Diallyl phthalate

Carcinogenicity

Description of key information

The 2 year carcinogenicity study in rats (NTP, 1985) did provide evidence of an increased incidence of mononuclear cell leukaemia associated with DAP administration but it was confined to high dose female rats (100 mg/kg/day) and is commonly found in control rats. The authors concluded the study provided only equivocal evidence of carcinogenicity. In a 2 year oral study (NTP, 1983) in B6C3F1 mice there was evidence of chronic inflammatory and hyperplastic responses of the forestomach leading to squamous cell papillomas which may have been associated with DAP administration. An increased incidence of lymphomas in male mice (100 mg/kg) was observed that was considered to be only equivocally related to DAP treatment. The equivocal or negative carcinogenicity data in rats and mice are considered to be of limited relevance to human exposure at the high doses

Key value for chemical safety assessment

Carcinogenicity: via oral route

Link to relevant study records

Reference

Endpoint:

carcinogenicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: Comparable to guideline study with acceptable restrictions: 2 instead of 3 dose levels, detailed observation not made

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

Deviations:

yes

Principles of method if other than guideline:

Diallyl phthtalate was administered by oral gavage to Fisher rats for 103 weeks in order to determine the carcinogenic potential of the substance

GLP compliance:

not specified

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories (Portage, MI)
- Age at study initiation: 6 wk old
- Housing: 5 animals per cage; cages Polycarbonate (Lab Products. Garfield, NJ, and Hazleton Systems, Aberdeen, MD)
- Diet: Pellets (Ralston Purina Co., St. Louis, MO); provided ad libitum
- Water (e.g. ad libitum): Tap water in bottles, acidified to pH 2.5 with HCl; provided ad libitum
- Acclimation period: 2 wks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24
- Humidity (%): 30-70
- Air changes (per hr): 12-15
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: necropsy date: 02-22-1982

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

103 wks

Frequency of treatment:

5 times/wk

Remarks:

Doses / Concentrations:
0, 50 & 100 mg/kg
Basis:
actual ingested

No. of animals per sex per dose:

50 rats/sex/dose

Control animals:

yes, concurrent vehicle

Details on study design:

Dose volume: 3.33 mg/ml

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: weekly for the initial 12 weeks of the studies and once every 4 weeks thereafter

BODY WEIGHT: Yes
- Time schedule for examinations: weekly for the initial 12 weeks of the studies and once every 4 weeks thereafter

HAEMATOLOGY: Yes

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

HAEMATOLOGY
Mononuclear cell leukemia in female rats, significantly greater incidence in the high dose group: diffuse infiltration of atypical mononuclear white blood cells into the liver sinusoids and the interfollicular pulp of the spleen

HISTOPATHOLOGY: NON-NEOPLASTIC
Chronic liver injury characterized by periportal necrosis and fibrosis, pigment accumulation in periportal histiocytes and excessive bile duct hyperplasia; effects more severe in the high dose group

Relevance of carcinogenic effects / potential:

Supporting evidence:
The apparent increase in mononuclear cell leukemia was statistically significant by both trend tests and pairwise comparisons.
The occurrence of mononuclear cell leukemia in vehicle control female rats in this study was within the range observed for historical controls.

Mitigating evidence:
There was no evidence for a diallylphthalaterelated increased occurrence of mononuclear cell leukemia in male rats or in the lower dose female rats.
Mononuclear cell leukemia is a rapidly progressing disease in Fischer 344 rats and can be difficult to diagnose in a definitive fashion.
The relatively high and variable spontaneous occurrence of mononuclear cell leukemia in aged Fischer 344 rats confounds the interpretation of an increased occurrence of this tumor type in dosed animals as evidence of a carcinogenic response.
No other chemically related increased incidences of neoplasia were observed in rats.

Conclusions:

Because of the variability in incidence of this neoplasm in aged Fischer 344 rats and the difficulty in definitively diagnosing this lesion in Fischer 344 rats, this increase was considered to be equivocal evidence of carcinogenicity of diallylphthalate in female rats. There was no evidence of carcinogenicity in male rats.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed

Carcinogenicity: via inhalation route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

DAP is not classified for carcinogenicity, because data of the animal studies were insufficient to indicate a clear cause and effect between DAP administration and the observed neo-plasmic symptoms, and the tumour types observed were of no or limited significance to humans.

Additional information

In the two chronic studies in mice and rats, the evidence of DAP induced carcinogenicity is equivocal and the tumour types described were of limited significance to humans.

Justification for selection of carcinogenicity via oral route endpoint:
These are studies of high quality, although carried out some time ago, are considered adequate for assessing the carcinogenicity endpoint .