[Federal Register: December 24, 2002 (Volume 67, Number 247)]
[Notices]
[Page 78459-78467]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr24de02-89]
-----------------------------------------------------------------------
ENVIRONMENTAL PROTECTION AGENCY
[OPP-2002-0283; FRL-7277-5]
Bronopol; Notice of Filing a Pesticide Petition to Establish a
Tolerance for a Certain Pesticide Chemical in or on Food
AGENCY: Environmental Protection Agency (EPA).
ACTION: Notice.
-----------------------------------------------------------------------
SUMMARY: This notice announces the initial filing of a pesticide
petition proposing the establishment of regulations for residues of a
certain pesticide chemical in or on various food commodities.
DATES: Comments, identified by docket ID number OPP-2002-0283, must be
received on or before January 23, 2003.
ADDRESSES: Comments may be submitted electronically, by mail, or
through hand delivery/courier. Follow the detailed instructions as
provided in Unit I. of the SUPPLEMENTARY INFORMATION.
FOR FURTHER INFORMATION CONTACT: Bipin Gandhi, Registration Division
(7505C), Office of Pesticide Programs, Environmental Protection Agency,
1200 Pennsylvania Ave., NW., Washington, DC 20460-0001; telephone
number: (703) 308-8380; e-mail address: gandhi.bipin@epa.gov.
SUPPLEMENTARY INFORMATION:
I. General Information
A. Does this Action Apply to Me?
You may be potentially affected by this action if you are an
agricultural producer, food manufacturer, pesticide manufacturer, or
antimicrobial pesticide manufacturer. Potentially affected entities may
include, but are not limited to:
[sbull] Industry (NAICS 111), e.g., Crop production.
[sbull] Industry (NAICS 112), e.g., Animal production.
[sbull] Industry (NAICS 311), e.g., Food manufacturing.
[[Page 78460]]
[sbull] Industry (NAICS 32532), e.g., Pesticide manufacturing.
[sbull] Industry (NAICS 32561), e.g., Antimicrobial pesticide.
This listing is not intended to be exhaustive, but rather provides
a guide for readers regarding entities likely to be affected by this
action. Other types of entities not listed in this unit could also be
affected. The North American Industrial Classification System (NAICS)
codes have been provided to assist you and others in determining
whether this action might apply to certain entities. If you have any
questions regarding the applicability of this action to a particular
entity, consult the person listed under FOR FURTHER INFORMATION
CONTACT.
B. How Can I Get Copies of this Document and Other Related Information?
1. Docket. EPA has established an official public docket for this
action under docket identification (ID) number OPP-2002-0283. The
official public docket consists of the documents specifically
referenced in this action, any public comments received, and other
information related to this action. Although a part of the official
docket, the public docket does not include Confidential Business
Information (CBI) or other information whose disclosure is restricted
by statute. The official public docket is the collection of materials
that is available for public viewing at the Public Information and
Records Integrity Branch (PIRIB), Rm. 119, Crystal Mall 2,
1921 Jefferson Davis Hwy., Arlington, VA. This docket facility is open
from 8:30 a.m. to 4 p.m., Monday through Friday, excluding legal
holidays. The docket telephone number is (703) 305-5805.
2. Electronic access. You may access this Federal Register document
electronically through the EPA Internet under the ``Federal Register''
listings at http://www.epa.gov/fedrgstr/.
An electronic version of the public docket is available through
EPA's electronic public docket and comment system, EPA Dockets. You may
use EPA Dockets at http://www.epa.gov/edocket/ to submit or view public
comments, access the index listing of the contents of the official
public docket, and to access those documents in the public docket that
are available electronically. Although not all docket materials may be
available electronically, you may still access any of the publicly
available docket materials through the docket facility identified in
Unit I.B.1. Once in the system, select ``search,'' then key in the
appropriate docket ID number.
Certain types of information will not be placed in the EPA Dockets.
Information claimed as CBI and other information whose disclosure is
restricted by statute, which is not included in the official public
docket, will not be available for public viewing in EPA's electronic
public docket. EPA's policy is that copyrighted material will not be
placed in EPA's electronic public docket but will be available only in
printed, paper form in the official public docket. To the extent
feasible, publicly available docket materials will be made available in
EPA's electronic public docket. When a document is selected from the
index list in EPA Dockets, the system will identify whether the
document is available for viewing in EPA's electronic public docket.
Although not all docket materials may be available electronically, you
may still access any of the publicly available docket materials through
the docket facility identified in Unit I.B. EPA intends to work towards
providing electronic access to all of the publicly available docket
materials through EPA's electronic public docket.
For public commenters, it is important to note that EPA's policy is
that public comments, whether submitted electronically or in paper,
will be made available for public viewing in EPA's electronic public
docket as EPA receives them and without change, unless the comment
contains copyrighted material, CBI, or other information whose
disclosure is restricted by statute. When EPA identifies a comment
containing copyrighted material, EPA will provide a reference to that
material in the version of the comment that is placed in EPA's
electronic public docket. The entire printed comment, including the
copyrighted material, will be available in the public docket.
Public comments submitted on computer disks that are mailed or
delivered to the docket will be transferred to EPA's electronic public
docket. Public comments that are mailed or delivered to the docket will
be scanned and placed in EPA's electronic public docket. Where
practical, physical objects will be photographed, and the photograph
will be placed in EPA's electronic public docket along with a brief
description written by the docket staff.
C. How and To Whom Do I Submit Comments?
You may submit comments electronically, by mail, or through hand
delivery/courier. To ensure proper receipt by EPA, identify the
appropriate docket ID number in the subject line on the first page of
your comment. Please ensure that your comments are submitted within the
specified comment period. Comments received after the close of the
comment period will be marked ``late.'' EPA is not required to consider
these late comments. If you wish to submit CBI or information that is
otherwise protected by statute, please follow the instructions in Unit
I.D. Do not use EPA Dockets or e-mail to submit CBI or information
protected by statute.
1. Electronically. If you submit an electronic comment as
prescribed in this unit, EPA recommends that you include your name,
mailing address, and an e-mail address or other contact information in
the body of your comment. Also include this contact information on the
outside of any disk or CD ROM you submit, and in any cover letter
accompanying the disk or CD ROM. This ensures that you can be
identified as the submitter of the comment and allows EPA to contact
you in case EPA cannot read your comment due to technical difficulties
or needs further information on the substance of your comment. EPA's
policy is that EPA will not edit your comment, and any identifying or
contact information provided in the body of a comment will be included
as part of the comment that is placed in the official public docket,
and made available in EPA's electronic public docket. If EPA cannot
read your comment due to technical difficulties and cannot contact you
for clarification, EPA may not be able to consider your comment.
i. EPA Dockets. Your use of EPA's electronic public docket to
submit comments to EPA electronically is EPA's preferred method for
receiving comments. Go directly to EPA Dockets at http://www.epa.gov/edocket
, and follow the online instructions for submitting comments.
