|Chronic Hazard Advisory Panel Report on Diisononyl Phthalate (DINP)
Diisononyl Phthalate (DINP) is a complex of branched C-9 isomers that is used as a
general purpose plasticizer to render polyvinyl chloride (PVC) flexible. It has a broad
range of applications in toy manufacturing, construction, and general consumer product
The Consumer Product Safety Commission convened a panel of scientific experts to
determine whether DINP in consumer products poses a chronic hazard and, if feasible,
indicate the probable harm to human health resulting from exposures to DINP. This is
the final report of that panel, the Chronic Hazard Advisory Panel (CHAP) on Diisononyl
Phthalate (DINP). On any particular issue, a range of viewpoints was held among panel
members. This document reports the majority view for each issue, which typically was
Human exposure to DINP may occur via oral, dermal, and inhalation exposure routes.
Based upon the physiochemical characteristics of DINP and limited monitoring data,
general environmental exposure to DINP in the U.S. adult population is likely to be
substantially lower than exposure to DEHP, which is estimated at 0.003-0.03 mg kg-1d-1
(milligrams per kilogram body weight per day). The most significant exposures to DINP
are likely to occur from the use of consumer items that consist of flexible plastic
plasticized using DINP. These consumer items currently include PVC toys routinely
mouthed by young children. Mouthing of DINP-containing toys may result in ingestion
exposures of 0.07 and 0.28 mg kg-1d-1 in reasonably highly exposed subsets of children
19-36 months old and 0-18 months old, respectively. Dermal uptake of DINP may also
occur through prolonged contact of DINP containing products with skin or mouth.
However, detailed data on the prevalence of DINP in consumer products that are in
sustained contact with skin, such as sandals and rainwear, are not available, and there is
fundamental uncertainty concerning the magnitude of dermal DINP uptake. Therefore,
estimation of potential dermal exposure from such products remains speculative.
DINP belongs to a class of structurally diverse chemicals called peroxisome proliferators.
These chemicals interact with a cellular receptor involved in lipid metabolism (i.e.,
peroxisome proliferator-activated receptor-α) to induce the proliferation of peroxisomes
in addition to other cellular responses. Because rodents and humans differ in responses
resulting from the activation of this receptor, a critical issue for the evaluation of rodent
toxicity studies to predict human risk is whether the receptor is involved. The non-cancer
toxicities discussed below are not believed to involve activation of this receptor.
Of the systemic effects from chronic exposure to DINP, spongiosis hepatis, a
degenerative lesion of the liver, is the most sensitive endpoint. The no observed adverse
effect levels (NOAELs) identified in laboratory animals exposed to DINP were 15
mg kg-1d-1 in one study and 88 mg kg-1d-1 in a second study
No human data were located on the reproductive or developmental toxicity associated
with DINP exposure; therefore, the evaluation of these endpoints has relied upon animal
studies. Using standard assays of prenatal oral exposure of rats to DINP, developmental
toxicity consisting of renal and skeletal abnormalities occurred with NOAELs of 100 and
200 mg kg-1d-1 in the two standard prenatal developmental studies in rats. A twogeneration study in the rat suggested an adverse effect upon pup weight gain with a
lowest observed adverse effect level (LOAEL) of 250 mg kg-1d-1. In a recently published
report of high dose exposure of rat dams to DINP during critical stages of fetal male
reproductive tract development, male reproductive tract malformations consistent with an
antiandrogenic effect were observed. Because of the large margin between doses to
pregnant women and those expected to be without effect in the animal assays, the risk to
reproductive and developmental processes in humans due to DINP exposure is extremely
low or non-existent.
Collectively, the majority of data indicate that DINP is non-genotoxic, consistent with
results obtained for other peroxisome proliferators. DINP has been tested in bacterial
mutation assays and mammalian gene mutation assays in vitro, with or without metabolic
activation, and found to be non-mutagenic. DINP has also been evaluated in both in vivo
and in vitro cytogenetic assays with results supporting the idea that DINP is not
genotoxic. Lastly, in vitro analysis of unscheduled DNA synthesis in rat hepatocytes
which are known target cells of peroxisome proliferators provided no evidence of
mutagenicity caused by DINP. Still, the peroxisome proliferation that results in rodents
from receptor activation following DINP exposure may cause gene damage by increasing
the level of hydrogen peroxide in the cell.
