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Toxicological information

Carcinogenicity

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Description of key information

Carcinogenicity: Negative

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Carcinogenicity: via dermal route

Link to relevant study records
Reference
Endpoint:
carcinogenicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable study, which meets basic scientific principles. Restriction are: reduced animal numbers due to a reduced survival of male animals in both dose groups and controls.
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 451 (Carcinogenicity Studies)
Deviations:
yes
Remarks:
- less than 50% survivors in the male group, only two dose groups tested, haematology and clinical chemistry performed additionally
Principles of method if other than guideline:
Method: other: Based upon the results of the 4-week study, doses of 0, 100, or 300µL diethylphthalate (0, 123, or 369 µg) 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.
GLP compliance:
yes
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Frederick Cancer Research Facility (Frederick, MD)
- Age at study initiation: 6 weeks
- Housing: 1 animal per cage,
- Diet: ad libitum, NIH-7 open formula meal (Zeigler Brothers, Gardeners, PA)
- Water: ad libitum, automatic watering system
- Acclimation period: 14 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-25
- Humidity (%): 28-74
- Air changes (per hr): >12
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: (first dose) From: 1985-02-06 (last dose) To: 1987-02-02
Route of administration:
dermal
Vehicle:
unchanged (no vehicle)
Duration of treatment / exposure:
103 weeks
Frequency of treatment:
5 d/w
Post exposure period:
none
Remarks:
Doses / Concentrations:
0.123, 0.369 mg (100, 300 µl of the neat test substance)| Corresponds to 320 and 1015 mg/kg/d for males and 520 and 1050 mg/kg/d for females.
Basis:
nominal conc.
No. of animals per sex per dose:
60
Control animals:
yes, concurrent no treatment
yes, historical
Details on study design:
Post-exposure period: none

- Dose selection rationale: animals were randomly assigned to groups by a computer generated randomization program
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: initially and then monthly

DERMAL IRRITATION (if dermal study): Yes

BODY WEIGHT: Yes
- Time schedule for examinations: initially and weekly for the first 13 weeks, monthly thereafter

HAEMATOLOGY: Yes
- Time schedule for collection of blood: blood smaples were collected from the retroorbital sinus of rats and mice at the 15-month interim evaluation
- Anaesthetic used for blood collection: No data
- Animals fasted: No data
- How many animals: up to 10 animals per dose group
- Parameters checked were examined: hematocrit, hemoglobin, erythrocytes, mean cell hemoglobin, mean cell hemoglobin concentration, leukocyte count and differential and nucleated erythrocytes
CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: blood smaples were collected from the retroorbital sinus of rats and mice at the 15-month interim evaluation
- Animals fasted: No data
- How many animals: up to 10 animals per dose group
- Parameters checked were examined: urea, nitrogen, creatinine, alkaline phosphatase, sorbitol dehydrogenase

URINALYSIS: No

Sacrifice and pathology:
GROSS PATHOLOGY: Yes - At necropsy, all organs and tissues were examined for gross lesions and all main tissues were fixed and preserved in 10% neutral buffered formalin

HISTOPATHOLOGY: Yes - Preserved tissues were processed for microscopic examination. Complete histopathologic examinations were performed on all control and high-dose animals at the 15-month interim evaluation and on all animals at 2 years. A quality assessment pathologist reviewed the caecum, forestomach, and mesenteric lymph nodes of male and female rats; the colon and liver of male rats; the clitorial gland of female rats; the lier of male and female mice; and the uterus and thyroid gland of female mice for accuracy and consistency of lesion diagnosis. An independent review of the proliferative lesions of the pituitary gland and testes of male rats was conducted to verify incidence values.
Statistics:
Statistical analysis for possible dose-related effects on survival used Cox's method for testing two groups for equality and Tarone's life table test to identify dose-related trends.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
effects observed, treatment-related
Details on results:
Result (carcinogenicity): negative

CLINICAL SIGNS AND MORTALITY
- mortality in all dose groups: 0 µl, 8% deaths; 100 µl, 12% deaths; 300 µl, 12% deaths
- no dose-reponse
- no adverse clinical effects
- no symptoms of dermatotoxicity