Once in the system, select ``search,'' and then key in docket ID number
OPP-2002-0283. The system is an ``anonymous access'' system, which
means EPA will not know your identity, e-mail address, or other contact
information unless you provide it in the body of your comment.
ii. E-mail. Comments may be sent by e-mail to opp-docket@epa.gov,
Attention: Docket ID Number OPP-2002-0283. In contrast to EPA's
electronic public docket, EPA's e-mail system is not an ``anonymous
access'' system. If you send an e-mail comment directly to the docket
without going through EPA's electronic public docket, EPA's e-mail
system automatically captures your e-mail address. E-mail addresses
that are automatically captured by EPA's e-mail system are included as
part of the comment that is
[[Page 78461]]
placed in the official public docket, and made available in EPA's
electronic public docket.
iii. Disk or CD ROM. You may submit comments on a disk or CD ROM
that you mail to the mailing address identified in Unit I.C.2. These
electronic submissions will be accepted in WordPerfect or ASCII file
format. Avoid the use of special characters and any form of encryption.
2. By mail. Send your comments to: Public Information and Records
Integrity Branch (PIRIB) (7502C), Office of Pesticide Programs (OPP),
Environmental Protection Agency, 1200 Pennsylvania Ave., NW.,
Washington, DC 20460-0001, Attention: Docket ID Number OPP-2002-0283.
3. By hand delivery or courier. Deliver your comments to: Public
Information and Records Integrity Branch (PIRIB), Office of Pesticide
Programs (OPP), Environmental Protection Agency, Rm. 119, Crystal Mall
2, 1921 Jefferson Davis Hwy., Arlington, VA, Attention: Docket
ID Number OPP-2002-0283. Such deliveries are only accepted during the
docket's normal hours of operation as identified in Unit I.B.1.
D. How Should I Submit CBI To the Agency?
Do not submit information that you consider to be CBI
electronically through EPA's electronic public docket or by e-mail. You
may claim information that you submit to EPA as CBI by marking any part
or all of that information as CBI (if you submit CBI on disk or CD ROM,
mark the outside of the disk or CD ROM as CBI and then identify
electronically within the disk or CD ROM the specific information that
is CBI). Information so marked will not be disclosed except in
accordance with procedures set forth in 40 CFR part 2.
In addition to one complete version of the comment that includes
any information claimed as CBI, a copy of the comment that does not
contain the information claimed as CBI must be submitted for inclusion
in the public docket and EPA's electronic public docket. If you submit
the copy that does not contain CBI on disk or CD ROM, mark the outside
of the disk or CD ROM clearly that it does not contain CBI. Information
not marked as CBI will be included in the public docket and EPA's
electronic public docket without prior notice. If you have any
questions about CBI or the procedures for claiming CBI, please consult
the person listed under FOR FURTHER INFORMATION CONTACT.
E. What Should I Consider as I Prepare My Comments for EPA?
You may find the following suggestions helpful for preparing your
comments:
1. Explain your views as clearly as possible.
2. Describe any assumptions that you used.
3. Provide copies of any technical information and/or data you used
that support your views.
4. If you estimate potential burden or costs, explain how you
arrived at the estimate that you provide.
5. Provide specific examples to illustrate your concerns.
6. Make sure to submit your comments by the deadline in this
notice.
7. To ensure proper receipt by EPA, be sure to identify the docket
ID number assigned to this action in the subject line on the first page
of your response. You may also provide the name, date, and Federal
Register citation.
II. What Action is the Agency Taking?
EPA has received a pesticide petition as follows proposing the
establishment and/or amendment of regulations for residues of a certain
pesticide chemical in or on various food commodities under section 408
of the Federal Food, Drug, and Cosmetic Act (FFDCA), 21 U.S.C. 346a.
EPA has determined that this petition contains data or information
regarding the elements set forth in FFDCA section 408(d)(2); however,
EPA has not fully evaluated the sufficiency of the submitted data at
this time or whether the data support granting of the petition.
Additional data may be needed before EPA rules on the petition.
List of Subjects
Environmental protection, Agricultural commodities, Feed additives,
Food additives, Pesticides and pests, Reporting and recordkeeping
requirements.
Dated: December 10, 2002.
Peter Caulkins,
Acting Director, Registration Division, Office of Pesticide Programs.
Summary of Petition
The petitioner summary of the pesticide petition is printed below
as required by FFDCA section 408(d)(3). The summary of the petition was
prepared by the petitioner and represents the view of the petitioner.
The petition summary announces the availability of a description of the
analytical methods available to EPA for the detection and measurement
of the pesticide chemical residues or an explanation of why no such
method is needed.
PP 2E6475
EPA has received a pesticide petition (PP 2E6475) from BASF
Corporation: 3000 Continental Drive - North, Mount Olive, NJ 07828-
1234; proposing, pursuant to section 408(d) of the FFDCA, 21 U.S.C.
346a(d), to amend 40 CFR part 180 to establish an exemption from the
requirement of a tolerance for 2-bromo-2-nitro-1,3-propanediol
(Bronopol) (CAS Reg. No. 52-51-7) in or on all raw agricultural
commodities when used as an in-can preservative in pesticide
formulations applied to growing crops, raw agricultural commodities
after harvest, and animals. EPA has determined that the petition
contains data or information regarding the elements set forth in
section 408(d)(2) of the FFDCA; however, EPA has not fully evaluated
the sufficiency of the submitted data at this time or whether the data
supports granting of the petition. Additional data may be needed before
EPA rules on the petition.
A. Residue Chemistry
1. Plant metabolism. Residue chemistry data are not generally
required by EPA regarding tolerance exemption petitions. Consequently
no plant metabolism data have been generated.
2. Analytical method. Since this petition is for an exemption from
the requirement of a tolerance, an enforcement analytical method for 2-
bromo-2-nitro-1, 3-propanediol is not needed.
3. Magnitude of residues. Based on the proposed amount of 2-bromo-
2-nitro-1,3-propanediol to be used in the final products (0.04% or less
by weight of the total formulation) and the recommended frequency and
rates of application to growing crops, raw agricultural commodities
after harvest, and animals, the residues are expected to be essentially
undetectable and not toxicologically significant.
