Screening-level Hazard Characterization of High Production Volume Chemicals Sponsored Chemical 1,2-bis(3,5-di-tert-butyl-4-hydroxyhydrocinnamoyl)hydrazine (irganox Md 1024, Cas No. 32687-78-8) [9th Ci Name: Benzenepropanoic Acid, 3,5-bis(1,1-dimethylethyl)-4-hydroxy-,-[3-[3,5-bis(1,1-dimethylethyl)-4-hydroxyphenyl]-1-oxopropyl]hydrazide]


SCREENING-LEVEL HAZARD CHARACTERIZATION
OF HIGH PRODUCTION VOLUME CHEMICALS
SPONSORED CHEMICAL
l,2-bis(3,5-di-tert-butyl-4-hydroxyhydrocinnamoyl)hydrazine
(IRGANOX MD 1024, CAS No. 32687-78-8)
CI Name: Benzenepropanoic acid, 3,5-bis(l,l-dimethylethyl)-4-hydroxy-,-[3-[3,5-
bis(l,l-dimethylethyl)-4-hydroxyphenyl]-l-oxopropyl]hydrazide]
March 2008
INTERIM
Prepared by
High Production Volume Chemicals Branch
Risk Assessment Division
Office of Pollution Prevention and Toxics
Environmental Protection Agency
1200 Pennsylvania Avenue, NW
Washington, DC 20460-0001

