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Home » Study Results & Research Projects » NTP Study Reports » All Long-Term Reports » Abstract for TR-429 - Diethylphthalate & Dimethylphthalate
Diethylphthalate and dimethylphthalate are used as phthalate plasticizers, in an extensive array of products. The chronic dermal toxicity of diethylphthalate was evaluated in male and female F344/N rats and B6C3F1 mice in 2-year studies. In a series of special studies, the tumor initiation or promotion potential of diethylphthalate or dimethylphthalate was evaluated in male Swiss (CD-1®) mice by an initiation/promotion model of skin carcinogenesis. The genetic toxicity of diethylphthalate and dimethylphthalate in Salmonella typhimurium and cultured Chinese hamster ovary cells was also evaluated.
Groups of 10 male and 10 female rats were dermally administered diethylphthalate at volumes of 0, 37.5, 75, 150, or 300 mL (0, 46, 92, 184, or 369 mg) applied neat, 5 days per week for 4 weeks. All male and female rats survived to the end of the study. No evidence of dermatotoxicity was observed, with no adverse clinical signs observed and no effects on weight gain or feed consumption. Relative liver weights of 300 mL males and females and 150 mL females were greater than those of controls. Relative kidney weights of 150 and 300 mL males and 150 mL females were greater than those of controls. No other adverse effects were observed in this study.
Groups of 10 male and 10 female mice were dermally administered diethylphthalate at volumes of 0, 12.5, 25, 50, or 100 mL (0, 15, 31, 62, or 123 m) applied neat, five days per week for 4 weeks. One control female died before the end of the study; all other mice survived. No evidence of dermatotoxicity or other adverse clinical signs were observed, and no clear adverse effects on weight gain or feed consumption were seen. Absolute and relative liver weights of 25 and 100 mL females were greater than those of the controls. Based on these 4-week study results, doses of 0, 35, and 100 mL diethylphthalate were recommended for the 2-year mouse studies. A chronic study in male and female B6C3F1 mice at 0, 35, and 100 mL (applied neat, once per day, 5 days per week) was started and subsequently stopped after 32 weeks when significant body weight reductions were noted in treated animals (males and females, 100 mL groups: 19% lower; males, 35 mL group: 12% lower; females, 35 mL group: 10% lower than controls). Based on these body weight reductions, doses of 0, 7.5, 15, and 30 mL in 100 mL acetone were recommended for the restart of the 2-year mouse study.
Based upon the results of the 4-week study, doses of 0, 100, or 300 mL diethylphthalate (0, 123, or 369 m) were chosen for the 2-year rat study. Groups of 60 male and 60 female rats received the doses applied neat 5 days per week for 103 weeks and up to 10 animals per group were evaluated after 15 months.
Survival, Body Weights, and Clinical Findings
Survival of dosed rats during the first 15 months was similar to
that of controls. However, 2-year survival was significantly reduced in all
groups of male rats (survival probabilities, males: 0 mL, 8%;
100 mL,
12%; and 300 mL, 12%). The mean body weights of 300 mL
males were slightly
less than those of the controls throughout the study. No adverse clinical signs
were observed, including no evidence of dermatotoxicity.
Pathology Findings
No morphological evidence of dermal or systemic toxicity was
observed in male or female rats. Skin neoplasms were not observed in female
rats and were only rarely observed in male rats. A high incidence of anterior
pituitary adenoma occurred in all groups of male and female rats. The
incidence
of anterior pituitary adenomas in the 0, 100, and 300 mL groups were:
males,
39/44, 41/49, 41/49; females, 38/50, 33/49, 33/48. The incidence of this
benign
tumor in control males (84%) exceeded the historical control mean incidence
[feed controls, (28.7%)] and range (12% to 60%). Anterior pituitary adenomas
were considered a primary contributing factor in the increased mortality
observed in all groups, regardless of treatment. A dose-related decreasing
trend in the incidence of mammary gland fibroadenomas was observed in
female
rats (21/50, 12/48, 7/50). The incidence of mononuclear cell leukemia in male
rats in this study was lower than the historical incidence and may be
attributable to the shortened life span of male rats. Similarly, the incidence
of interstitial cell tumors of the testes was markedly decreased in all groups
of males (4/50, 3/50, 8/50), relative to historical control rates (90.1%; range
74%-98%). The incidence of fatty liver degeneration was notably lower in
dosed
rats than in controls (males: 26/50, 8/50, 4/51; females: 23/50, 11/50,
3/50).
Groups of 60 male and 60 female mice received doses of 0, 7.5, 15, or 30 mL diethylphthalate (0, 9, 18, or 37 m) in 100 mL acetone 5 days per week for 103 weeks with a 1 week recovery period, and up to 10 animals per group were evaluated after 15 months.
Survival, Body Weights, and Clinical Findings
Two-year survival of dosed mice was similar to that of controls:
43/50, 41/48, 46/50, and 43/50 (males), and 41/50, 38/51, 37/49, and 36/49
(females). Mean body weights of dosed male and female mice were similar to
those of the controls throughout the study. No adverse clinical signs were
observed in mice, including no gross evidence of dermatotoxicity. Feed
consumption by male and female mice was similar to or up to 13% greater
than
that by controls.