B. Toxicological Profile
1. Acute toxicity. Bronopol was given as single oral doses of 200,
280, 390, 550, or 770 mg/kg, as a solution in distilled water, to
groups of ten male and ten female rats. The rats were observed for a
seven-day period. Overt signs of toxicity were seen immediately after
dosing with 280 mg/kg or more, and within 1 hour in males given 200 mg/
kg. The signs included sedation, wheezing, gasping, nasal exudate,
cyanosis, increased salivation and ataxia. Animals given 550 or 770 mg/
kg
[[Page 78462]]
also had slow or labored respiration, and two females became prostrate.
Most deaths occurred within 19 hours after dosing, but some occurred up
to 72 hours. There were no gross abnormalities at autopsy of the
decedents or in animals killed at the end of the study. The
LD50 in male rats was 307 mg/kg and in female rats was 342
mg/kg.
In a further oral study groups of ten male rats were given single
doses of Bronopol at 36, 54, 80, 120, 270, 400, or 600 mg/kg, as a
suspension in 0.4% aqueous Cellosize solution. The rats were observed
for up to ten days after treatment. Overt signs of toxicity were seen
within 30 minutes after dosing with 80 mg/kg or more, and included
wheezing, gasping or labored respiration and nasal exudate. Animals in
the higher dose groups were inactive and adopted a low or hunched body
position. Deaths occurred in these groups up to five days after
treatment; macroscopic findings in the decedents included evidence of
gastrointestinal irritation at 120 mg/kg or more, enlarged and dark red
adrenals in some animals given 400 or 600 mg/kg, small spleens in a few
rats given 80 or 120 mg/kg, and pale areas on the livers at 600 mg/kg.
At terminal autopsy, one animal given 400 mg/kg also had a small
spleen. Statistical analysis of the mortality data indicated that the
LD50 was 254 mg/kg.
In an acute inhalation study a group of six rats and two groups of
eight rats were exposed for 6-hour periods to Bronopol dust at nominal
concentrations of 5, 0.5, or 0.05 mg per liter air respectively. The
animals were then kept under observation for up to 14 days. Exposure of
rats to 5 mg dust per liter air caused severe eye irritation, dyspnea
and loss of bodyweight. Exposure to 0.5 mg dust per liter air caused
only slight eye irritation and mild dyspnea, while no definite signs of
irritation were observed in animals exposed to 0.05 mg dust per air.
In a second inhalation study four groups of 10 rats (5 males and 5
females) were exposed to Bronopol at 0 (filtered air negative control),
0.038, 0.089 or 0.588 mg/ by inhalation (nose-only) over a period of 4
hours. Exposure was followed by an observation period of 14 days. In
the high dose group one animal died overnight after exposure, and 2
more animals were killed during the following day because of severe eye
inflammation. Signs of marked irritancy were recorded in high dose
animals but disappeared by the third observation day. Minor treatment-
related signs (piloerection and hunched posture) were observed on the
day of treatment in some intermediate dose rats. There was no effect in
the low dose group. There were no treatment-related effects on body
weight or treatment-related pathological findings except for local
dermatitis and ulceration in 2 high dose animals possibly attributable
to dermal exposure to the test article.
Several studies as summarized below determined 2-bromo-2-nitro-1,3-
propanediol to be irritant to the eye. Bronopol in polyethylene glycol
300-0.1 ml volumes of 0.5 or 2% Bronopol in polyethylene glycol 300
were instilled into one eye of each of six rabbits, three rabbits per
concentration. The other eye in each case was treated with solvent
only. The 2% solution was instilled only once, whereas the 0.5%
solution was instilled on four successive days. The 2% solution of
Bronopol in polyethylene glycol 300, instilled once, caused moderate
inflammation and slight conjunctival edema which subsided after 5
hours. The 0.5% solution, instilled on four successive days, had
effects similar to those produced by the solvent alone.
Bronopol in saline - Two drops of a solution containing 0.5% w/v
Bronopol in normal saline were applied to one eye of three New Zealand
White rabbits once daily on four successive days. The other eye
(control) of each rabbit was treated with normal saline. The eyes were
examined for irritation at 15 and 30 minutes, and at 1, 2, 3, 4, and 24
hours after treatment each day. One rabbit developed moderate
inflammation and very slight edema of the conjunctiva between two and
four hours after the first application, but this subsided within 24
hours. No other reactions were observed.
Bronopol in polyethylene glycol 400 - One drop of Bronopol at 0
(vehicle control), 0.5, 2, or 5% in polyethylene glycol 400 was added
to one eye of 12 rabbits, 3 animals per test concentration. The other
eye of each rabbit was left untreated. After 24 hours the eyes were
irrigated with 300 ml of lukewarm water. Ocular reactions were assessed
according to the FDA method at 1, 24, 48, and 72 hours, and then 7, 14,
and 21 days after treatment.Immediately after treatment, with all the
solutions, most rabbits exhibited head shaking and blinking and/or
rubbing the treated eye. After 1 hour all the animals developed
conjunctival reactions which had largely subsided by 24 hours, except
in the most severely affected cases. One rabbit treated with 5%
Bronopol had conjunctival reactions that persisted for 72 hours. The
lower concentrations produced less severe and less persistent
conjunctival reactions, and none of the concentrations elicited
reactions in the cornea or iris. It was concluded that Bronopol in
polyethylene glycol 400 was irritant at 5% but not at 2 or 0.5%, when
instilled once only into the eye of the New Zealand White rabbit.
Bronopol is also irritant to the skin. In a cumulative irritancy
study dilutions of Bronopol at 0 (vehicle control), 0.1, 0.5, 1, 2.5,
and 5% in petrolatum was applied daily for 21 days to the same site on
the back of 8 men. The treatment sites were occluded. Readings were
made daily on a scale of 0 to 4. The skin irritancy threshold
concentration of Bronopol was approximately 0.5 to 1.0%. To determine
if the subjects had been sensitized, they were further elicited after a
10-day rest period. Two subjects reacted at 0.5 and 1% Bronopol. One
reacted at 0.1%. These men received a product use test consisting of
applications (without patching) to the cubital fossa twice daily for 7
days. These were negative.
In a single, 4 hour, semi-occluded dermal application of undiluted
Bronopol to the skin of six rabbits produced severe dermal reactions,
including eschar formation, necrosis and severe edema. Other adverse
dermal reactions noted were slight hemorrhage of the dermal
capillaries, blanching or brown discoloration of the skin, desquamation
and scar tissue. The absence of fur growth was also occasionally noted
on day fourteen with further effects indicative of corrosion. A primary
irritation index of 6.2 was produced and evidence of corrosive effects
were noted fourteen days after treatment. Undiluted Bronopol was found
to be a severe irritant/corrosive to rabbit skin.