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SCREENING-LEVEL HAZARD CHARACTERIZATION
OF HIGH PRODUCTION VOLUME CHEMICALS
The High Production Volume (HPV) Challenge Program1 is a voluntary initiative aimed at developing and making
publicly available screening-level health and environmental effects information on chemicals manufactured in or
imported into the United States in quantities greater than one million pounds per year. In the Challenge Program,
producers and importers of HPV chemicals voluntarily sponsor chemicals; sponsorship entails the identification and
initial assessment of the adequacy of existing toxicity data/information, conducting new testing if adequate data do
not exist, and making both new and existing data and information available to the public. Each complete data
submission contains data on 18 internationally agreed to "SIDS" (Screening Information Data Set'2) endpoints that
are screening-level indicators of potential hazards (toxicity) for humans or the environment.
The Environmental Protection Agency's Office of Pollution Prevention and Toxics (OPPT) is evaluating the data
submitted in the HPV Challenge Program on approximately 1400 sponsored chemicals. OPPT is using a hazard-
based screening process to prioritize review of the submissions. The hazard-based screening process consists of two
tiers described below briefly and in more detail on the Hazard Characterization website3.
Tier 1 is a computerized sorting process whereby key elements of a submitted data set are compared to established
criteria to "bin" chemicals/categories for OPPT review. This is an automated process performed on the data as
submitted by the sponsor. It does not include evaluation of the quality or completeness of the data.
In Tier 2, a screening-level hazard characterization is developed by EPA that consists of an objective evaluation of
the quality and completeness of the data set provided in the Challenge Program submissions. The evaluation is
performed according to established EPA guidance4 and is based primarily on hazard data provided by sponsors.
EPA may also include additional or updated hazard information of which EPA, sponsors or other parties have
become aware. The hazard characterization may also identify data gaps that will become the basis for a subsequent
data needs assessment where deemed necessary. Under the HPV Challenge Program, chemicals that have similar
chemical structures, properties and biological activities may be grouped together and their data shared across the
resulting category. This approach often significantly reduces the need for conducting tests for all endpoints for all
category members. As part of Tier 2, evaluation of chemical category rationale and composition and data
extrapolation(s) among category members is performed in accord with established EPA and OECD5 guidance.
The screening-level hazard characterizations that emerge from Tier 2 are important contributors to OPPT's existing
chemicals review process. These hazard characterizations are technical documents intended to support subsequent
decisions and actions by OPPT. Accordingly, the documents are not written with the goal of informing the general
public. However, they do provide a vehicle for public access to a concise assessment of the raw technical data on
HPV chemicals and provide information previously not readily available to the public. The public, including
sponsors, may offer comments on the hazard characterization documents.
The screening-level hazard characterizations, as the name indicates, do not evaluate the potential risks of a chemical
or a chemical category, but will serve as a starting point for such reviews. In 2007, EPA received data on uses of
and exposures to high-volume TSCA existing chemicals, submitted in accordance with the requirements of the
Inventory Update Reporting (IUR) rule. For the chemicals in the HPV Challenge Program, EPA will review the
IUR data to evaluate exposure potential. The resulting exposure information will then be combined with the
screening-level hazard characterizations to develop screening-level risk characterizations4'6. The screening-level
risk characterizations will inform EPA on the need for further work on individual chemicals or categories. Efforts
are currently underway to consider how best to utilize these screening-level risk characterizations as part of a risk-
based decision-making process on HPV chemicals which applies the results of the successful U.S. High Production
Volume Challenge Program and the IUR to support judgments concerning the need, if any, for further action.
1 U.S. EPA. High Production Volume (HPV) Challenge Program; http://www.epa.gov/chemrtk/index.htm.
2 U.S. EPA. HPV Challenge Program - Information Sources; http://www.epa.gov/chemrtk/pubs/general/guidocs.htm.
3 U.S. EPA. HPV Chemicals Hazard Characterization website (http://www.epa.gov/hpvis/abouthc.html).
4 U.S. EPA. Risk Assessment Guidelines; http://cfpub.epa.gov/ncea/raf/rafguid.cfm.
5 OECD. Guidance on the Development and Use of Chemical Categories; http://www.oecd.org/dataoecd/60/47/1947509.pdf.
6 U.S. EPA. Risk Characterization Program; http://www.epa.gov/osa/spc/2riskchr.htm.
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SCREENING-LEVEL HAZARD CHARACTERIZATION
IRGANOX MD 1024 (CAS No. 32687-78-8)
Introduction
The sponsor, Ciba Specialty Chemicals Corporation, submitted a Test Plan and Robust Summaries to EPA for
IRGANOX MD 1024 [l,2-bis(3,5-di-tert-butyl-4-hydroxyhydrocinnamoyl)hydrazine] (CAS No. 32687-78-8;
9th CI name: Benzenepropanoic acid, 3,5-bis(l,l-dimethylethyl)-4-hydroxy-,-[3-[3,5-bis(l,l-dimethylethyl)-4-
