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Carcinogenicity

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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:
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 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

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 .

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.