An acute rabbit dermal toxicity study gave a dermal LD50
of > 2,000 mg/kg body weight. The study was based on the EEC, OECD and
EPA/OPPTS guidelines. A single oral dose of 2,000 mg/kg body weight of
the test material preparation in 0.5% Tylose was applied in a group of
ten rats (five males and five females) to the clipped epidermis (dorsal
and dorsolateral parts of the trunk) and covered by a semi occlusive
dressing for 24 hours. No mortality occurred. Signs of toxicity noted
in the 2,000 mg/kg groups comprised poor general state, dyspnea and
apathy. Findings were observed until including study day 1. The
following skin effects were observed at the application site: white
discoloration, erythema, edema, eczematoid skin change, scaling, and
crust formation. Findings were observed until termination of the study.
The animals did not gain weight during the first post exposure
observation week but restarted to gain weight thereafter. No
abnormalities were noted in the animals necropsied at the end of the
study,
[[Page 78463]]
except in the skin of the application site, where incrustation and full
thickness necrosis (9/10 animals) was observed. Under the conditions of
this study, the acute dermal median lethal dose (LD50) of
the test substance was found to be greater than 2000 mg/kg body weight
for male and female animals.
2-bromo-2-nitro-1,3-propanediol is classed as a weak skin
sensitizer as indicated in four Magnusson and Kligman guinea pig skin
sensitization studies as summarized below.
Study 1 - The test method was the Magnusson and Kligman guinea pig
maximization test, but using 10 test animals, 4 treated controls and 4
untreated controls. Induction in the test animals was by intradermal
injections of 0.03% w/v Bronopol in saline and Complete Freunds
Adjuvant in the shoulder region. The induction process was supplemented
7 days later by 1.5% w/v Bronopol in distilled water applied under
occlusion to the injection sites. Fourteen days later the animals were
challenged on the shaved flank by occluded patch with 0.4% w/v Bronopol
in distilled water. Twenty-four hours after the challenge the patch was
removed and the reaction site examined 24 and 48 hours after removal. A
further 3 challenges were made at either 1 or 2 week intervals. The
treated controls were 4 guinea pigs treated the same as the test
animals except that the test substance was omitted from the intradermal
injection and the covered patch induction procedures. At each challenge
4 previously untreated animals were challenged as per the test animals.
This group formed the untreated control. In the Magnusson and Kligman
Maximization test, sensitization is normally assessed after one
challenge. At this stage in this test there was no sensitization. One
animal was sensitized after 2 challenges and a further animal after 3
challenges. In this test 2/10 animals sensitized after one challenge is
classified as a mild sensitizer (Grade II), but since 3 challenges were
necessary before 2/10 animals were sensitized, the sensitization
potential must be regarded as less than mild, hence Bronopol was found
to be a weak sensitizer by this method.
Study 2 - Induction was carried out as in Study 1 except that 9
guinea pigs were used; induction was 0.02% Bronopol in saline and
induction supplementation was 6-7 days later with 5% Bronopol in
saline. Fourteen days later the animals were challenged (24 hour
occluded patch) with 1% Bronopol in saline. One week later the animals
were subjected to a cross-reaction challenge with 2% formalin. Further
challenges were made with Bronopol and formalin after 2 and 3 weeks.
Any challenge reactions were recorded after 24 and 48 hours. 2/9
animals showed sensitization reactions to Bronopol at challenge 1.
Animals were not challenged with Bronopol at challenge 2. No
sensitization reactions were seen at challenge 3 and 1/9 animals showed
an equivocal reaction at challenge 4. 1/9 animals showed an equivocal
reaction to formalin at challenge 2, but there was no evidence of
cross-reaction at challenges 3 and 4. It was concluded that Bronopol
was a weak sensitizer under the conditions of this test. There was no
significant evidence of cross-reaction to challenge with formalin.
Study 3 - Induction was carried out as in Study 1 except that 9
guinea pigs were used; induction was 0.02% Bronopol in saline and
induction supplementation was 6-7 days later with 2.5% Bronopol in
saline. Fourteen days later the animals were challenged (24 hour
occluded patch) with 0.25% Bronopol in saline; a second challenge was
made after a further 7 days. Any challenge reactions were recorded
after 24 and 48 hours. There was no evidence of sensitization in the 9
animals tested at either challenge, and it was concluded that Bronopol
was not a sensitizer under the conditions of this test.
Study 4 - Induction was carried out as in Study 1 except that
induction was 0.02% Myacide BT (a minimum of 98% Bronopol) in saline
and induction supplementation was 6-7 days later with 2.5% Myacide BT
in saline. Fourteen days later the animals were challenged (24 hour
occluded patch) with 0.25% Myacide BT in saline; a second challenge was
made after a further 7 days. Any challenge reactions were recorded
after 24 and 48 hours. There was no evidence of sensitization in the 10
animals tested at either challenge, and it was concluded that Myacide
BT was not a sensitizer under the conditions of this test. The overall
conclusion was that Bronopol has a very low, and variable,
sensitization potential in the stringent Magnusson and Kligman guinea
pig maximization test and is at most a weak sensitizer in this species.
There was no evidence that the animals had become sensitized to
formalin.