hydroxyphenyl]-l-oxopropyl]hydrazide) on December 12, 2003. EPA posted the submission on the ChemRTK
HPV Challenge website on January 14, 2004
(http://www.epa.gov/chemrtk/pubs/summaries/irganox/cl4894tc.htm). EPA comments on the original
submission were posted to the website on June 2, 2004. Public comments were also received and posted to the
website.
This screening-level hazard characterization is based primarily on the review of the test plan and robust summaries
of studies submitted by the sponsor(s) under the HPV Challenge Program. In preparing the hazard characterization
EPA considered its own comments and public comments on the original submission as well as the sponsor's
responses to comments and revisions made to the submission. A summary table of SIDS endpoint data with the
structure(s) of the sponsored chemical(s) is included in the appendix. The screening-level hazard characterization
for enviromnental and human health toxicity is based largely on SIDS endpoints and is described according to
established EPA or OECD effect level definitions and hazard assessment practices.
Summary - Conclusion
The estimated log Kow of IRGANOX MD 1024 indicates that its potential to bioaccumulate is expected to be high.
IRGANOX MD 1024 is not readily biodegradable, indicating that it has the potential to persist in the enviromnent.
The evaluation of available toxicity data for fish, aquatic invertebrates and aquatic plants indicates the potential
acute hazard of IRGANOX MD 1024 to aquatic organisms is low. The aquatic toxicity data submitted were
difficult to interpret because they were generated in the presence of solvent(s), the concentration of chemical in the
test water was not measured and effects concentrations reported were above the chemical's water solubility limit.
The data were judged unreliable, but EPA could conclude qualitatively that there were no effects observed at
saturation. While the acute testing did not show toxicity in aquatic organisms, the measured water solubility of
IRGANOX MD 1024 indicates it is soluble or miscible in water at concentrations that could cause chronic effects.
Therefore, EPA continues to recommend chronic aquatic toxicity testing for IRGANOX MD 1024.
Acute oral and inhalation toxicity of IRGANOX MD 1024 in rats is low. IRGANOX MD 1024 is minimally
irritating to rabbits' skin and moderately irritating to rabbits' eyes. IRGANOX MD 1024 is not a human skin
sensitizer. Following repeated oral exposures of rats for 3 months, the liver was the target organ for toxicity in
males. Reduced mean liver weight was observed and corresponded histopathologically to inflammatory cell
infiltration. A decrease in testes weights in high-dose males could not be correlated histopathologically. In females,
changes in clinical chemistry at high doses did not correlate with histopathological changes. The examination of the
male and female reproductive organs from the repeated-dose toxicity test was unremarkable. In a developmental
toxicity study in rats, no treatment-related effects were observed. IRGANOX MD 1024 did not induce gene
mutation in bacteria or micronuclei in an in vivo test.
The potential health hazard of IRGANOX MD 1024 is low.
Chronic invertebrate toxicity and remains a data gap under the HPV Challenge Program. Subsequent consideration
of fate and exposure information will inform a determination of the need to obtain chronic aquatic toxicity data.
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1. Physical - Chemical Properties and Environmental Fate
A summary of physical-chemical properties and environmental fate data submitted is provided in the Appendix. For
the purpose of the screening-level hazard characterization, the review and summary of these data was limited to the
octanol-water partition coefficient and biodegradation endpoints as indictors of bioaccumulation and persistence,
respectively.
Octanol-Water Partition Coefficient
Log Kow: 7.79 (estimated)
Biodegradation
In the modified Sturm method using activated sludge as inoculum, 1% IRGANOX MD 1024 degraded after 28 days.
IRGANOX MD 1024 is not readily biodegradable.
Conclusion: The estimated log Kow of IRGANOX MD 1024 indicates that its potential to bioaccumulate is
expected to be high. IRGANOX MD 1024 is not readily biodegradable, indicating that it has the potential to persist
in the environment.
2. Environmental Effects - Aquatic Toxicity
Acute Toxicity to Fish
Rainbow trout (Salmo gairdneri), Carp (Cyprinus carpio), Catfish (Ictalurus melas), Bluegill (Lepomis
macrochirus) and Golden orfe (Leuciscus idus melanotus) were exposed to IRGANOX MD 1024, dissolved in
acetone, at nominal concentrations of 0, 37, 49, 65 and 100 mg/L under static conditions for 96 hours. There were
no mortalities and the sponsor reported a 96-h LC50 of > 100 mg/L. The substance was tested above its water
solubility limit, in the presence of solvent and no analytical measurements were made on the test water. Therefore,
EPA considers the no effect concentration to be the water solubility limit (saturation), which for IRGANOX MD
1024 would be approximately 2.8 x 10"4 (estimated) to < 1 mg/L (measured) mg/L.
No effects at saturation
Acute Toxicity to Aquatic Invertebrates
Daphnia magna were exposed to IRGANOX MD 1024 at nominal concentrations of 1.0, 1.8, 3.2, 5.8, 10, 18, 32, 58
and 100 mg/L under static conditions for 24 hours. A 24-hour EC50 of 15 mg/L was reported. The substance was
tested above its water solubility limit and no analytical measurements were made on the test water. Therefore, EPA
