UNITED STATES ENVIRONMENTAL PROTECTION AGENCY

WASHINGTON, DC 20460

			OFFICE OF  PREVENTION, PESTICIDES,  AND TOXIC SUBSTANCES

 

								October 31, 2007

MEMORANDUM:

Subject:	Octhilinone: Response to comments on the Toxicology
Disciplinary Chapter and the Risk Assessment for the Reregistration
Eligibility Decision Document.

To:		K. Avivah Jacob, Chemical Review Manager,

		Regulatory Management Branch II

Antimicrobials Division (7510P)

From: 		Timothy F. McMahon, Ph.D.

Senior Toxicologist

Antimicrobials Division (7510P)

	 

DP Barcode: 		

Chemical Name:2-n-Octyl-4-isothiazolin-3-one (Octhilinone or OIT)	

		

PC Code:		099901 

CAS Registry No. 	26530-20-1

In a letter dated August 17, 2007 from the registrants of Octhilinone 
(Rohm and Haas Company and Acti-Chem Specialties, Inc.), comments were
made on the Agency’s Reregistration Eligibility Decision Document
disciplinary chapters for Octhilinone.  The purpose of this memorandum
is to respond to the comments made on the Toxicology Disciplinary
chapter and the Risk Assessment chapter for Octhilinone. 

The comments with regard to the risk assessment were made on pages 9-12
of the registrants’ letter, while the comments on the Toxicology
chapter were made on pages 13-21 of the registrants’ letter. 

Comments on the Risk Assessment for OIT

Comment (1): 

Based on existing Agency policy and precedent, OIT should be regulated
solely as an irritant and no dermal risk assessment should be conducted
for any occupational or residential use. 

The registrants claim that the Agency has determined that no dermal risk
assessment is appropriate under circumstances in the case of severely
irritating or corrosive chemicals.  The registrants cite examples from
the Health Effects Division, OPP, for endothall where dermal risk
assessments were not conducted on the basis of the irritation potential
of endothall. 

Agency response:  

The Antimicrobials Division, OPP, in conjunction with scientists from
the Health Effects Division and the Biopesticides Division, OPP,
developed a policy regarding the use of dermal irritation as an endpoint
for risk assessment in 2006.  It was necessary to develop such a policy
based on the unique exposure patterns for certain antimicrobial uses,
particularly with regard to treated articles (carpet, fabrics, treated
wood).  This policy has been applied to several chemicals for which RED
documents have been developed, and is also applied in the case of OIT
for the short-term dermal risk assessment only. 

Comments on the Toxicology Disciplinary Chapter for OIT 

Comment (1):

On page 7 of the Toxicology chapter, the phrase “non-guideline”
appears before the study title header.  

Agency response:  

 Although this is a non-guideline study, the designation belongs at the
end of the summary and will be relocated to that section.   

Comment (2): 

The comment was made that a subchronic oral toxicity study in rodents is
not required to support the current registered uses of OIT as there are
no food uses. However, oral subchronic toxicity studies in the rat and
dog have been conducted. 

Agency Response: 

Subchronic toxicity testing is a data requirement for all use patterns
of antimicrobial pesticides and is not limited to food uses only. The
comment by the registrants above was made in reference to the
unacceptable classification assigned to the subchronic toxicity test
summaries presented in the Toxicology chapter.  There are acceptable
subchronic toxicity tests for OIT by the dermal and inhalation routes. 
When the newly submitted subchronic toxicity data are reviewed, these
summaries can be added in the future to the Toxicology chapter if found
to be acceptable. 

Comment (3):

On page 9 of the Toxicology chapter, “non-guideline” appears before
the study title header.  

Agency response:  

Although this is a non-guideline study, the designation belongs at the
end of the summary and will be relocated to that section.   

Comment (4): 

With regard to the 21-day dermal toxicity study in rabbits summarized on
page 10-11 of the Toxicology chapter, the registrants note that the
discussion of this study should be corrected to identify severe
irritation as the ‘critical effect’ and that “the body weight gain
effects are secondary to the severe irritation.

Agency response: 

The 21-day dermal toxicity study was considered unacceptable and was not
used for risk assessment purposes. 

Comment (5):

With respect to the 90-day dermal toxicity in rats listed on pages 11-12
of the Toxicology chapter, the registrants state that the discussion of
this study should be corrected to state that, “in fact, there is no
systemic toxicity found in the study. The minor effects are clearly
secondary to severe irritation in the compromised animals at the high
dose level.”

Agency response:  

The 90-day dermal toxicity study listed on pages 11-12 of the Toxicology
chapter stated both systemic effects and skin effects from dermal
application of OIT. The hematologic effects observed in this study have
been observed in other studies conducted with OIT and thus are
considered relevant for determination of  doses causing systemic
toxicity.  The irritation effects were considered separately in this
study. 

Comment (6): 

The registrants commented that the discussion of the 90-day dermal
toxicity study in the rat (MRID 43935706) summarized on pages 12-13 of
the Toxicology chapter needs to be revised in light of submission of an
amendment to the report (MRID 44307101) where microscopic examination of
the lower dose groups was reported. 

Agency response: 

Comment (7):

The registrants state that the 10-day inhalation toxicity study was only
a dose range-finding study and was not intended to fulfill a guideline
requirement.  The study should not be interpreted to infer a NOAEL
value. 

Agency response:

If the study was conducted as a range-finding study, the conclusions in
the Toxicology chapter can be modified to reflect this.  Note, however,
that this study was not used for risk assessment purposes and has no
influence on the current risk assessment for OIT. 