DINP is clearly carcinogenic to the rodent, inducing hepatocellular carcinoma in rats and
mice of both sexes, renal tubular carcinoma in male rats, and mononuclear cell leukemia
in male and female rats. Because nearly all male Fischer rats develop studies testicular
interstitial cell tumors, the technical grade DINP studies in Fischer rats provide no
information on the potential for development of these tumors. The chemical has not been
tested for carcinogenicity in young rodents, an important limitation given that infants and
toddlers are the ones most exposed to DINP. Chronic carcinogenicity studies have not
been conducted in non-rodent species. Because of the lack of confidence in the relevance
of the DINP rodent studies to humans, studies in species believed to produce results of
greater relevance are clearly needed.
Peroxisome proliferators are a structurally diverse group of non-mutagenic chemicals that
induce predictable pleiotropic responses including the development of liver tumors in rats
and mice. These nonmutagenic chemicals interact variably with peroxisome proliferatoractivated receptors (PPARs), which are members of the nuclear receptor superfamily.
Evidence derived from PPARα gene disruption indicates that of the three PPAR isotypes
(α, β/δ, and γ), the isoform PPARα is essential for the pleiotropic responses induced by
peroxisome proliferators including the development of hepatocellular carcinomas. While
the evidence is overwhelming that events downstream of PPARα activation lead to liver
cancer in rodents, the relative roles of the possible, nonexclusive, downstream
mechanisms – oxidative stress, apoptosis, and cell proliferation, with or without Kupffer
cell involvement – are unclear. DINP is classifiable as a hepatic peroxisome proliferator
and in that regard the liver tumors developing in rats and mice chronically exposed to
DINP can be mechanistically related to PPARα activation. The PPARα-mediated
mechanism of hepatocarcinogenesis is pronounced in rodents, but believed not readily
induced in humans, especially at the doses resulting from current use of consumer
products. The human risk was therefore seen as negligible or non-existent. The male rat
α2µ-globulin mechanism of action for the production of rat kidney tumors has been
postulated. Criteria for supporting an α2µ-globulin mechanism of action were applied
and found to be met. The renal tumors in male rats at the high dose of DINP were
therefore treated as rat specific and were not used to predict human risk. The
mononuclear cell leukemia (MCL) in Fischer 344 (F344) rats was viewed of
questionable significance and was not used in human risk prediction.
The available data indicate that humans do not receive DINP doses from current uses of
DINP-containing consumer products that are associated with a significant increase in
cancer risk. The most sensitive toxicity endpoint is spongiosis hepatis, observed in male
F344 rats. A Benchmark Dose (BD05) estimate of 12 mg kg-1d-1 has been calculated. The
corresponding acceptable daily intake (ADI) would be 0.120 mg kg-1d-1 based upon the
application of a 100-fold combined uncertainty/adjustment factor. Background exposures
to DINP and other phthalates could not be considered due to scientific uncertainties (see
Section XI). One of the two estimates of plausible upper-bound DINP exposure is greater
than the recommended ADI of 0.12 mg kg-1d-1. Namely, the estimate of 0.28 mg kg-1d-1
for ingested DINP among any children 0-18 months old who mouth PVC plastic toys
containing DINP for 3 hours/day exceeds the recommended ADI. This implies that there
may be a DINP risk for any young children who routinely mouth DINP-plasticized toys
for 75 minutes/day or more. For the majority of children, the exposure to DINP from
DINP containing toys would be expected to pose a minimal to non-existent risk of injury.
The exposure estimates addressed oral exposures only. Dermal exposure is expected from
products plasticized with DINP in prolonged contact with external skin or oral mucosa;
however the magnitude of this exposure is uncertain. The CHAP recommends
experiments be undertaken to reduce this important source of uncertainty in the risk
The CHAP is conveying these findings in the series of questions and answers provided
below. As noted above, the answers to the questions represent a majority view of the
CHAP and are not necessarily the view of every member of the CHAP.
