SCREENING-LEVEL HAZARD CHARACTERIZATION
OF HIGH PRODUCTION VOLUME CHEMICALS
SPONSORED CHEMICAL
Methylcyclopentadienyl Manganese Tricarbonyl (MMT) (CAS No. 12108-13-3)
CI Name: Manganese, tricarbonyl[(l,2,3,4,5- .eta.)-l-methyl-2,4-cyclopentadien-l-yl]-]
December 2007
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
-------
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 Set1'2) 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 guidance2'4 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 EPA2 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.
2
-------
SCREENING-LEVEL HAZARD CHARACTERIZATION
Methylcyclopentadienyl Manganese Tricarbonyl (MMT) (CAS No. 12108-13-3)
Introduction
The sponsor, The American Chemistry Council Petroleum Additives Panel Health, Environmental and Regulatory
Task Group, submitted a Test Plan and Robust Summaries to EPA for methylcyclopentadienyl manganese
tricarbonyl (MMT) (CAS No. 12108-13-3; 9th CI name: manganese, tricarbonyl[(l,2,3,4,5-.eta.)-l-methyl-
2,4-cyclopentadien-l-yl]-) on December 10, 2003. EPA posted the submission on the ChemRTK HPV Challenge
website on January 14, 2004 (http://www.epa.gov/chemrtk/pubs/summaries/mthmntri/cl4889tc.htm'). EPA
comments on the original submission were posted to the website on May 25, 2004. Public comments were also
received and posted to the website. The sponsor submitted updated/revised documents on December 5, 2006, which
were posted to the ChemRTK website on January 31, 2007.
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 environmental and human health effects is based largely on SIDS endpoints and is described according to
established EPA or OECD effect level definitions and hazard assessment practices.
Sum m ;m-Conclusion
The lou K of mollis lc> clopeiiiadiem I manganese incarhnm I (MMI'i indicates llial lis potential to hmacciiniiilale
ise\pecled in he low \1\1I is nnl readiK biodegradable, indicating llial il lias ihe pnieniial In persisi in ilie
en\ irniimeiii
The e\ aliialinn nf a\ ailahle aquatic ln\icil> dala I'ni aqnalic m\ eilehiales indicates that the pnieniial ha/aid nf \1\1I
In ai|iialic nrgamsiiis is high Dala nil llie acnle ln\icil> nl' MM T In fish and aquatic plants were nnl snhmilled
\cnle nnil ln\icil> nl' MM T in rals is mnderale and acnle dermal ln\icil> in rahhils and acnle inhalalinii ln\icil> in
rals is high Dermal effects. including er> lliema. edema. iiTiialinn and dcst|iianialimi. were nhser\ ed in rahhils m llie
acnle dermal ln\icil> lesi kepealed-dnse iiihalalimi c\pnsiirc nf rals. mice and ninnkess I'nr 14-weeks resulted in
decreased hnd> weight (rals and mice), increased l!l \ iratsi. increased alkaline phnsphalase acli\ n\ mils) and
hisinpalhnlngical changes in llie lungs sind> was
snhniiiled. hm nn hisinpalhnlngical changes were nhser\ed in reprndiicliN e iissnes in llie 14-week repealed
inhalalinii e\pnsnre sindies cnndncled in rals. mice and mnnkess In llie de\elnpnienial ln\icil> sinds in rals.
decreased nialeriial hnd> weight gam and decreased I'elal hnd\ weight and I'elal skeletal nialfninialmiis (hem nhsi
were seen al the Inwesi dnse. Mlhniigh nn clinical signs nl' iieiiinln\icil> were nhser\ ed. n aciinli/alimi in the w lute
mailer nl' the hram stem and cerebellar Inlia w ere nhser\ ed in male ninnkes s I'nllnw nig llie 14 weeks nl' repeated
inhalalinii e\pnsnre. MM T was nnl miilagemc in haclcnal cells and did ik (nrali. \\ ailahle dala suggest thai MMT has slight pnieniial in he gennln\ic
\cnie ln\icil> in fish and ln\icil> In aqnalic plains were ideiiiil'ied as dala gaps under llie I ll'V ( hallenge I'lngram
3
-------
1. Physical-Chemical Properties and Environmental Fate
A summary of physical-chemical 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 indicators of bioaccumulation and persistence,
respectively.
Octanol-Water Partition Coefficient
Log Kow: 3.7
Ready Biodegradation
In the Closed Bottle method using secondary effluent collected from a domestic wastewater treatment plant as
inoculum, 46% of MMT was degraded after 28 days.