considers the no effect concentration to be the water solubility limit (saturation), which for IRGANOX MD 1024
would be approximately 2.8 x 10"4 (estimated) to < 1 mg/L (measured) mg/L.
No effects at saturation
Toxicity to Aquatic Plants
Green algae (Scenedesmus subspicatus) were exposed to IRGANOX MD 1024, dissolved in Tween 80, at nominal
concentrations of 1.23, 3.7, 11.33 and 100 mg/L for 72 hours under static conditions. A 72-hour EC50 of 19.8 mg/L
was reported. The substance was tested above its water solubility limit, in the presence of solvent and no analytical
measurements were made on the test water. Therefore, EPA considers the no effect concentration to be the water
solubility limit (saturation), which for IRGANOX MD 1024 would be approximately 2.8 x 10"4 (estimated) to < 1
mg/L (measured) mg/L.
No effects at saturation
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Chronic Toxicity to Aquatic Organisms
In comments on the original test plan, EPA recognized the inadequacies in the acute toxicity tests submitted and
recommended, based on the physical-chemical properties of IRGANOX MD 1024 recommended a chronic daphnid
toxicity tests be conducted.
Conclusion: The evaluation of available toxicity data for fish, aquatic invertebrates and aquatic plants indicates the
potential acute hazard of IRGANOX MD 1024 to aquatic organisms is low. The aquatic toxicity data submitted
were difficult to interpret because they were generated in the presence of solvent(s), the concentration of chemical in
the test water was not measured and effects concentrations reported were above the chemical's water solubility limit.
The data were judged unreliable, but EPA could conclude qualitatively that there were no effects observed at
saturation. While the acute testing did not show toxicity in aquatic organisms, the measured water solubility of
IRGANOX MD 1024 indicates it is soluble or miscible in water at concentrations that could cause chronic effects.
Therefore, EPA continues to recommend chronic aquatic toxicity testing for IRGANOX MD 1024.
Chronic invertebrate toxicity remains a data gaps under the HPV Challenge Program. Subsequent consideration of
fate and exposure information will inform a determination of the need to obtain chronic aquatic toxicity data.
3. Human Health Effects
Acute Oral Toxicity
(1) Tif:RAIF (SPF) rats (5/dose, no information on sex) were administered IRGANOX MD 1024 suspended in
polyethylene glycol (PEG 400) via gavage at doses of 4000, 5000, 6000 and 7000 mg/kg-bw. Clinical signs of
toxicity included sedation, dyspnea, curved position and ruffled fur. Surviving animals appeared normal by 8 days
after dosing.
LD50 > 7000 mg/kg-bw
(2) Chinese hamsters (5/sex/dose) were administered IRGANOX MD 1024 via gavage at 5000 mg/kg-bw (other
higher doses were not listed in the robust summary). Clinical signs of toxicity included sedation, dyspnea, curved
position and ruffled fur. No substance-related gross organ changes were noted. Mortality was 20% in the higher
dose group.
LD50 > 5000 mg/kg-bw
(3) Mice (5/sex/dose) and rats (5/sex/dose) were administered IRGANOX MD 1024 via gavage at 2500 and 5000
mg/kg-bw in a 20% gum arabic suspension. They were observed for 8 days. No mortality was observed.
LD50 > 5000 mg/kg-bw
Acute Inhalation Toxicity
(1) Albino rats (5/sex/dose) were exposed to IRGANOX MD 1024 fumes and vapor at an average concentration of
110 mg/m3 (approximately 0.11 mg/L), for 4 hours and were observed for 14 days. No clinical signs of toxicity
were observed. Necropsy revealed moderate lung hyperemia in five rats. No gross pathologic alterations were
observed in any of the other tissues and organs examined.
LC50 > ~ 0.11 mg/L
(2) Albino rats (5/sex/dose) were exposed to IRGANOX MD 1024 dust at an average concentration of 0.27 mg/L for
4 hours and were observed for 14 days after exposure. No mortality, changes in behavior or adverse effects on body
weight were observed. Necropsy revealed slight lung hyperemia. No gross pathologic alterations were observed in
any of the other tissues and organs examined.
LCS0 > 0.27 mg/L
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Repeated-Dose Toxicity
(1)	RAIF rats (10/sex/dose) were administered IRGANOX MD 1024 in the diet at concentrations of 0, 1000, 3000
and 10,000 ppm (approximately 1013 and 936 mg/kg-bw/day, for males and females, respectively—summary
included only these values) for 28 days. No abnormalities in weight gain and food consumption in comparison to
control groups were observed. No mortality or clinical signs of local and/or systemic toxicity were observed.
Macroscopic examination was unremarkable.
NOAEL ~1000 mg/kg-bw/day (based on no effects at highest dose tested)
(2)	Tif:RAIF (SPF) rats (20/sex/dose) were administered IRGANOX MD 1024 in the diet at concentrations of 0,
400, 2000 and 10,000 ppm (0, 25, 123 and 624 mg/kg-bw/day in males and 0, 27, 127 and 667 mg/kg-bw/day in
females) for 3 months. Body weight gain and food consumption were comparable to controls. No mortalities,
clinical symptoms and signs of local and/or systemic toxicity were observed. Ophthalmic and hearing examinations
were unremarkable. The only macroscopic and microscopic changes observed in histopathology related to
inflammatory cell infiltration in the liver of males (> 2000 ppm). At the highest dose tested (10,000 ppm), the
following were observed: decreased mean testes weight correlating to decreased body weight, decrease in total
protein concentration and albumin concentration in females. There was a statistically significant decrease (p<0.05)