2. Genotoxicty. Mutagenicity studies including in vitro/in vivo in
mouse erythrocytes (micronucleus assay), chromosomal aberration test in
human lymphocytes, Salmonella typhimurium plate (Ames) tests with and
without activation were negative. Bronopol did not induce mutations in
the in vitro bacterial mutagenicity assay (TX 86004) or the V79 cell
mutation assay (TX 86043), neither was there evidence of activity in
assays for host-mediated bacterial mutagenicity or dominant lethality
conducted in mice TX 74034). Furthermore, there was no increase in the
incidence of micronuclei in polychromatic erythrocytes of bone marrow
from male and female mice, 24, 48, or 72 hours after administration of
single oral doses up to a maximum tolerated level of 160 mg/kg (TX
86001). However, weak in vitro clastogenic activity was detected in
cultured human lymphocytes exposed for 24 hours, in the absence of S-9,
to Bronopol at 30 [mu]g/ml (TX 86049). Bronopol is normally self-
stabilizing at about pH 4 in aqueous media, but decomposes at elevated
temperature and more alkaline pH to release formaldehyde as a breakdown
product. Under the conditions of the human lymphocyte chromosome assay,
only about 10% of an initial 30 [mu]g/ml concentration of Bronopol in
the culture medium (pH 6.9) could be detected by analysis after 2 hours
incubation at 370 C (DT 86029), and a formaldehyde concentration of 4.2
[mu]g/ml was found at this time (DT 86030); the calculated value for
formaldehyde released from complete breakdown of the 30 [mu]g/ml
concentration of Bronopol is 4.5 [mu]g/ml. Formaldehyde shows
clastogenic properties in vitro that include the induction of
chromosome aberrations in human lymphocytes. Furthermore, in a
lymphocyte assay conducted in-house (TX 86050), formaldehyde, in the
absence of S-9 activation, elicited chromosome damage that was
qualitatively and quantitatively similar to that seen in the assay of
Bronopol. These findings, supported by the analytical data, indicate
that the in vitro clastogenicity seen with Bronopol is due to its
breakdown to formaldehyde. Although formaldehyde is a clastogen in
vitro, its reactivity precludes distribution in vivo, so it is inactive
in bone marrow and germ cells. The relative instability of Bronopol,
like that of other non-carcinogenic formaldehyde-releasing agents, does
not allow it to transport formaldehyde to these sites. In contrast, the
carcinogen, hexamethylphosphoramide (HMPA), is more stable and requires
metabolic activation to release formaldehyde; as a result, HMPA is
clastogenic in bone marrow and has adverse effects in germ cells. In
conclusion, the testing of Bronopol over a wide range of genetic
endpoints has revealed only a single adverse finding, namely weak in
vitro clastogenicity, and this result is clearly
[[Page 78464]]
attributable to the release of formaldehyde from Bronopol under the
conditions of the lymphocyte assay. The consensus of negative findings
in short-term in vitro tests, together with the negative finding in an
in vivo test for chromosome damage and the absence of oncogenicity in
the life span studies in rats and mice (see below), indicates that
Bronopol does not present a genotoxic hazard.
In a 2-year rat (drinking water) chronic toxicity and
tumorgenicity, Bronopol dissolved in tap water was dosed to 28 day old
rats in 4 groups (45 male and 45 female in the main groups and 15 male
and 15 female in the satellite groups) via the drinking water for 104
weeks at 0 (untreated control), 10, 40, and 160 mg/kg/day. The main
groups were reserved for evaluation of tumorigenic potential and were
not used for blood and urine samples during the study; the satellite
groups were used for blood and urine samples during the study and were
not included in the tumorigenicity assessment. The results at the
various dose levels may be summarized as follows:
160 mg/kg/day
[sbull] Reduced grooming activity during the final year of
treatment.
[sbull] Significantly increased mortality.
[sbull] Reduced weight gain from week 3 onwards among males and
from week 7 onwards among females.
[sbull] Lower food intake among males from week 13 onwards.
[sbull] Marked reduction in water intake throughout the dosing
period and an associated reduction in urine volume noted at weeks 25,
52, and 103.
[sbull] Increase incidence of progressive glomerulonephrosis in
males and females.
[sbull] At week 52, urine repeatedly positive for hemoglobin in 4/
10 males and 1/10 females, at week 77 in 4/10 males and 3/10 females,
and at week 103 in 10/10 males and 1/10 females.
[sbull] Stomach lesions in 20 males and 15 females and the gastric
lymph nodes showed dilation of the sinusoids in 4 males and 5 females.
[sbull] Squamous metaplasia, inflammation or atrophic acini in the
salivary glands of 12 males and 11 females.
40 mg/kg/day
[sbull] Reduced weight gain from weeks 27 to 78 among males.
[sbull] Lower food intake from weeks 53 to 78 among males.
[sbull] Moderate reduction in water intake throughout the dosing
period.
[sbull] At week 77, urine repeatedly positive for hemoglobin in 6/
10 males and at week 103 in 3/10 males.
[sbull] Stomach lesion in 1 male.
[sbull] Squamous metaplasia, inflammation or atrophic acini in the
salivary glands of 12 males and 2 females.
10 mg/kg/day
[sbull] Small but definite reduction in water intake throughout the
dosing period.
[sbull] At week 77, urine repeatedly positive for hemoglobin in 2/
10 males and at week 103 in 2/9 males.
[sbull] Stomach lesions in 1 male and 1 female.
[sbull] Squamous metaplasia and/or inflammation or atrophic acini
in the salivary glands of 5 males and 1 female.
Control
[sbull] At week 52, urine repeatedly positive for hemoglobin in 1/
10 males and 0/10 females, at week 77 in 2/10 males and 0/10 females,
and at week 103 in 3/10 males and 1/10 females.
[sbull] Stomach lesions in 1 male and 2 females.
[sbull] Squamous metaplasia and/or inflammation or atrophic acini
in the salivary glands of 3 males and 2 females.
The evidence of toxic effects related to the administration of
Bronopol was a reduction in food intake, impaired food utilization
efficiency associated with reduced bodyweight gain, and increased
mortality. Changes in the stomach and gastric lymph nodes were
attributed to the irritant effect of Bronopol. Unpalatability reduced
the water intake and was associated with a reduced output of urine, an
increased incidence of hemoglobinuria and an exacerbation of the
spontaneous incidence of progressive glomerulonephrosis. Treatment with
Bronopol exacerbated a spontaneous change in the salivary glands. These
effects were dose related and apart from a small effect on water intake
that was related to palatability, there was no evidence of toxicity at
10 mg/kg/day. There was no evidence to suggest that the administration
of Bronopol affected the tumor incidence. In summary, the study gave a
systemic no observed adverse effect level (NOAEL) of 10 mg/kg/day, a
lowest effect level (LEL) of 40 mg/kg/day and found 2-bromo-2-nitro-
1,3-propanediol (Bronopol) to be not carcinogenic.