1. What is the critical endpoint to use to determine the ADI?
The critical endpoint is spongiosis hepatis in male F344 rats.
2. What is the Acceptable Daily Intake (ADI) for DINP?
The ADI based on a BD05 and a 100-fold combined uncertainty/adjustment factor
would be 0.120 mg kg-1d-1.
3. Are the results of the carcinogenicity bioassays on DINP adequate and sufficient to
conclude that DINP is a rodent carcinogen?
Yes, DINP is clearly carcinogenic to the rodent, inducing hepatocellular
carcinoma in rats and mice of both sexes and mononuclear cell leukemia in male
and female rats. There is limited evidence of carcinogenicity based upon renal
tubular carcinoma in male rats.
4. Is the carcinogenicity of DINP in rodents relevant to a determination of
carcinogenicity in humans?
The hepatocarcinogenicity of DINP in rodents may be relevant to a determination
of carcinogenicity in humans. Renal tubular carcinoma does not appear to be
relevant to a determination of carcinogenicity of DINP in humans. Mononuclear
cell leukemia is of unclear relevance for a determination of carcinogenicity of
DINP in humans. See #6 for a further explanation.
5. Is DINP genotoxic?
The majority of data indicate that DINP is non-genotoxic, consistent with results
obtained from analysis of other chemicals which function similarly to cause liver
cancer in rodents through peroxisome proliferator-activated receptor-α (PPARα).
The peroxisome proliferation that results in rodents from receptor activation
following DINP exposure may cause gene damage by increasing the level of
hydrogen peroxide in the cell.
6. What is the mechanism by which DINP causes cancer in rodents and what is the
relevance of such data to a determination of human risk?
DINP appears to induce liver cancer in rodents by a PPARα-mediated mechanism
that is pronounced in rodents, but believed not readily induced in humans under
current exposure conditions involving consumer products. The human risk was
therefore seen as negligible.
DINP appears to act by an α2µ−globulin mechanism to cause renal tubular
carcinoma. The CHAP considers this to be a rodent specific mechanism and
unlikely to be relevant to a determination of human risk. Mononuclear cell
leukemia also may be a rodent-specific cancer of unclear relevance to a
determination of human risk.
7. What is the carcinogenic risk to humans from exposure to DINP in consumer
The CHAP concludes that humans do not currently receive DINP doses from
DINP-containing consumer products that are plausibly associated with a
significant increase in cancer risk.
8. Is DINP a developmental or reproductive toxicant and would the exposures from
consumer products result in developmental or reproductive risks?
Studies in rats at a high dose indicate an adverse effect on pup weight gain and
male reproductive tract malformations consistent with an antiandrogenic effect.
However, because of the large margin between doses to pregnant women and
those expected to be without effect in the animal assays, the risk to reproductive
and developmental processes in humans due to DINP exposure is extremely low
9. Is there evidence that children are more sensitive to the effects of DINP and if so how
should that be incorporated into any risk determination?
No data are available on the effect of DINP on children or immature experimental
animals, nor are there data that indicate that immature animals are more sensitive
to causes of spongiosis hepatis, the critical endpoint used by the Panel in the
DINP risk assessment.
10. How should background levels of DINP and other phthalates be incorporated into a
determination of risk?
There are no data on the interaction or additivity of dialkyl phthalate-induced
toxic effects. Even if they act through a common mechanism, DAP effects are not
necessarily additive, although the assumption of additivity for low exposure levels
is a generally accepted conservative approach to addressing this source of
uncertainty, as well as one that has theoretical support in the case that damage
occurs by statistically independent increments.
However, because of the difficulty in developing reliable estimates of phthalate
exposure for the population of interest (infants and toddlers) and uncertainties on
how exposure estimates should be combined for comparison with the ADI, further
explicit consideration of environmental background DAP exposures is not
11. What conclusions, if any, can be reached about the skin penetration of DINP as a
result of dermal contact? Should potential risks from dermal exposures be evaluated in
the same manner as those from oral exposure?