MMT is not readily biodegradable.
Conclusion: The log Kow of MMT indicates that its potential to bioaccumulate is expected to be low. MMT is not
readily biodegradable, indicating that it has the potential to persist in the environment.
2. Environmental Effects - Aquatic Toxicity
Acute Toxicity to Fish
No data were submitted for this endpoint.
Acute Toxicity to Aquatic Invertebrates
Daphnia magna (10/replicate, 2 replicates/concentration) were exposed to MMT at nominal concentrations of 0,
0.65, 1.3, 2.5, 5.0 and 10 mg/L under static conditions for 48 hours. Mean measured concentrations were 0, 0.29,
0.65, 1.0, 2.0 and 3.5mg/L. Analytical concentrations for the time 0-hour samples yielded an average of 56% of
nominal. By 48 hours, concentrations had decreased to an average of 28% of nominal. Immobility and surfacing
were observed at all measured concentrations above 0.29 mg/L.
48-h EC50= 0.83 mg/L
Toxicity to Aquatic Plants
No data were submitted for this endpoint
Conclusion: The evaluation of available aquatic toxicity data for aquatic invertebrates indicates that the potential
hazard of MMT to aquatic organisms is high. Data on the acute toxicity of MMT to fish and aquatic plants were not
submitted.
In the initial test plan submitted to EPA, the sponsor proposed to conduct acute toxicity studies for fish and algae.
The submitted revised test plan and revised robust summaries do not indicate that these studies were conducted. The
sponsor indicated in the revised test plan (submitted on December 5, 2006) that fish toxicity testing was not needed
due to the low likelihood of exposure of organisms residing in the water column to toxic concentrations (due to rapid
photolysis of MMT in the water column and partitioning of MMT into sediment). The submitted data on photolysis
and the decrease in chemical concentration in the aquatic invertebrate test appear to support the claim that MMT
dissipate in water over time. However, within the 48 hour duration of the daphnid test MMT concentrations were
sufficient to be highly toxic to these aquatic organisms (EC50 = 0.83 mg/L). Therefore, EPA continues to
recommend the acute fish and aquatic plant toxicity tests in order to characterize acute hazard to each class of
aquatic organisms.
4
-------
3. Human Health Effects
Acute Oral Toxicity
(1) Sprague-Dawley rats (5/sex/dose) were administered MMT in corn oil via gavage at 40, 63, 100 or 158 mg/kg-
bw, observed for 14 days following dosing and necropsied at the end of the observation period. Dose-related
salivation, weakness and diarrhea were observed 4-24 hours after dosing. Deaths occurred at all doses in females
and at the two highest doses in males. Findings on necropsy were limited to residual test material in the stomach
and intestine, accompanied by discoloration of adjacent viscera. Surviving animals gained weight. Based on
mortality incidence data, females were more sensitive than males.
LDS0 = 58 mg/kg-bw
(2) Sprague-Dawley rats (5/sex/dose) were administered MMT in corn oil via gavage at 126, 158, 200 or 251
mg/kg-bw, observed for 14 days following dosing and necropsied at the end of the observation period. Deaths
occurred at all doses in females and at 158 mg/kg-bw and above in males. All deaths occurred within 3 days of
dosing. Findings on necropsy were limited to residual test material in the gastrointestinal tract. Surviving animals
gained weight.
LDS0 = 175 mg/kg-bw
Acute Inhalation Toxicity
Male rats (10/concentration; strain not specified) were exposed to MMT vapor via inhalation at measured
concentrations of 0, 0.047, 0.054, 0.070, 0.087 or 0.100 mg/L for 4 hours, observed for 14 days following exposure
and necropsied at the end of the observation period. Decreased activity and conjunctivitis were observed during
exposures and decreased activity, labored breathing and conjunctivitis were observed 1-4 days after exposure.
Deaths occurred at all concentrations through post-exposure day 3. All rats exposed to MMT failed to gain weight
during the first post-exposure week, but had gained weight at the end of the 2-week observation period. Focal
hemorrhage of the lungs was observed on necropsy of surviving animals.