3. Reproductive and developmental toxicity. In a two-generation
reproduction study in rats Bronopol was administered to rats in the
drinking water at concentrations of 25, 70, or 200 mg/kg/day. Thirteen
males and 26 females were treated for a minimum of 80 days prior to
mating. They were mated on two separate occasions to produce the F1a
and F1b litters. Weanlings from the F1b litters were randomly selected
(13 males and 26 females) to become parents of the next generation. The
F1 parents were treated for a minimum of 87 days prior to mating, and
were mated on two separate occasions to produce the F2a and F2b
litters. In the F0 generation, one female from each of the control and
low-dose groups, and one male and five females from the high-dose group
died or were sacrificed in extremis during the study; in the F1
generation, one female from each of the low-, mid- and high-dose groups
died before the end of the study. There were no treatment-related
aspects, so these deaths were considered to have been incidental to
Bronopol. Food consumption for the high-dose group was consistently
lower than controls for the F0 males, for F0 females during the initial
two weeks of treatment and the lactation periods for both mates, and
for F1 females during the lactation period of the F2a mate. Water
consumption was reduced in all treated groups, in a dose-related
manner, throughout most of the study; this contributed to the lower
achieved dosages of Bronopol that animals received, namely 22.55, 55.2,
or 147 mg/kg. The female fertility index for the high-dose group was
slightly lower than control at the F1 mate only. Mean body weights of
the offspring of the F0 and F1 high-dose parents (F1a and F1b, and F2a
and F2b, respectively) were lower than the control throughout the
lactation periods. Mean body weights of the F1b pups from the low- and
mid-dose groups were slightly lower than control on day 21 of the
lactation period. There were no other test article-related macroscopic
or microscopic changes. There was a dose-related increase in the kidney
weights of treated F0 females, though the difference between the low
dose group and controls was minimal. In the high-dose group animals
there was a decrease in the absolute weights of the livers, and
possibly also the hearts, of F1 males, and in the absolute liver
weights of F2b males and females; these females also had lower absolute
kidney weights. In conclusion, ingestion of Bronopol elicited signs of
toxicity at all dosages, though the only reproductive or litter
parameter affected at the 25 and 70 mg/kg/day dosages was body weight
of F1b pups at weaning, where a minimal decrease was seen.
An early rat dermal developmental toxicity study gave a maternal
NOAEL > 40 mg/kg/day (HDT) considering 2-bromo-2-nitro-1,3-propanediol
as a severe dermal irritant in rats. Further development toxicity
studies have been carried out for both the rat and the rabbit. In the
rat study three groups of 24 timed-mated female rats were dosed once
daily, orally by gavage, with
[[Page 78465]]
solutions of Bronopol at dose levels of 10, 28, or 80 mg/kg/day from
days 6 to 15 of pregnancy, inclusive. A similar group of females were
dosed with the vehicle (purified water acidified to pH 4) by the same
route and over the same period, and served as controls. Maternal
clinical signs, bodyweights and food consumption were recorded. On day
20 of pregnancy, the females were killed and a necropsy was performed.
Numbers of corpora lutea and live and dead implantations were recorded.
Live fetuses were weighed, sexed and examined for external and visceral
abnormalities. Two thirds of the fetuses were also examined for
skeletal abnormalities. There was evidence of maternal toxicity
following oral gavage administration of Bronopol at 80 mg/kg/day,
characterized by retarded bodyweight gain over days 6 to 7 of
pregnancy. There was no evidence of maternal toxicity at either 10 or
28 mg/kg/day. There was no evidence of developmental toxicity at any of
the dose levels investigated. There may be an association of treatment
at 80 mg/kg/day with advanced ossification of sacral arches and at 28
and 80 mg/kg/day with advanced ossification of the forelimb phalanges.
However, neither of these findings in these groups was unusually
advanced when compared to historical background data.
In a second study using rabbit groups of 18, 19, or 20 timed-mated
female animals were dosed daily between 7 and 19 days of pregnancy,
inclusive, by the oral route with aqueous solutions of Bronopol at dose
levels of 0 (control), 5, 20, 40, and 80 mg/kg/day. Day 0 of pregnancy
was the day of mating. 80 mg/kg/day was selected as a level which
should elicit maternal effects. However, in the event that the effects
may have been too severe, 40 mg/kg/day was selected as the next highest
level known to be tolerated by the pregnant rabbit. The lower dose
level of 5 mg/kg/day and the intermediate dose level of 20 mg/kg/day
were expected to be `no effect' levels. Maternal clinical condition,
bodyweight, and food consumption were recorded. The females were killed
on day 28 of pregnancy and a necropsy was performed. They were weighed,
sexed and examined for external, visceral, and skeletal abnormalities.
At 80 mg/kg/day, Bronopol elicited severe maternal toxicity at the
onset of dosing. The animals recovered after dosing ceased, but the
outcome of pregnancy was affected. There was embryotoxicity
characterized by growth retardation and a slightly higher than expected
incidence of fetal abnormalities. This embryotoxicity was considered
likely to be related to the maternal toxicity. At 40 mg/kg/day, which
was considered to be the highest level likely to be tolerated by the
pregnant rabbit without eliciting severe maternal toxicity, there was
no evidence of adverse effects of treatment on the pregnant rabbit or
developing embryos. This dose level was therefore considered to be the
`no effect' level of Bronopol with regard to developmental toxicity.
4. Subchronic toxicity. A 13-week rat gavage study showed a NOAEL
of 20 mg/kg/day and a lowest observed adverse effect level (LOAEL) of
80 mg/kg/day. Bronopol as a solution in distilled water was dosed to CD
rats (4 groups of 20 males and 20 females) by oral gavage once per day,
seven days per week for 13 weeks at 0 (untreated control), 20, 80, and
160 mg/kg/day. Reaction to treatment was as follows:
160 mg/kg/day - Severe respiratory distress and abdominal
distension; reduced bodyweight gain and food consumption; death of 22
males and 14 females (includes 4 male and 3 female rats which replaced
rats dying after one dose); all surviving rats were killed on day 9;
autopsy showed gaseous and fluid distension of the gastro-intestinal
tract in the majority of decedents; ulceration, epithelial hyperplasia
and hyperkeratosis or congested vessels in the stomachs of 2 males and
4 females.
80 mg/kg/day - Severe respiratory distress and abdominal
distension, the latter sign confined to 6 males and 6 females which
subsequently died. At week 6, only 4 males and 2 females showed slight
respiratory difficulty. Seven males and 9 females died with autopsy
showing gaseous and fluid distension of the gastro-intestinal tract;
reduced bodyweight gain and food consumption for the first week of
treatment only; renal changes in 2 males.
20 mg/kg/day - In one male, respiratory distress, which
subsequently regressed; renal changes in 2 males.
A 13-week dog gavage study showed a NOAEL of 8 mg/kg/day and LOAEL
of 20 mg/kg/day. Bronopol dissolved in water was dosed to Beagle dogs
(4 groups of 3 males and 3 females) by oral gavage once per day, seven
days per week for 3 months (13 weeks) at 0 (untreated control), 4, 8,
and 20 mg/kg/day. One pair of dogs was dosed at levels of 20- 40 mg/kg/
day, over a period of 2 weeks in order to determine the vomiting
threshold of Bronopol. This was found to be at a dosage of
approximately 20 mg/kg/day. During the study vomiting occurred within
30 minutes of dosing and no other clinical signs were observed.