Pathology Findings
No morphological evidence of dermal toxicity was observed in
male
or female mice. No skin neoplasms were observed in dosed male mice. In
female
mice receiving 30 mL, one squamous cell carcinoma and one
basal cell
carcinoma were seen at the site of application. An increased incidence of liver
neoplasms was observed in dosed male and female mice. The incidence of
hepatocellular adenoma or carcinoma (combined) in B6C3F1 mice in the 0,
7.5,
15, and 30 mL groups were: (males) 9/50, 14/50, 14/50, and 18/50;
(females)
7/50, 16/51, 19/50, and 12/50. The incidence of adenoma or carcinoma
(combined)
was increased in 30 mL male mice and the incidences of adenoma and
of adenoma
or carcinoma (combined) were increased in 7.5 and 15 mL females. A
positive
dose-related trend in the incidence of adenoma or carcinoma (combined) was
also
observed in male mice. The incidence of basophilic hepatic foci was
increased
in 15 mL male mice (0/50, 1/50, 9/50, 3/50). The increased incidence of
liver
neoplasms in this study was considered equivocal because the incidence of
hepatocellular neoplasms in control and dosed males was within the historical
range and because there was no clear dose-response relationship in females.
No
other treatment-related findings were observed in this study.
Groups of 50 male mice were dosed dermally with diethylphthalate or dimethylphthalate to study their effect as initiators and promoters. Diethylphthalate and dimethylphthalate were tested as initiators with and without the known skin tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Diethyl phthalate and dimethylphthalate were tested as promoters with and without the known skin tumor initiator 7,12-dimethylbenzanthrancene (DMBA). Comparative control groups used during the study of diethylphthalate and dimethylphthalate included: vehicle control (acetone/acetone); initiation/promotion control (DMBA/TPA); initiator control (DMBA/acetone); and promoter control (acetone/TPA).
Based on the incidence of skin neoplasms diagnosed histologically and the multiplicity of skin neoplasms, there was no suggestion that either diethylphthalate or dimethylphthalate was able to initiate skin carcinogenesis when chronically promoted by TPA. Further, there was no evidence that either diethylphthalate or dimethylphthalate was able to promote skin carcinogenesis in skin previously initiated with DMBA. High incidences of both squamous cell papillomas and squamous cell carcinomas occurred among the initiation/promotion control animals initiated with DMBA and promoted with TPA. All TPA-dosed groups had significantly greater incidences of dermal acanthosis, ulceration, exudation, and hyperkeratosis than controls.
Neither diethylphthalate (10-10,000 m/plate) nor dimethylphthalate (33-6,666 m/plate) induced gene mutations in Salmonella typhimurium strains TA98, TA100, TA1535, or TA1537, with or without rat and hamster liver S9. In cultured Chinese hamster ovary cells, both diethylphthalate and dimethylphthalate induced sister chromatid exchanges in the presence of S9. Neither induced sister chromatid exchanges in the absence of S9. Neither chemical induced chromosomal aberrations, with or without S9, in cultured Chinese hamster ovary cells.
Under the conditions of these 2-year dermal studies, there was no evidence of carcinogenic activity of diethylphthalate in male or female F344/N rats receiving 100 or 300 mL. The sensitivity of the male rat study was reduced due to low survival in all groups. There was equivocal evidence of carcinogenic activity of diethylphthalate in male and female B6C3F1 mice based on increased incidences of hepatocellular neoplasms, primarily adenomas.
In an initiation/promotion model of skin carcinogenesis, there was no evidence of initiating activity of diethylphthalate or dimethylphthalate in male Swiss (CD-1®) mice. Further, there was no evidence of promotion activity of diethylphthalate or dimethylphthalate in male Swiss (CD-1®) mice. The promoting activity of TPA following DMBA initiation was confirmed in these studies.
Minor dermal acanthosis was observed following dermal application of diethylphthalate in male and female F344/N rats dosed for 2 years and in male Swiss (CD-1®) mice dosed for 1 year.
Synonyms:
Diethylphthalate (CAS No. 84-66-2): 1,2-benzenedicarboxylic
acid, diethyl ester; DEP; diethyl 1,2-benzenedicarboxylate;
diethyl o-phthalate;
diethyl phthalate; ethyl phthalate; o-benzenedicarboxylic
acid diethyl ester; phthalic acid, diethyl ester; RCRA U088
Dimethylphthalate (CAS No. 131-11-3): 1,2-benzenedicarboxylic acid, dimethyl ester; dimethyl 1,2-benzenedicarboxylate; dimethyl benzene-o-dicarboxylate; dimethyl benzeneorthodicarboxylate; dimethyl o-phthalate; dimethyl phthalate; DMP; FIFRA 028002; methyl phthalate; go-dimethyl phthalate; phthalic acid, dimethyl ester; phthalic acid methyl ester; RCRA U102
Report Date: May 1995
Pathology Tables, Survival and Growth Curves from NTP 2-year Studies
Target Organs & Incidences from 2-year Studies
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Web page last updated on October 11, 2007
The National Institute of Environmental Health Sciences is one of the National Institutes of Health within the U.S. Department of Health and Human Services. The National Toxicology Program is headquartered on the NIEHS campus in Research Triangle Park, NC.