The U.S. Environmental Protection Agency (U.S. EPA),
an authoritative body for purposes of Proposition 65 (22 CCR Section
12306(l)), identifies chemicals as causing developmental or reproductive
toxicity in implementing its Toxic Release Inventory (TRI) program
(i.e., Section 313 of the Emergency Planning and Community
Right-to-Know Act of 1986 (EPCRA)). On this basis the U.S. EPA,
in 1994, added a number of chemicals to the TRI list and published
its findings in the Federal Register (59:1788-1859, 1994 and 59:61432-61485,
1994). The Office of Environmental Health Hazard Assessment (OEHHA)
has reviewed the bases for these TRI chemical additions in the
context of the regulatory criteria governing Proposition 65 listing
via the authoritative bodies mechanism (Title 22, California Code
of Regulations, Section 12306 (22 CCR 12306)).
OEHHA determined for several TRI chemicals that
the 22 CCR 12306 regulatory criteria were met and is in the process
of placing these chemicals on the Proposition 65 list of chemicals
known to cause reproductive toxicity. OEHHA has determined that
these criteria have not been met for some of the chemicals added
by U.S. EPA in 1994 to the TRI list on the basis of reproductive
or developmental toxicity. These chemicals are listed in Table
1. In each case the scientific criteria for "as causing reproductive
toxicity" given in regulation (22 CCR 12306(g)) were not
satisfied, as described below.
In accordance with 22 CCR 12306(i), three of the
chemicals in Table 1, quizalofop-ethyl, sodium nitrite and triphenyltin
hydroxide, will be referred to the Developmental and Reproductive
Toxicant Identification Committee of the OEHHA Science Advisory
Board because this determination was made subsequent to the issuance
of a notice of intent to list (California Regulatory Notice Register
(CRNR), February 26, 1999; December 4, 1998; and January 21, 1999,
respectively). Therefore, at a future meeting, the Committee will
opine whether "the chemical has been clearly shown through
scientifically valid testing according to generally accepted principles"
to cause reproductive toxicity. A CRNR notice for one other chemical
in Table 1 (naled (November 20, 1998)) announced that the regulatory
criteria for listing may have been met. However, because a notice
of intent to list was not issued, this chemical will not be referred
to the Committee for its review.
Table 1: TRI chemicals not meeting the scientific
criteria (22 CCR 12306(g)) for authoritative bodies listing as
causing reproductive toxicity under Proposition 65
Quizalofop-ethyl (076578-14-8)
Sodium Nitrite (007632-00-0)
Triphenyltin hydroxide
(000076-87-9)
Anilazine (CAS No. 000101-05-3)
U.S. EPA (Federal Register 59(8):1798, 1994) bases
its finding of developmental toxicity on one rat and one rabbit
developmental study. The citation for both is the 1993 'Tox-Oneliner'
database, which is no longer available. The 1997 Tox-Oneliner
for anilazine describes the results of three developmental toxicity
studies, two in rats and one in rabbits. One of the rat studies
appears to correspond to the rat study described in the 1993 Tox-Oneliner,
in which no effects were identified even at the highest dose tested.
Both the second rat study and the rabbit study have notations
stating, "Study is missing so much information, no conclusions
will be drawn."
Naled (CAS No. 000300-76-5)
The U.S. EPA based its finding of female reproductive
toxicity on a two-generation reproduction study of naled in rats
in which decreased litter size, survival, and pup body weight
were observed in the higher dose group. The only effect associated
with pre-natal exposures was a statistically significant decreased
litter size at birth in the F2b litter. However, 13% of the male
and female F1 parents of this litter, died of toxicity-related
causes. This level of parental toxicity is considered "excessive"
under the U.S. EPA Guidelines for Developmental Toxicity Risk
Assessment (Federal Register 56(234): 63798-63826, 1991). Due
to the excessive maternal toxicity, this study is of limited usefulness
for judging the impact of naled on litter size. With respect to
postnatal findings, statistically significant decreased postnatal
pup survival was observed in the F1 and F2b litters, and statistically
significant decreased postnatal weight was observed in the F1
litter. However, all of these followed postnatal exposure of the
lactating dams to the chemical. Under the U.S. EPA Guidelines
for Developmental Toxicity Risk Assessment, the definition of
developmental toxicity includes effects resulting from exposure
during the postnatal developmental period, while under the current
interpretation, the Proposition 65 statute precludes listing on
the basis of developmental effects resulting from postnatal exposures.
Quizalofop-ethyl (CAS
No. 076578-14-8)
Addition of quizalofop-ethyl to the TRI list on
the basis of reproductive toxicity relied upon a single six month
feeding study in beagle dogs (Subchronic Toxicity Study in Dogs
with NC-302 by Oral Administration for 26 Weeks. Nippon Experimental
Medical Research Institute, 1982). Histopathological examination
of testicular tissue at the end of the study revealed atrophy
of seminiferous tubules in two of six male dogs in the highest
dose group tested. This change was described as not so severe
as to cause disturbance in spermatogenesis, and was not statistically
significant by pair-wise comparison with the control group. No
adverse effects in testes of control, lowdose or middose males
were reported. A second study in beagle dogs exposed to the same
dose by the same route, but for a duration of one year, failed
to find any adverse testicular effects upon histopathological
examination (NC-302: 52 Week Oral (Dietary Administration) Toxicity
Study in the Beagle Dog. Nissan Chemical Industries, 1985). The
small number of animals exhibiting the effect and the minimal
severity of the effect in the first study, and the failure to
replicate the effect with a longer exposure to the same dose level
suggests that the original finding may not be treatment related.