in absolute and relative liver and gonad weights and increase in absolute kidney weight in the 10,000 ppm males. A
statistically significant decrease in the relative liver, gonad and heart weights was also seen at 2000 ppm males.
LOAEL (male) ~ 123 mg/kg-bw/day (based on changes in organ weights and liver histopathology)
NOAEL (male) ~ 25 mg/kg-bw/day
LOAEL (female) ~ 667 mg/kg-bw/day (based on changes in clinical chemistry)
NOAEL (female) ~ 127 mg/kg-bw/day
(3)	Wistar-CF, multipurpose strain rats (12/sex) were administered IRGANOX MD 1024 via diet at 0 and 500 ppm
(~ 0 and 25 mg/kg-bw/day) for 28 days. Control animals showed signs of infection (round cell infiltrations and
granulomas in the liver and kidneys); however, histopathological changes in the organ were not observed. In the
treated-animals, no changes were seen in the liver (males), spleen or kidneys. The relative liver weights of the
treated females were higher than that for the controls, without correlated histopathological findings.
NOAEL ~ 25 mg/kg-bw/day (based on no treatment-related effects at the only dose tested)
(4)	Rats (5/sex/dose) were applied 0.4 mL (-0.04 mg/kg-bw/day)IRGANOX MD 1024 suspended in 5% gum
arabic, to the dorsal skin, once a day for six consecutive days for 4 weeks and were observed for 29 days. The
application was wiped off with a moist sponge on each day after 3 hours. No irritation or treatment-related effects
were observed.
Reproductive Toxicity
A reproductive toxicity test was not submitted. Evaluation of reproductive organs from the 90-day repeated-dose
toxicity study and availability of a developmental toxicity study address the reproductive toxicity endpoint for the
purposes of the HPV Challenge Program.
In the 90-day repeated-dose study with rats described previously, the reproductive organs were examined grossly
and microscopically. At the highest dose tested, there was a significant (p < 0.05) decrease in the mean testes
weight which correlated with a slight decrease in body weight. No histopathological changes in either the male or
female gonads were observed.
Developmental Toxicity
Pregnant Sprague-Dawley rats (24 animals/dose) were exposed to IRGANOX MD 1024 via gavage at doses of 0,
500, 1500 and 3000 mg/kg-bw/day on days 6 - 15 of gestation. Body weight gain and food consumption of dams
were comparable to controls. Implantation rates, embryo lethality and/or resorption and male to female ratios were
comparable for all groups. Fusion of placentas, implantation sites consisting of embryonic resorption and a poorly
developed male fetus was noted for one female at 500 mg/kg-bw/day. The gross inspection of live fetuses revealed
one fetus with omphalocele at the low dose. Skeletal assessment revealed instances of irregular sternebral
ossification in the treatment groups and in the vehicle control. Abnormal wide suture was found in one fetus at the
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high dose. The incidence of delayed ossification of the phalangeal nuclei of the hind-limbs was increased in high-
dose males compared to controls, but was not considered to be toxicologically significant in the absence of other
clinical signs of toxicity at the dose tested.
NOAEL (maternal toxicity) = 3000 mg/kg-bw/day (based on no adverse effects at the highest dose tested)
NOAEL (developmental toxicity) = 3000 mg/kg-bw/day (based on no adverse effects at the highest dose tested)
Genetic Toxicity - Gene Mutation
In vitro
(1) Salmonella strains TA98, TA100, TA1535, TA1537, TA1538 were exposed to IRGANOX MD 1024 at
concentrations of 25, 75, 225, 675 and 2025 |ig/0.1 ml with and without metabolic activation. Cytotoxicity was not
evident at any of the concentrations tested. Positive and solvent controls were included in the assay and gave the
expected response. Precipitation was observed at concentrations of 675 p.g/0.1 ml and greater.
IRGANOX MD 1024 was not mutagenic in this assay.
Genetic Toxicity - Chromosomal Aberration
In vivo
Chinese hamsters (6/sex/dose) were administered IRGANOX MD 1024 via gavage at doses of 0, 1250, 2500 or
5000 mg/kg-bw/day once per day for 2 days. Cyclophosphamide was used as the positive control and arachnid oil
was the negative control. The positive control responded as expected. IRGANOX MD 1024 treatment did not
increase the percent of cells with the number of micronuclei or anomalies of nuclei.
IRGANOX MD 1024 did not induce micronuclei in this assay.
Additional Information
Skin Irritation
(1) New Zealand white rabbits were dermally administered 0.5 mL IRGANOX MD 1024 on abraded and intact skin
at two sites on the back of the animals under occluded conditions for 24 hours. After 24 hours, the wrapping was
removed and the application sites were examined and scored for erythema and edema. Observations of the
application sites were made at 72 hours also.
IRGANOX MD 1024 was minimally irritating to rabbit skin in this assay.
(2) In the sensitization study with human volunteers, described below, primary irritation was not observed.
IRGANOX MD 1024 is not irritating to human skin in this assay.
Eye Irritation
Albino rabbits (9) were instilled 100 mg undiluted IRGANOX MD 1024 in the right eye. The left eye served as the
control. The eyes of three of the rabbits were rinsed with tap water after a 2-second contact period. The eyes of
three other rabbits were rinsed with tap water after a 4-second contact period. The eyes of the remaining three
rabbits were not washed. The cornea, iris and palpebral conjunctiva were examined at 1, 24, 48, 72 and 96 hours,
and 7 days following exposure. Transient iridal and conjunctival irritation were noted in all animals within an hour