4-h LCS0 = 0.076 mg/L
Acute Dermal Toxicity
(1) Male and female New Zealand White rabbits (4/dose, sex distribution not indicated) were administered undiluted
MMT via the dermal route at 112, 126, 141 or 158 mg/kg-bw to abraded and intact skin under occluded conditions
for 24 hours and were observed for 14 days. Necropsies were performed on all animals at the end of the observation
period. Deaths occurred at > 126 mg/kg-bw and within 72 hours of dosing. Slight erythema and moderate edema
were observed 24 hours post-exposure. At necropsy, congestion or possible internal hemorrhage was observed in
the "major organs" (not specified in the robust summary). Surviving animals gained weight.
LDS0 = 140 mg/kg-bw
(2) Male and female New Zealand White rabbits (4/dose, sex distribution not indicated) were administered undiluted
MMT via the dermal route at 502, 795, 1260 or 2000 mg/kg-bw to abraded and intact skin under occluded
conditions for 24 hours and were observed for 14 days. Necropsies were performed on all animals at the end of the
observation period. Deaths occurred at all doses and within 6 days of exposure. Slight to well-defined erythema
and slight edema were observed within 24 hours of dosing. Surviving animals initially lost weight, but had gained
weight by the end of the observation period. At necropsy, internal hemorrhage, particularly of the kidney, was
observed in animals treated with > 795 mg/kg-bw.
LDS0 = 795 mg/kg-bw
(3) Male and female New Zealand White rabbits (4/dose; distribution by sex not indicated) were administered
undiluted MMT via the dermal route at 250, 350, 500 or 710 mg/kg-bw to abraded and intact skin under occluded
conditions for 24 hours and were observed for 14 days. Collars were used throughout the study to prevent ingestion
of the test material. Necropsies were performed on all animals at the end of the observation period. Deaths
occurred at all doses and within 11 days of exposure. During the first 24 hours, convulsions (> 500 mg/kg-bw),
ataxia (250 and 500 mg/kg-bw) and hypoactivity (250 and 500 mg/kg-bw) were observed. Slight weight loss was
5
-------
observed in all treated animals at the end of 2 weeks. At necropsy, lung consolidation, red spots on intestines and
lungs and nasal discharge were observed (> 350 mg/kg-bw).
LDS0 = 420 mg/kg-bw
(4) Male and female New Zealand White rabbits (4/dose; distribution by sex not indicated) were administered
undiluted MMT via the dermal route at 118.5, 177.8, 266.7, 400 or 2000 mg/kg-bw to abraded and intact skin under
occluded conditions for 24 hours and were observed for 14 days. Deaths occurred at > 177.8 mg/kg-bw and within
4 days of exposure. At 2000 mg/kg-bw, excitation, tremors and convulsions were observed within 15 minutes of
dosing until death and excitation was observed at 400 mg/kg-bw. Moderate irritation and edema and well-defined
erythema were observed. Moderate desquamation was observed 7 and 14 days after dosing. On necropsy, lung
hemorrhage was observed in high-dose animals. Pulmonary edema and lung discoloration were observed in all
animals surviving to study termination.
LDS0 = 197 mg/kg-bw
Repeated-Dose Toxicity
(1) Sprague Dawley rats (10/sex/concentration) were exposed to MMT vapor via inhalation at concentrations of 0,
0.30, 3.5 or 30.2 |ig/L (0, 0.0003, 0.0035 or 0.0302 mg/L; mean measured concentration) for 6 hours/day, 5
days/week for 14 weeks. Mortality was observed in 1/10 males at the high concentration and 3/10 and 2/10 females
in the middle and high concentration, respectively. Clinical signs of toxicity included rough coat, lethargy and
dyspnea at the high concentration. Body weight was reduced in high-exposure animals throughout the study
(magnitude of effect and statistical significance not reported in the robust summary). No treatment-related
hematological effects were observed. Statistically significant, dose-related increases in blood urea nitrogen (BUN)
were observed in male and female rats in all exposure groups (p = 0.05; group means were reported in the robust
summary). Serum alkaline phosphatase activity was slightly elevated in animals in the high-exposure group, with a
significant increase in males. Focal pneumonitis and histopathological change consisting of increased number of
alveolar macrophages with fine granular brown material in the cytoplasm were observed in lungs of rats exposed at
the high concentration.
