia associated with triadimefon) have not been previously reported, the results are generally consistent with previous reports and highlight the importance and relative ease of incorporation of developmental evaluations into a multidisciplinary screening battery.

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confidence: 95%

A multidisciplinary approach to toxicological screening: II. Developmental toxicity

Narotsky

Kavlock

1995

Journal of Toxicology and Environmental Health

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“…The NOAEL for foetotoxicity and teratogenicity in the rat was about 200 mg/kg body weight and day after oral administration (Hellwig et al 1997). After inhalation, the NOAEC was 50 mg/m 3 ; at 300 mg/m 3 retardations were observed in the foetuses together with maternal toxicity (Merkle et al 1988). Prenatal studies of developmental toxicity in CD-1 mice revealed malformations (open eyes, exophthalmia, exencephaly, short or no tails, major blood vessel malformations, fused or branched ribs and fused thoracic vertebral centra) at doses of 91 mg/kg body weight and day and above and foetotoxicity at 95 mg/kg body weight and day and above.…”

Section: Manifesto (Reproductive and Developmental Toxicity)mentioning

confidence: 98%

“…Maternal toxicity was observed in the animals of the high exposure group in the form of reduced body weight gains on day 21 of gestation. The NOAEC (no observed adverse effect concentration) for toxic effects on prenatal development and maternal toxicity was 50 mg/m 3 (Merkle et al 1988). …”

Section: Prenatal Exposure Inhalationmentioning

confidence: 99%

Di(2‐ethylhexyl) phthalate (DEHP) [MAK Value Documentation, 2016]

Hartwig

Arand²

2017

The MAK‐Collection for Occupational Health and Safety

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The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re‐evaluated the developmental toxicity of di(2‐ethylhexyl) phthalate (DEHP) [117‐81‐7]. In 2014, the maximum concentration at the work place (MAK value) of DEHP has been set to 2 mgm for the inhalable fraction. In some studies, a correlation between prenatal DEHP exposure and effects on anogenital distance of male newborns, birth weight and pregnancy duration in humans are found, however, the results are not consistent. Teratogenicity is observed in rats only at maternally toxic doses of 1000 mg/kg bw and day and above, in mice at 91 mg/kg bw and day. NOAELs for teratogenicity are 200 mg/kg bw and day for rats and 44 mg/kg body weight and day for mice, the latter corresponding to 29 mg/m 3 after scaling to a concentration at the work place. In contrast to mouse and marmoset the rat is very sensitive to DEHP effects on the male reproductive organs. From a three generation study the Commission deduces a NOAEL for pre‐ and postnatal developmental toxicity to the male reproductive organs and for fetotoxicity of 46 mg/kg bw and day for rats, corresponding to 54 mg/m 3 after scaling to a concentration at the work place. The reported effects, small testes, reduced absolute weights of testis and epididymis, are considered by the Commission as not being adverse because they do not show correlating consequences for the next generation or dose‐response relationship and changes in relative organ weights and histopathological correlates are not observed. After in utero exposure, germ cell organization, mRNA expression and protein level of StAR („steroidogenic acute regulatory protein“) in testes are affected at 100 mg/kg bw and day and above. These effects resulted in a NOAEL for prenatal developmental effects of the male reproductive organs of 30 mg/kg bw and day for rats, corresponding to 35 mg/m 3 . For mice in prenatal developmental studies a NOAEL for fetotoxicity as well as prenatal developmental toxicity of 48 mg/kg bw and day is derived, corresponding to 32 mg/m 3 . Damage to the embryo or foetus is unlikely when the MAK value is observed and DEHP is classified in Pregnancy Risk Group C.

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“…Gestationstag. Die NOAEC für prä-natale Entwicklungstoxizität und Maternaltoxizität betrug 50 mg/m 3 (Merkle et al 1988). …”

Section: Pränatale Exposition Inhalativunclassified

“…Der NOAEL für Fetotoxizität und Teratogenität betrug für die Ratte nach oraler Gabe etwa 200 mg/kg KG und Tag (Hellwig et al 1997). Nach Inhalation betrug die NOAEC 50 mg/m 3 , bei 300 mg/m 3 wiesen die Feten Retardierungen bei gleichzeitiger Maternaltoxizität auf (Merkle et al 1988 …”

Section: Studien Zu Dehp-enthaltenden Pvc-infusionsschläuchenunclassified

Di‐(2‐ethylhexyl)phthalat (DEHP) [MAK Value Documentation in German language, 2016]

Hartwig

Arand²

2016

The MAK‐Collection for Occupational Health and Safety

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The German Commission for the Investigation of Health Hazards of Chemical Compounds in the Work Area has re‐evaluated the developmental toxicity of di(2‐ethylhexyl) phthalate (DEHP). In 2014, the maximum concentration at the workplace (MAK value) of DEHP was set to 2 mg/m 3 for the inhalable fraction. In some studies, a correlation between prenatal DEHP exposure and effects on anogenital distance of male newborns, birth weight and pregnancy duration in humans is found; however, the results are not consistent. Teratogenicity is observed in rats only at maternally toxic doses of 1000 mg/kg bw and day and above, in mice at 91 mg/kg bw and day. NOAELs for teratogenicity are 200 mg/kg bw and day for rats and 44 mg/kg bw and day for mice, the latter corresponding to 29 mg/m 3 after scaling to a concentration at the workplace. In contrast to mouse and marmoset, the rat is very sensitive to the effects of DEHP on the male reproductive organs. From a three‐generation study, the Commission deduces a NOAEL for pre‐ and postnatal developmental toxicity to the male reproductive organs and for foetotoxicity of 46 mg/kg bw and day for rats, corresponding to 54 mg/m 3 after scaling to a concentration at the workplace. The Commission does not consider the reported effects – small testes, reduced absolute weights of testis and epididymis – to be adverse because they do not show correlating consequences for the next generation, there is no dose‐response relationship to changes in relative organ weights and histopathological correlates are not observed. Germ cell organization, mRNA expression and protein level of StAR („steroidogenic acute regulatory protein“) in testes are affected after in utero exposure to 100 mg/kg bw and day and above. These effects resulted in a NOAEL for prenatal developmental effects of the male reproductive organs of 30 mg/kg bw and day for rats, corresponding to 35 mg/m 3 . For mice a NOAEL for foetotoxicity as well as prenatal developmental toxicity of 48 mg/kg bw and day is derived in prenatal developmental studies, corresponding to 32 mg/m 3 . Thus, damage to the embryo or foetus is unlikely when the MAK value is observed and DEHP is classified in Pregnancy Risk Group C.

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Developmental toxicity in rats after inhalation exposure of di-2-ethylhexylphthalate (DEHP)

Cited by 21 publications

References 10 publications

A multidisciplinary approach to toxicological screening: II. Developmental toxicity

A multidisciplinary approach to toxicological screening: II. Developmental toxicity

Di(2‐ethylhexyl) phthalate (DEHP) [MAK Value Documentation, 2016]

Di‐(2‐ethylhexyl)phthalat (DEHP) [MAK Value Documentation in German language, 2016]

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