Sodium Nitrite (CAS
No. 007632-00-0)
U.S. EPA (Federal Register 59:1788-1859, 1994) added
sodium nitrite to the TRI list of reported chemicals on the basis
of the following information:
"230. Sodium nitrite (CAS No. 007632-00-0)
(CERCLA) (Ref. 8). Sodium nitrite causes conversion (oxidation)
of hemoglobin to methemoglobin. Methemoglobin cannot combine reversibly
with oxygen and its formation can cause anemic hypoxia which may
lead to intense cyanosis. Infants are particularly susceptible to
this effect because of their higher stomach pH, immature enzyme
systems, the reduced capacity of newborn erythrocytes to reduce
methemoglobin to hemoglobin, and the increased rate of nitrite-induced
oxidation of fetal hemoglobin to methemoglobin (approximately twice
the rate of adult hemoglobin oxidation). Coma and methemoglobinemia/
carboxyhemoglobinemia were reported in a human that received sodium
nitrite (71 mg/kg) orally. In animal studies, methemoglobinemia
was reported in dogs that received an intravenous dose of 30 mg/kg
sodium nitrite and in rats administered a 10 mg/kg dose of sodium
nitrite subcutaneously." "Fetotoxicity (fetal death) was
reported following oral exposure of pregnant rats to sodium nitrite
(30 mg/kg/day) during gestation days 1 through 22. In mice exposed
orally to 80 mg/kg/day during gestation days 6 to 15 there
was increased preimplantation loss and fetal death, and in mice
exposed to a lower dose (20 mg/kg/day) during gestation days
1 to 14, abnormalities of the blood or lymphatic system were reported
in offspring. In offspring of rats orally exposed to 26 to 256 mg/kg/day
during pregnancy (gestation days 1 through 22) and/or during lactation
(20 to 21 days after birth), effects on growth including biochemical
and/or metabolic changes were noted."
Neonatal methemoglobinemia is a serious, life-threatening,
and well-documented toxic consequence of nitrite exposure. It
is also a toxic endpoint which is encompassed by U.S. EPA's
definition of developmental toxicity as:
"…adverse effects on the developing organism
that may result from exposure prior to conception (either parent),
during prenatal development, or postnatally to the time of sexual
maturation."
However, as currently interpreted the Proposition
65 statute precludes listing on the basis of developmental effects
resulting solely from postnatal exposures. Therefore, in determining
whether the criteria specified in 22 CCR 12306(g) have been met,
only data that pertain to prenatal exposures are considered. Thus,
methemoglobinemia in exposed human neonates resulting from postnatal
exposures do not provide a basis for listing a chemical as causing
reproductive toxicity under Proposition 65.
The four animal studies cited by U.S. EPA in which
exposures occurred that were entirely prenatal all provide some
indication of a potential hazard posed by sodium nitrite to the
developing organism. These four studies were conducted by various
protocols, focused on diverse endpoints, and do not support each
other in identifying a particular target of sodium nitrite toxicity.
Three of the studies cited have limitations in design and reporting
such that they contribute little to hazard identification. In
a developmental toxicity study in rats (Schuval and Gruener, Am
J Pub Hlth, 62(8):1045-1052, 1972.), the only developmental effect
mentioned in the study report was, "[t]he litters in the
control group contained 10 fetuses, 9.5 in Group I and 8.5 fetuses
in Group II." Statistical analyses were not provided and
the statistical significance of the result was not reported. In
a developmental toxicity study in mice (Globus and Samuel, Teratology
118:367-378, 1978), using a single experimental dose (0.5 mg/kg/day),
erythropoiesis was evaluated as numbers of either hepatic erythrocytes
or all fetal hepatic red blood cells as a percent of total hepatic
blood cells. The percentages of these cells were significantly
increased in day 14 and 16 embryos, but not day 18 embryos. These
effects could not be correlated with any actual increase in peripheral
RBC counts, hence the functional significance of the observed
changes is unclear. In another developmental toxicity study in
rats (Roth et al., Fund Appl Toxicol 9:668-677, 1987), the text
makes statements pertaining to the cross-fostering portion of
the study which appear to indicate some effect of prenatal exposure
on early pup growth. The statements are not supported by tabular
or graphical presentation of actual data.
In evaluating the remaining study (Shiobara, Nichi
Eishi 42(2):836-846, 1987.), published in Japanese, OEHHA initially
relied on the English summary and tables, which reported reduced
litter size. Subsequently, detailed review of a full translation
of the text of the study paper, casts significant doubt over the
conclusions that can be drawn from the study. The reported findings
of decreased litter size among treated animals may not be the
result of treatment. Since treatment began on day six of gestation,
the same day implantation occurs, and since there was a significant
increase in pre-implantation loss, the change in litter size may
be an artifact of this non-treatment-related variation in implantation
frequency. Thus, the body of evidence related to prenatal exposures
cited by U.S. EPA is not of sufficient quantity to satisfy the
regulatory criteria for listing under the authoritative bodies
provision (i.e., 22 CCR 12306(g)).
Triphenyltin hydroxide
(CAS No. 000076-87-9)
A single study of developmental toxicity in rats
formed the basis for TRI identification of triphenyltin hydroxide
(Winek et al., Toxicol. Annu. 3:281-96, 1979). Three experimental
groups of six timed mated females per group received the chemical
orally on days 1-7, 8-14 and 14-18 of gestation, respectively.
There were two control animals per treatment group. Maternal mortality
in the second and third groups (17% and 33%, respectively) exceeded
the U.S. EPA definition of minimal maternal toxicity. The first
treatment group, which had no maternal mortality, showed a complete
failure of pregnancy, with no fetuses or resorption sites, and
no endometrial proliferation or increased vascularity. These effects
are indicative of female reproductive toxicity rather than developmental
toxicity, the endpoint identified by U.S. EPA.
For questions regarding Proposition 65, please contact the Cynthia
Oshita in the Proposition 65 Implementation Program
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