Dermal uptake of DINP may occur through prolonged contact of DINP containing
products with skin or mouth. However, detailed data on the prevalence of DINP
in consumer products that are in sustained contact with skin, such as sandals and
rainwear, are not available, and there is fundamental uncertainty concerning the
magnitude of dermal DINP uptake. Therefore, estimation of potential dermal
exposure from such products remains speculative.
12. Is the available exposure information adequate to permit the Panel to estimate the
probable harm, if any, to human health that will result from exposure to DINP from the
“reasonable and foreseeable” use of consumer products?
Estimated DINP exposures to children through toys and/or bedding/shoes/
clothing, and to adults from shoes/clothing, are preliminary at best. Recognizing
the limitations of the data, nevertheless, a prediction about the potential oral
exposure to children under the age of three to certain consumer products can be
made. Exposure information is inadequate to make predictions about dermal
13. If such an estimate were made, what methodologies were used in estimating the
magnitude of the risk and what was the rationale for adopting that methodology?
A safety factor approach was applied to a non-cancer endpoint. To induce liver
cancer, DINP acts by a PPARα mechanism that is pronounced in rodents and that
is not readily induced in humans under current exposure conditions. Thus, the
human risk from cancer was seen as insignificant.
14. What are the uncertainties attendant with determining the risk to children from
exposure to DINP in consumer products?
There are uncertainties associated both with the determination of exposure and the
determination of hazard. Those associated with exposure include:
• lack of knowledge about what portion of toys contain DINP
• lack of knowledge about what other consumer products contain DINP
• lack of knowledge about how much DINP migrates out of toys and
other consumer products
• uncertainties about how much time each day a child spends with toys
and other DINP containing objects in their mouths
• lack of knowledge about how much, if any, DINP would be dermally
The uncertainties associated with the hazard include:
• the degree to which spongiosis hepatis in rodents is relevant to humans
• how to extrapolate an effect from a lifetime exposure in rodents to a
two-to-three year exposure in young children
• lack of knowledge of effects of early in life exposures; there are no
toxicological data for exposures corresponding to infancy and toddler
• lack of knowledge of effects in non-rodents; there are no chronic
studies in non-rodent mammals
• lack of knowledge of PPARα expression and related responses in the
young; there are no data in human infants and children and scant data
in non-human species
• lack of knowledge on mechanisms by which PPARα induces rodent
15. What is the risk to children from the oral exposure to DINP?
One of the two estimates of plausible upper-bound DINP exposure listed in Table
IV-7 (Section IV) is greater than the ADI of 0.12 mg kg-1d-1 recommended above
for DINP. Namely, the estimate of 0.28 mg kg-1d-1 for ingested DINP among any
children 0-18 months old who mouth PVC plastic toys containing DINP for 3
hours/day exceeds the recommended ADI. This implies that there may be a risk
of health effects from DINP exposure for any young children who routinely
mouth DINP-plasticized toys for 75 minutes/day or more. For the majority of
children, the exposure to DINP from DINP containing toys would be expected to
pose a minimal to non-existent risk of injury. Further research addressing topics
listed above (see question #14) could reduce the uncertainty associated with this
characterization of DINP risk from consumer products....
In December 1998, the Commission staff completed an analysis, “The Risk of Chronic
Toxicity Associated with Exposure to Diisononyl Phthalate (DINP) in Children’s
Products.” As a result of this analysis and recommendations made by CPSC staff, toy
manufacturers voluntarily agreed to remove DINP from rattles and teethers and another
phthalate from pacifiers and baby bottle nipples. In addition, a number of large retail
chains agreed not to sell rattles, teethers, pacifiers, or baby bottle nipples that contained
phthalates. Staff indicated at that time that there were a number of uncertainties in the
staff’s analysis and recommended that the Commission:
• continue work to develop a laboratory test method that more accurately
estimates the amount of phthalate released when products are mouthed by
• conduct additional testing of products intended for children under 3 years of
age that contain DINP