LOAEL = 0.0302 mg/L (based on decreased body weights)
NOAEL = 0.0035 mg/L
(2) Swiss Webster mice (10/sex/concentration) were exposed to MMT vapor via inhalation at concentrations of 0,
0.30, 3.5 or 30.2 |ig/L (0, 0.0003, 0.0035 or 0.0302 mg/L; mean measured exposure) for 6 hours/day, 5 days/week
for 14 weeks. Due to excessive toxicity, animals at the high concentration were sacrificed after 5 weeks of
treatment. Mortality occurred in 2/10 male mice each in the mid- and high-exposure groups and 1/10, 1/10 and 5/10
female mice in the control, low-exposure and high-exposure groups, respectively. Clinical signs of toxicity included
rough coat, lethargy and dyspnea at the high concentration. Body weight was reduced in high-concentration
animals. At the middle concentration, decreased body weight was observed in males and females beginning at
weeks 14 and 3, respectively. The following organ weight changes were observed: mean kidney weights were
elevated in mid-exposure males and females; liver weights were elevated in low- and mid-exposure females; and
spleen and gonad weights were decreased in high-exposure females at their early (week 5) termination.
Histopathological changes in the lungs were bronchial epithelial hyperplasia, squamous metaplasia, erosion and
bronchial wall fibrosis in males and females at the high concentration.
LOAEL = 0.0003 mg/L/day (based on increased liver weights in females)
NOAEL = Not established
6
-------
(3) Cynomolgus monkeys (6 males/concentration) were exposed to MMT vapor via inhalation at concentrations of
0, 0.30, 3.5 or 30.2 |ig/L (0, 0.0003, 0.0035 or 0.0302 mg/L; mean measured concentration) for 6 hours/day, 5
days/week for 14 weeks. Three animals/concentration were sacrificed at the end of the 14-week exposure period
and the remaining 3 animals/concentration were sacrificed after an additional 14-day post-treatment observation
period. No mortalities and clinical signs were observed. Body and organ weights were unaffected by treatment. No
treatment-related hematological or clinical chemistry effects were observed. Urinalysis showed a slight increase in
ketones in high-exposure animals. Histopathological examination revealed slight to moderate vacuolization in the
white matter of the brain stem and cerebellar folia in 5/6 high-exposure animals (compared to 3/6, 2/6 and 3/6 in the
control, low- and mid-exposure groups, respectively). No pulmonary findings were observed at any exposure
concentration.
LOAEL = 0.0302 mg/L/day (based on histopathological changes in the brain and increased ketones in urine)
NOAEL = 0.0035 mg/L/day
Reproductive Toxicity
A reproductive toxicity test was not submitted. Evaluation of reproductive organs from the 14-week inhalation
repeated-dose toxicity studies and availability of a developmental toxicity study address the reproductive toxicity
endpoint for the purposes of the HPV Challenge Program.
(1) In the 14-week repeated-dose inhalation study in rats described previously, no macroscopic or microscopic
effects on reproductive organs were observed at any exposure concentration.
(2) In the 14-week repeated-dose inhalation study in mice described previously, no macroscopic or microscopic
effects on reproductive organs were observed at any exposure concentration.
(3) In the 14-week repeated-dose inhalation study in mice described previously, no macroscopic or microscopic
effects on reproductive organs were observed at any exposure concentration.
Developmental Toxicity
Sprague-Dawley CD rats (25 females/dose) were administered MMT in corn oil via gavage at 0, 2.0, 4.5, 6.5 or 9.0
mg/kg-bw/day on gestational days 6 - 15. All dams were sacrificed on day 20 of gestation and the following
parameters were assessed: uterine weight, location of viable and nonviable fetuses, early and late resorptions,
number of total implants and corpora lutea and maternal liver weight. Abdominal and thoracic cavities of dams
were examined. Fetuses were examined for external, internal and skeletal malformations and variations. Fetal sex
and weight were determined. No treatment-related mortalities of dams were observed. At the high dose, the
incidence of matting and staining of anogenital fur was slightly increased. Treatment-related body weight changes
in dams were observed throughout the study as follows: decreased body weight gain over the entire gestational
period (all doses); reduced body weight gain and mean weight loss on gestational days 6 - 9 at 6.5 mg/kg-bw/day;
moderate reduction of mean weight gain at > 6.5 mg/kg-bw/day; and decreased body weight on gestational day 9 at
9.0 mg/kg-bw/day. The robust summary did not report the magnitude of these effects, dose-response data or a trend
analysis of body weight data. No treatment-related liver weight changes or adverse reproductive effects were
observed. A slight reduction in mean fetal weight was noted in all treatment groups. The incidence of rib
malformation (bent ribs) was increased in all treatment groups compared to controls.