of instillation of the test material. Within 48-72 hours, the ocular tissues of all animals had returned to normal. The
test material was minimally irritating to washed eyes and moderately irritating to unwashed eyes.
IRGANOX MD 1024 was moderately irritating to rabbit eyes in this assay.
Skin Sensitization
(1) In a repeated insult patch test to the skin, 59 human volunteers were dermally applied with 0.1 mL IRGANOX
MD 1024 in 0.3% dimethylphthalate, under occluded conditions to a pre-designated site on the upper arm of each
subject. After 24 hours, the patches were removed and the contact sites were examined. The contact sites were left
untreated and uncovered for a 'rest' period of 24 hours. After the rest period, they were re-examined. If no
irritation was observed, the test material was re-applied to the same site. If irritation was observed, a new
application site was chosen. This procedure was repeated for one week, after which the volunteers were challenged
with the test material to the original contact sites after 14 days. No visible skin changes consistent with criteria
deemed characteristic of a primary irritant, fatiguing agent or sensitizer were observed for any of the volunteers.
IRGANOX MD 1024 is not a skin sensitizer.
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(2) In another repeated insult patch test to the skin, 50 human volunteers were treated with neat IRGANOX MD
1024 for the first application, 10 % in corn oil for applications 2 and 3, and 1% in corn oil thereafter. After 24
hours, the patches were removed and the contact sites were examined. The contact sites were left untreated and
uncovered for a 'rest' period of 24 hours. After the rest period, they were re-examined. This procedure was
repeated 2 times, after which the test material was applied without rest another 6 times. The volunteers were
challenged with the test material to a different skin contact site after 15 days without a patch. The observations were
made at 24, 48 and 72 hours following application to detect immediate and delayed sensitization reactions. No
sensitization was observed for any of the volunteers.
IRGANOX MD 1024 is not a skin sensitizer.
Conclusion: Acute oral and inhalation toxicity of IRGANOX MD 1024 in rats is low. IRGANOX MD 1024 is
minimally irritating to rabbits' skin and moderately irritating to rabbits' eyes. IRGANOX MD 1024 is not a human
skin sensitizer. Following repeated oral exposures of rats for 3 months, the liver was the target organ for toxicity in
males. Reduced mean liver weight was observed and corresponded histopathologically to inflammatory cell
infiltration. A decrease in testes weights in high-dose males could not be correlated histopathologically. In females,
changes in clinical chemistry at high doses did not correlate with histopathological changes. The examination of the
male and female reproductive organs from the repeated-dose toxicity test was unremarkable. In a developmental
toxicity study in rats, no treatment-related effects were observed. IRGANOX MD 1024 did not induce gene
mutation in bacteria or micronuclei in an in vivo test.
The potential health hazard of IRGANOX MD 1024 is low.
4. Hazard Characterization
The estimated log Kow of IRGANOX MD 1024 indicates that its potential to bioaccumulate is expected to be high.
IRGANOX MD 1024 is not readily biodegradable, indicating that it has the potential to persist in the environment.
The evaluation of available toxicity data for fish, aquatic invertebrates and aquatic plants indicates the potential
acute hazard of IRGANOX MD 1024 to aquatic organisms is low. The aquatic toxicity data submitted were
difficult to interpret because they were generated in the presence of solvent(s), the concentration of chemical in the
test water was not measured and effects concentrations reported were above the chemical's water solubility limit.
The data were judged unreliable, but EPA could conclude qualitatively that there were no effects observed at
saturation. While the acute testing did not show toxicity in aquatic organisms, the measured water solubility of
IRGANOX MD 1024 indicates it is soluble or miscible in water at concentrations that could cause chronic effects.
Therefore, EPA continues to recommend chronic aquatic toxicity testing for IRGANOX MD 1024.
Acute oral and inhalation toxicity of IRGANOX MD 1024 in rats is low. IRGANOX MD 1024 is minimally
irritating to rabbits' skin and moderately irritating to rabbits' eyes. IRGANOX MD 1024 is not a human skin
sensitizer. Following repeated oral exposures of rats for 3 months, the liver was the target organ for toxicity in
males. Reduced mean liver weight was observed and corresponded histopathologically to inflammatory cell
infiltration. A decrease in testes weights in high-dose males could not be correlated histopathologically. In females,
changes in clinical chemistry at high doses did not correlate with histopathological changes. The examination of the
male and female reproductive organs from the repeated-dose toxicity test was unremarkable. In a developmental
toxicity study in rats, no treatment-related effects were observed. IRGANOX MD 1024 did not induce gene
mutation in bacteria or micronuclei in an in vivo test.
The potential health hazard of IRGANOX MD 1024 is low.
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5. Data Gaps
Chronic invertebrate toxicity and remains a data gap under the HPV Challenge Program. Subsequent consideration
of fate and exposure information will inform a determination of the need to obtain chronic aquatic toxicity data.
9