BODY WEIGHT AND WEIGHT GAIN
- mean bw of 300µl dose group were slightly reduced

OTHER FINDINGS
- see "remarks on results including figures and tables" for further details
Dose descriptor:
dose level: no carcinogenic effect
Effect level:
>= 1 050 mg/kg bw/day (nominal)
Sex:
female
Basis for effect level:
other: gross pathology; histopathology; other: neoplasms
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Dose descriptor:
dose level: no carcinogenic effect
Effect level:
>= 1 015 mg/kg bw/day (nominal)
Sex:
male
Basis for effect level:
other: gross pathology; histopathology; other: neoplasms
Remarks on result:
other: Effect type: carcinogenicity (migrated information)
Skin neoplasms were not observed in females and were only rarely found in males. A high incidence of anterior 
pituitary adenoma occurred in all groups including control (67-87%). According to the authors, the incidence of this
benign tumor in control males (84%) exceeded the historical control mean incidence (feed controls: 29%) and range
(12-60%). These tumors were considered to be a primary contributing factor in the increased mortality observed in
all groups, regardless of treatment. A dose-related decreasing trend of mammary gland fibroadenomas was
observed in females. The incidence of mononuclear cell leukemia in males was lower than the historical incidence.
Similarly, the incidence of interstitial cell tumors of the testes was markedly decreased in all groups of males
relative to historical control rates. However, this decrease in tumor incidence might be attributable to the shortened life
span.

According to the authors, there was no evidence of a carcinogenic activity of the test substance in F344 rats.

Conclusions:
There was no evidence of carcinogenic activity of diethyl phthalate in male or female F344/N rats receiving 100 or 300 mL. However, the sensitivity of the male rat study was reduced due to low survival in all groups.
Executive summary:

Carcinogenicity has been investigated in the rat using methods equivalent or similar to those described by OECD Guideline 451 (Carcinogenicity Studies). Diethyl phthalate was tested in male and female F344/N rats (60 animals per sex and dose group) with doses of 0, 100 µl and 300µl undiluted test substance dermally for 103 weeks (5x/ week).

 

There was reduced survival of male rats in all dose groups and controls without dose-dependency.

 

Diethyl phthalate was judged to be not carcinogenic in a 2 -year study with male and female F344/N rats via dermal application. There was no increased tumor incidence outside of the historical control range at the doses tested. The dose level without substance-related effects, for both males and females was therefore considered to be >= 300µl test substance, corresponding to an treatment of >=1015 mg/kg bw/day for males and >=1050 mg/kg bw/day for females (based on gross pathology, histopoathology and neoplasms).

 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 015 mg/kg bw/day
Study duration:
chronic
Species:
rat

Additional information

Carcinogenicity has been investigated in the mouse and rat using methods equivalent or similar to those described by OECD Guideline 451 (Carcinogenicity Studies). Quality of both studies may be restricted by reduced survival at the end of the study period.

Diethyl phthalate was tested in male and female B6C3F1 mice (60 animals per sex and dose group) with doses of 0, 7.5, 15 and 30µl test substance in 100µl acetone applied dermally for 103 weeks (5x/ week). Male and female F344/N rats (60 animals per sex and dose group) were treated with doses of 0, 100 µl and 300µl undiluted test substance dermally for 103 weeks (5x/ week).

 

In mice, no skin neoplasms were observed in treated males. One squamous cell carcinoma and one basal cell carcinoma at the application site were found in high dose females. An increased incidence of liver neoplasms was observed in the treated mice. The combined incidence of hepatocellular adenoma or carcinoma in the 0, 7.5, 15, and 30 µl groups were 9/50, 14/50, 14/50, and 18/50 in males and 7/50, 16/51,19/50, and 12/50 in females. The incidence of adenoma and carcinoma (combined) was increased in high dose group males and the incidences of adenoma and of adenoma and carcinoma (combined) were increased in 7.5 and 15 µl females. A positive dose-related trend in the incidence of adenoma and carcinoma (combined) was also observed in males. The authors consider the evidence for carcinogenicity to be 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. The dose level without substance-related effects for both males and females was considered to be at 30µl test substance, corresponding to an treatment of >=1050 mg/kg bw/day for males and >=1100 mg/kg bw/day for females.

 

In rats, there was no increased tumor incidence outside of the historical control range at the doses tested. The dose level without substance-related effects, for both males and females was therefore considered to be >= 300µl test substance, corresponding to a treatment of >=1015 mg/kg bw/day for males and >=1050 mg/kg bw/day for females (based on gross pathology, histopoathology and neoplasms).

Justification for classification or non-classification

There was no evidence of carcinogenic activity of diethyl phthalate in male or female F344/N rats. There was equivocal evidence of carcinogenic activity in male and female B6C3F1 mice based on increased incidences of hepatocellular neoplasms, primarily adenomas.

These findings are insufficient to justify classification