LOAEL (maternal toxicity) = 2.0 mg/kg-bw/day (based on decreased weight gain)
LOAEL (developmental toxicity) = 2.0 mg/kg-bw/day (based on decreased fetal weight and bent ribs)
NOAEL (maternal/developmental toxicity) = Not established
7
-------
Genetic Toxicity - Gene Mutation
In vitro
In a reverse mutation assay, Salmonella typhimurium strains TA98, TA100, TA1535, TA1537 and TA1538 were
exposed to MMT at concentrations of 0, 10, 50, 100, 500, 1000 or 5000 |ig/plate in the presence and absence of
metabolic activation. Vehicle (not specified in the robust summary) was used. Cytotoxic concentrations ranged
from 500 to 5000 |ig/plate and varied with strain and metabolic activation. Positive controls were run concurrently
and yielded appropriate responses.
MMT was not mutagenic in this assay.
Genetic Toxicity - Chromosomal Aberrations
In vitro
Chinese hamster lung (CHL) cells were exposed to MMT at concentrations of 0, 0.01, 0.02 or 0.04 |iL/mL in the
presence and absence of metabolic activation. No vehicle was used. Cytotoxic concentrations were not reported in
the robust summary. Positive controls were run concurrently and yielded appropriate responses. The percentage of
cells with chromosomal aberrations was increased at > 0.02 |iL/mL in the presence, but not absence, of metabolic
activation.
MMT induced chromosome aberrations in this assay.
In vivo
(1) Male and female C57B1 mice were administered three doses of MMT via the intraperitoneal route at 0, 12.5, 25
or 50 mg/kg-bw in olive oil. Twenty four hours after the third dose, animals were sacrificed and bone marrow
erythrocytes were examined for the presence of micronuclei. A dose range-finding assay indicated that doses > 50
mg/kg-bw could cause animal deaths or distress. No dose-related increases or differences in micronuclei formation
were observed. Cytotoxicity was not observed. Positive controls were run concurrently and yielded appropriate
responses.
MMT did not induce micronuclei in this assay.
(2) Male and female C57B1 mice were administered single doses of MMT in corn oil via the intraperitoneal route at
0, 50, 75 or 100 mg/kg-bw (with a 24-hour post-dose holding period) or at 0, 75 or 100 mg/kg-bw (with a 48-hour
post-dose holding period). After the holding periods, animals at each dose were sacrificed and bone marrow
erythrocytes were examined for the presence of micronuclei. A dose range-finding assay indicated that doses > 100
mg/kg-bw could cause animal deaths. No dose-related increases or differences in micronuclei formation were
observed. Cytotoxicity was observed in male mice sacrificed 48 hours after treatment. Positive controls were run
concurrently and yielded appropriate responses.
MMT did not induce micronuclei in this assay.
Conclusion: Acute oral toxicity of MMT in rats is moderate and acute dermal toxicity in rabbits and acute
inhalation toxicity in rats is high. Dermal effects, including erythema, edema, irritation and desquamation, were
observed in rabbits in the acute dermal toxicity test. Repeated-dose inhalation exposure of rats, mice and monkeys
for 14-weeks resulted in decreased body weight (rats and mice), increased BUN (rats), increased alkaline
phosphatase activity (rats) and histopathological changes to the lungs (rats and mice) and brain (monkeys). No
reproductive toxicity study was submitted, but no histopathological changes were observed in reproductive tissues in
the 14-week repeated inhalation exposure studies conducted in rats, mice and monkeys. In the developmental
toxicity study in rats, decreased maternal body weight gain and decreased fetal body weight and fetal skeletal
malformations (bent ribs) were seen at the lowest dose. Although no clinical signs of neurotoxicity were observed,
vacuolization in the white matter of the brain stem and cerebellar folia were observed in male monkeys following
the 14 weeks of repeated inhalation exposure. MMT was not mutagenic in bacterial cells and did not induce
micronuclei in mouse bone marrow erythrocytes in vivo. However, MMT induced chromosomal aberrations in
mammalian cells in vitro in the presence of metabolic activation.
The potential health hazard of MMT is high based on acute (inhalation), repeated-dose (inhalation) and
developmental toxicity (oral). Available data suggest that MMT has slight potential to be genotoxic.
8
-------
4. Hazard Characterization
The log Kow of methylcyclopentadienyl manganese tricarbonyl (MMT) indicates that its potential to bioaccumulate
is expected to be low. MMT is not readily biodegradable, indicating that it has the potential to persist in the
environment.
The evaluation of available aquatic toxicity data for aquatic invertebrates indicates that the potential hazard of MMT
to aquatic organisms is high. Data on the acute toxicity of MMT to fish and aquatic plants were not submitted.