Macroscopic post mortem examination revealed no abnormalities. In the
main study there were no deaths. Vomiting, mainly at 20 mg/kg/day,
within 0.5 hour of dosing was observed with occasional passage of
liquid feces and red-stained mucus in isolated animals, both dosed and
control. There were no adverse effects on food or water consumption, or
on bodyweight. There were no abnormalities of the eye; no macroscopic
post mortem abnormalities; or morphological changes or variations from
normal in histological tissue examination which could be related to
dosage of the test compound. After dosing for 6 weeks, one animal
receiving 8 mg/kg/day had a serum alkaline phosphatase value
approximating to the upper limit of normality of 35 King Armstrong
units; after 12 weeks, however, the value was well within normal
limits. After dosing for 12 weeks the group mean total white cell
count, although within normal limits, was significantly lower in dogs
receiving 8 and 20 mg/kg/day than in the controls. One animal receiving
4 mg/kg/day had a serum glutamic-pyruvic transaminase value after 12
weeks which exceeded the upper limit of normality of 50 mU/ml. Apart
from the liver of one dog receiving 20 mg/kg/day which was heavier than
would normally be expected, all organ weights were within normal
limits. However, when expressed as a percentage of bodyweight the mean
liver and spleen weights for dogs receiving 20 mg/kg/day were
significantly heavier than the control values.
5. Chronic toxicity. A 2-year toxicity/carcinogenicity Bronopol
study (administration via drinking water) in rats showed a NOAEL of >=
7 mg/kg/day and a LEL of < 32 mg/kg/day. For more detail see the
carcinogenicity summary in Unit B.2.
In a study on potential local and tumorigenic effects from repeated
dermal application to mice Bronopol dissolved in 90% acetone/water was
applied to the shaved dorsum of 3 groups of mice (52 male and 52 female
per group) at 0 (vehicle control), 0.2%, and 0.5%. Application was at
the rate of 0.3 ml per mouse on three days (Monday, Wednesday, and
Friday) in each week for 80 weeks. The results are summarized as
follows:
[sbull] Among some mice treated with 0.5% Bronopol, there was
minimal hair loss at the periphery of the shaved area during the first
three weeks of treatment.
[sbull] A marginally inferior survival rate was recorded among male
mice, although the prime cause of death
[[Page 78466]]
among decedents showed no relation to treatment.
[sbull] Between weeks 26 and 52, an inferior bodyweight gain was
recorded among male mice treated with 0.5% Bronopol, although
bodyweight gain over the 80 week treatment period was comparable with
that of the controls. Bodyweight gain among other treated mice was not
disturbed by treatment.
[sbull] Food intake and efficiency of food utilization showed no
disturbance by treatment.
[sbull] Macroscopic examination of decedents and mice killed after
80 weeks of treatment, revealed pathology which was common to some
animals from control and treated groups.
[sbull] Microscopic examination of decedents and mice killed at
termination revealed changes consistent with the age and strain of
mouse employed.
[sbull] Treatment with Bronopol did not alter the spontaneous tumor
profile of the mice.
6. Animal metabolism. Rat and dogs were used in a metabolic study
with both oral and cutaneous dosing as follows: Oral Dosing in Rats was
by stomach tube with aqueous solutions of [14C]-Bronopol (1 mg/kg).
Oral Dosing Dogs - Beagle dogs were dosed with [14C]-Bronopol (2 mg)
mixed with unlabelled Bronopol (6-8 mg) as an aqueous solution in
gelatin capsules. Cutaneous Dosing Rats and Rabbits - Initially
solutions of [14C]-Bronopol (4 mg/kg) in water, acetone and acetone/
water (9:1, v/v) were applied to the clipped backs of rats to determine
the influence of the vehicle on percutaneous absorption. Acetone was
determined to be the preferred application vehicle. In the main tests
an acetone solution of [14C]-Bronopol (4.8 mg/ml) was applied to
shaved/depilated areas of the backs of rats and rabbits at the rates of
0.05 ml per rat and 0.2-0.4 ml per rabbit, the treated areas being
occluded with secured polythene. After an oral dose of [14C]-Bronopol
(1 mg/kg) to rats or dogs, the radioactivity was completely absorbed,
evenly distributed and rapidly excreted. Excretion was almost complete
in 24 hours. During 5 days, rats excreted 83.3% in the urine, 5.8% in
the feces (via the bile) and 8.4% in the expired air; 1.6% was still
retained probably by incorporation into pathways of intermediary
metabolism of [14C]-glycerol produced by biotransformation of [14C]-
Bronopol. During 5 days, dogs excreted 81.8% in the urine and 3.1% in
the feces. After an oral dose of [14C]-Bronopol (1 mg/kg), peak blood
levels of radioactivity were reached in rats and dogs within 2 hours,
and declined with an initial half-life of 4 +/- 1 hour. After an oral
dose of [14C]-Bronopol (1 mg/kg) to the rat and the dog, Bronopol and
its metabolites were evenly distributed. Only in tissues concerned with
excretion did levels of radioactivity exceed those in the blood. When
applied to the skin of rats, [14C]-Bronopol was absorbed to a greater
extent from an acetone solvent vehicle than from water:acetone (1:9, v/
v) or water alone. In rats, at least 7 and 15% of an applied dose was
percutaneously absorbed during 24 and 96 hours respectively. In
rabbits, at least 9% of an applied dose was percutaneously absorbed
during 24 hours. Pretreatment of rabbit skin with a depilatory enhanced
absorption. Microhistoautoradiographs of rabbit skin showed that [14C]-
Bronopol was mainly localized on the epidermis around the hair
follicles. The limited percutaneous absorption of Bronopol may occur
through the hair follicles. Five metabolites, which were more polar
than Bronopol, were detected in the urine of rats and dogs given an
oral dose of [14C]-Bronopol. One metabolite, shown by comparison of
infra-red and mass spectra with synthetic material to be 2-
nitropropane-1,3-diol, accounted for more than 40% of the administered
dose. Unchanged Bronopol, which is unstable in plasma, was not
detected. A similar pattern of urinary metabolites of [14C]-Bronopol
was found after cutaneous application as after oral administration of
the compound.
Further metabolic studies were carried out in male and female rats
following single oral doses of [14C]-Bronopol at 10 and 50 mg/kg and
repeated dosing at 10 mg/kg/day with Bronopol for 14 days followed by a
single oral dose, 10 mg/kg of [14C]-Bronopol. The compound was well
absorbed and rapidly excreted mainly via urine. Radioactivity found in
the carcass and tissues at 168 hours after dosing accounted for less
than 3% of dose. There were no major consistent differences between
male and female rats. Bronopol was highly metabolized and intact
compound was not detected in the urine. The urinary metabolite
chromatographic patterns contained numerous polar metabolites and
similar patterns were found for each group. The major metabolite
observed was equivalent to desbromo-bronopol (2-nitro-propane-1,3-
diol). Extensive metabolism led to radiolabeled one-carbon units
excreted as carbon dioxide in expired air.