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APPENDIX
Summary Tabic of the Screening Information Data Set
as Submitted under the U.S. HPV Challenge Program
Endpoints
SPONSORED CHEMICAL

IRGANOX MD 1024

(32687-78-8)
Structure
hvch-

HO~vT>y NH-NH
HjC / / °
>CH <

Hjfc CHs \
C H 3 . /
hc-hp>
ch" /—\ ™
h° X'
H,c Jh,
Summary of Physical-Chemical Properties and Environmental Fate Data
Melting Point (°C)
227-232
Boiling Point (°C)
741.68
Vapor Pressure (hPa at 25°C)
1.385 x 10"20
Log K„w
7.79
Water Solubility (mg/L at 25°C)
< 1 at 20°C
Direct Photodegradation
—
Indirect (OH )Photodegradation Half-Life (t1/2)
2.3 hours
Stability in Water (Hydrolysis) Half-Life (ti/2)
> 1 year
Biodegradation
1
% after 28 days
Not readily biodegradable
Fugacity

(Level III Model)

Air (%)
0.027
Water (%)
1.23
Soil (%)
35.6
Sediment (%)
63.2
Summary of Environmental Effects - Aquatic Toxicity Data
Fish

96-hr LCS0 (mg/L)
NES
Aquatic Invertebrates

48-hr EC50 (mg/L)
NES
Aquatic Plants

96-hr ECso (mg/L)
NES
Chronic Aquatic Toxicity
Data Gap
— indicates endpoint was not addressed for this chemical; NES = no effects at saturation (solubility limit).
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Summary Tabic of the Screening Information Data Set
as Submitted under the U.S. HPV Challenge Program
Endpoints
SPONSORED CHEMICAL
IRGANOX MD 1024
(32687-78-8)
Summary of Human Health Data
Acute Oral Toxicity
LDS0 (mg/kg-bw)
> 5000 - > 7000
Acute Inhalation Toxicity
LCS0 (mg/L)
>0.11
Repeated-Dose Toxicity
NOAEL/LOAEL (mg/kg-bw/day)
NOAEL ~ 1000 (28-d)
(male)
(female)
NOAEL ~ 25
LOAEL ~ 123
NOAEL ~ 127
LOAEL ~ 667
Reproductive Toxicity
NOAEL/LOAEL (mg/kg-bw/day)
Evaluation of reproductive organs from the 90-day study
revealed no effects.
Developmental Toxicity
NOAEL/LOAEL (mg/kg-bw/day)

Maternal/Developmental Toxicity
NOAEL = 3000
Genetic Toxicity - Gene Mutations
In vitro
Negative
Genetic Toxicity - Chromosomal Aberrations
In vivo
Negative
Additional Information -
Skin irritation
Eye irritation
Sensitization
Minimally irritating
Moderately irritating
Not sensitizing
— indicates endpoint was not addressed for this chemical.
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