Acute oral toxicity of MMT in rats is moderate and acute dermal toxicity in rabbits and acute inhalation toxicity in
rats is high. Dermal effects, including erythema, edema, irritation and desquamation, were observed in rabbits in the
acute dermal toxicity test. Repeated-dose inhalation exposure of rats, mice and monkeys for 14-weeks resulted in
decreased body weight (rats and mice), increased BUN (rats), increased alkaline phosphatase activity (rats) and
histopathological changes to the lungs (rats and mice) and brain (monkeys). No reproductive toxicity study was
submitted, but no histopathological changes were observed in reproductive tissues in the 14-week repeated
inhalation exposure studies conducted in rats, mice and monkeys. In the developmental toxicity study in rats,
decreased maternal body weight gain and decreased fetal body weight and fetal skeletal malformations (bent ribs)
were seen at the lowest dose. Although no clinical signs of neurotoxicity were observed, vacuolization in the white
matter of the brain stem and cerebellar folia were observed in male monkeys following the 14 weeks of repeated
inhalation exposure. MMT was not mutagenic in bacterial cells and did not induce micronuclei in mouse bone
marrow erythrocytes in vivo. However, MMT induced chromosomal aberrations in mammalian cells in vitro in the
presence of metabolic activation.
The potential health hazard of MMT is high based on acute (inhalation), repeated-dose (inhalation) and
developmental toxicity (oral). Available data suggest that MMT has slight potential to be genotoxic.
5. Data Gaps
Acute toxicity to fish and toxicity to aquatic plants were identified as data gaps under the HPV Challenge Program.
9
-------
APPENDIX
Summary Tabic of the Screening Information Data Set
as Submitted underthe U.S. HPV Challenge Program
Endpoints
SPONSORED CHEMICAL
Mcthylcyclopcntadicnyl manganese tricarbonyl
(MMT)
(12108-13-3)
Structure
OH
III
c
ho^ /
Mn^
/ =OH
0^cHi
Summary of Physical-Chemical Properties and Environmental Fate Data
Boiling Point (°C)
231.671
Vapor Pressure
(hPa at 25°C)
9.7 (100 °C)1
Log K„w
3.7
Water Solubility
(mg/L at 25°C)
29
Direct Photodegradation
Half-life in deionized water exposed to daylight = 0.93
min
Stability in Water (Hydrolysis) (ti/2)
0.2 - 1.5 yr (anaerobic and aerobic conditions)
Biodegradation at 28 days (%)
46
Not readily biodegradable
Summary of Environmental Effects - Aquatic Toxicity Data
Fish
96-h LCS0 (mg/L)
No data—Data Gap
Aquatic Invertebrates
48-h ECS0 (mg/L)
0.83
Aquatic Plants
96-h ECS0 (mg/L)
No data—Data Gap
10
-------
Summary Tabic of the Screening Information Data Set
as Submitted underthe U.S. HPV Challenge Program
Endpoints
SPONSORED CHEMICAL
Mcthylcyclopcntadicnyl manganese tricarbonyl
(MMT)
(12108-13-3)
Summary of Human Health Data
Acute Oral Toxicity
LDS0 (mg/kg-bw)
58-175
Acute Inhalation Toxicity
LCS0 (mg/L)
0.076
Acute Dermal Toxicity
LDS0 (mg/kg-bw)
140 - 795
Repeated-Dose Toxicity
NOAEL/LOAEL
Inhalation (mg/L/day)
(Rats)
NO A F.I. = 0.0035
LOAEL = 0.0302
(Mice)
NOAEL = Not established
LOAEL = 0.0003
(Monkeys)
NOAEL = 0.0035
LOAEL = 0.0302
Reproductive Toxicity
NOAEL/LOAEL
Inhalation (mg/L/day)
No effects were seen following evaluation of
reproductive organs in 14-wk inhalation studies in rats,
mice and monkeys.
Developmental Toxicity
NOAEL/LOAEL
Oral (mg/kg-bw/day)
Maternal and Developmental Toxicity
LOAEL = 2.0
NOAEL = Not established
Genetic Toxicity - Gene Mutation
In vitro
Negative
Genetic Toxicity - Chromosomal Aberrations
In vitro
Positive
Genetic Toxicity - Chromosomal Aberrations
In vivo
Negative
- indicates that endpoint was not addressed for this chemical.
'The sponsor did not indicate whether this value was measured or estimated.
11
------- |