7. Metabolite toxicology. As determined in the animal metabolism
studies in Unit B.6. numerous polar metabolites were identified in
urine from rat and dog. Unchanged 2-bromo-2-nitro-1,3-propanediol was
not detected. The major peak in most samples corresponded to
desbromobronopol (debrominated bronopol), i.e. 2-nitropropane-1, 3-
diol. This metabolite is not considered of toxicological concern.
8. Endocrine disruption. No specific tests have been conducted with
2-bromo-2-nitro-1,3-propanediol to determine whether the chemical may
have an effect in humans that is similar to an effect produced by a
naturally occurring estrogen or other endocrine effects. However, there
were no significant findings in other relevant toxicity tests, i.e.,
teratology and multi-generation reproduction studies, which would
suggest that 2-bromo-2-nitro-1,3-propanediol produces effects
characteristic of the disruption of endocrine functions.
C. Aggregate Exposure
1. Dietary exposure--i. Food. The proposed use of 2-bromo-2-nitro-
1, 3-propanediol as a preservative in end-use pesticide formulations
applied to growing crops, raw agricultural commodities after harvest,
and animals is not expected to result in any significant additional,
dietary exposure, due to the low concentration of 2-bromo-2-nitro-1, 3-
propanediol employed in the formulation and the extremely low
probability of significant contact by the general public following
treatment.
2-bromo-2-nitro-1, 3-propanediol has FDA approval for indirect food
contact use as a preservative in adhesives that are components of food
packaging or storage materials (21 CFR 175.105); as a slimicide for use
in pulp and papermaking at a maximum level of 0.6 lb/ton of dry weight
fiber (21 CFR 176.300); and paper components in contact with aqueous
and fatty foods at a level not to exceed 0.01% by weight of those
components (21 CFR 176.170). These uses are not expected to result in
quantifiable residues of 2-bromo-2-nitro-1, 3-propanediol in the diet.
Uses as a preservative in concentrates of agricultural pesticide
products also is not expected to be a source of quantifiable residues
in food.
There are no acute or chronic toxicological concerns associated
with the proposed use of 2-bromo-2-nitro-1,3-propanediol as an inert
ingredient in concentrates of agricultural pesticide products. An acute
dietary risk assessment, therefore, is not required. Chronic exposure
to 2-bromo-2-nitropropane-1, 3-diol through food is essentially
insignificant.
ii. Drinking water. Contamination of drinking water would not be
expected to
[[Page 78467]]
occur under the proposed use conditions of 2-bromo-2-nitro-1, 3-
propanediol as a preservative at very low concentrations in pesticide
products intended for applications, principally to growing crops, raw
agricultural commodities after harvest, and animals; as either a direct
pour-on application or as a spray. Neither method of application is
expected to contaminate water supplies intended for human consumption.
Bronopol is not applied to water and is not used for the disinfection
of human or animal drinking water.
2. Non-dietary exposure. 2-bromo-2-nitro-1, 3-propanediol is used
as an industrial biocide for the prevention of biofouling in areas such
as recirculating water in cooling towers and evaporative condensers,
air conditioners, air washers and humidifier systems, oil, gas and
industrial process water, metal working fluids and paper mill pulp and
process water; and for the preservation of surfactants, adhesives,
starch, pigment and extender slurries, paints, latex and antifoam
emulsions, absorbent clays, water based printing inks and print
solutions, water based pesticides and chemical toilet solutions. The
margins of exposure (MOEs) calculated for direct applicators
occupationally exposed by either the dermal or inhalation route, based
on worst-case estimates, revealed there is no level for concern.
Estimated exposures to professional painters using paint preserved with
2-bromo-2-nitro-1, 3-propanediol were used as the worst-case for
estimating secondary occupational exposure risk. MOEs were not exceeded
and EPA has concluded that risk associated with secondary exposure are
not of concern.
2-bromo-2-nitro-1, 3-propanediol is also used in the preservation
of consumer, household and institutional products. Based on the worst-
case estimate for professional painters chronically exposed to 2-bromo-
2-nitro-1, 3-propanediol, EPA has concluded that risk associated with
these uses are not of concern.
2-bromo-2-nitro-1, 3-propanediol also is used to preserve
pharmaceuticals, cosmetics, and toiletries, which are regulated by FDA.
The Cosmetic, Toiletries and Fragrance Association's (CTFA's) Cosmetic
Ingredient Review (1980) states that 2-bromo-2-nitro-1,3-propanediol is
safe as a cosmetic ingredient at concentrations up to 0.1% except where
there is a risk of nitrosamine or nitrosamide formation. Similarly, 2-
bromo-2-nitro-1,3-propanediol is listed in Annex VI of the EC Cosmetics
directive as an approved preservative for use up to 0.1% except where
there is a risk of nitrosamine formation.
Based on toxicity data, an aggregate risk or likelihood of the
occurrence of an adverse health effect resulting from all routes of
exposure to 2-bromo-2-nitro-1, 3-propanediol is not expected.
D. Cumulative Effects
There is no reliable information that would indicate or suggest
that 2-bromo-2-nitro-1, 3-propanediol has any toxic effects on mammals
that would be cumulative with those of any other chemical.
E. Safety Determination
1. U.S. population. The reference dose (RfD) for 2-bromo-2-nitro-1,
3-propanediol based on the 2-year chronic study (drinking water) in
rats with a NOAEL of 10 mg/kg/day and using an uncertainty factor of
100 is calculated to be 0.1 mg/kg of body weight (bwt)/day. The
estimated worst-case theoretical maximum residue contribution (TMRC)
resulting from this action will be 0.000024 mg/kg/bwt/day for the
overall U.S. population and represents 0.024 percent of the RfD. Based
upon this information and review of its use, EPA has found that, when
used in accordance with good agricultural practice, this ingredient is
useful and a tolerance is not necessary to protect the public health.
2. Infants and children. Nothing in the available literature would
suggest that infants and children are more sensitive to the effects of
2-bromo-2-nitro-1, 3-propanediol than adults. Exposure of infants to 2-
bromo-2-nitro-1, 3-propanediol resulting from its proposed use as an
inert ingredient in certain pesticide formulations is expected to be
negligible and will not put infants and children at increased risk.
F. International Tolerances
BASF Corporation is not aware of the existence of any international
tolerances for 2-bromo-2-nitro-1, 3-propanediol.
[FR Doc. 02-32400 Filed 12-23-02; 8:45 am]
BILLING CODE 6560-50-S