Comment (8):

The registrant states that “EPA’s assessment of this study (MRID
41544701) is incomplete. There is no evidence of systemic toxicity at
any dose tested.”  It is further stated that “it is inapprorpriate
to calculate a systemic NOEL from this 90-day study, as there was no
systemic toxicity…”

Agency response: 

The selection of the NOAEL of  0.64 mg/m3 in this study would not change
if the other effects listed under the LOAEL (clinical signs,  decreased
body weights, fluid in the uterus, and the pulmonary histopathological
findings at the terminal sacrifice for males and females) were removed. 
The histopathological effects are considered systemic and are also
recognized as a result of the irritancy of the test chemical. 

Comment (9): 

The registrants have commented on Section 4.3 of the Toxicology chapter
regarding developmental toxicity of OIT.  They have commented that there
are no systemic effects observed in any of the developmental toxicity
studies summarized in the chapter. 

Agency response: 

The NOAEL values determined from review of the developmental toxicity
data do not change whether one includes or excludes the effects claimed
by the registrant as the result of the irritancy of the chemical. 

Comment (10):

The registrant has commented on section 4.4 of the Toxicology chapter,
reproductive toxicity.  The registrant states that a reproductive
toxicity study is not required for OIT as there are no food uses.
However, a 2-generation reproductive toxicity study has been recently
submitted to evaluate reproductive toxicity of OIT in rats. 

Agency response: 

The Agency has not, as of this date, completed a formal review of the
reproductive toxicity study on OIT. When such review is final, the
executive summary can be made available for the Toxicology chapter.  The
Agency agrees that there are no dietary exposures from the currently
registered uses of OIT. 

Comment (11): 

The registrant has commented on Section 4.5 of the Toxicology chaper for
OIT. The registrant states that chronic toxicity studies in rodents are
not required to support the current registered uses of OIT as there are
no food uses. Based on the available data for OIT and related
isothiazolone biocides, OIT does not present a chronic hazard. 

Agency response: 

The Agency is currently deliberating whether data from
structurally-related isothiazolone biocides can be used to address the
chronic toxicity of OIT.  There are no acceptable chronic toxicity data
on OIT itself. 

Comment (12): 

The registrant has commented on Section 4.6 of the Toxicology chapter.
The registrant states that OIT does not present a carcinogenic hazard
based on the available data for OIT and related isothiazolone biocides. 

Agency response: 

The Agency is currently deliberating whether available data from
structurally-related isothiazolone biocides can be used to address the
carcinogenicity of OIT.  There are no acceptable carcinogenicity data on
OIT itself. 

Comment (13): 

The registrant commented on Section 4.7, Mutagenicity. The registrant
states that the mutgenicity database is complete and that OIT does not
pose a genotoxic hazard. 

Agency response:

The Agency recognizes that the majority of the mutagenicity data on OIT
are negative.  The Agency notes however, that one study (MRID 40647503)
is presumptively positive for chromosome aberrations in the absence of
data to clarify whether the effect was based on the test material,
experimentation conditions, or a combination of both.  The California
Department of Pesticide Regulation in its summary of Toxicology data for
OIT agreed with the positive response observed in this study. 

Comment (14):

The registrant has commented on Section 4.8, Neurotoxicity. The
registrant states that there is no evidence for neurotoxicity of OIT in
the database and that requiring an acute neurotoxicity screening battery
on the basis of results of acute oral and dermal testing is inconsistent
with the results of repeat dose toxicity testing, where no evidence of
neurotoxicity testing is observed.

Agency response: 

The Agency reserves the decision on the requirement for an acute
neurotoxicity screening battery pending review of the recently submitted
subchronic study in the rat, where functional observations were included
and no evidence of neurotoxicity was reported. If final review of this
study shows no evidence of neurotoxicity, then the Agency will not
require further neurotoxicity testing for OIT. 

Comment (15): 

The registrant has commented on Section 4.9 of the Toxicology chapter.
The registrant has stated that a general metabolism study is not
required for OIT.  However, a metabolism study has been conducted and
recently submitted to the Agency. 

Agency response: 

The Agency can include the summary of the submitted metabolism study
once the study review is finalized. 

Comment (16): 

The registrant has commented that the statement regarding dermal
absorption on page 21 of the Toxicology chapter be eliminated. A dermal
absorption factor is not required for OIT. 

Agency response: 

The Agency acknowledges that currently a dermal absorption factor was
not needed for OIT on the basis of route-specific toxicity studies on
which to base a dermal risk assessment.  A dermal absorption study was
recently submitted and can be used for any future purpose if found to be
acceptable.  The statement as it appears in on page 21 (“Since a
dermal endpoint was selected from a dermal toxicity study, a dermal
absorption factor is not needed for Octhilinone”) is not
inappropriate. 

Comment (17):

The registrant has commented that the statement on pages 21-22 of the
Toxicology chapter regarding pre- and post-natal toxicity are not
appropriate to this section. 

Agency response: 

The Agency agrees that the comments in this section are related to
neurotoxicity and not pre- and post-natal toxicity of OIT. Thus these
comments have been removed and a statement more specific to pre- and
post-natal toxicity has been written. 

Comment (18): 

The registrant states that the Toxicology study summary table needs to
be significantly revised in accordance with the comments made above on
the various studies for OIT.  The Toxicity endpoint selection table
should also be revised to reflect that no dermal assessment should be
conducted based on the irritancy of OIT. 

Agency response: 

The Agency is satisfied with the conclusions currently shown in the
Toxicology summary table. 

The Agency is also not changing the selected endpoints for OIT with
regard to dermal risk assessement.  The selected studies and effects are
consistent with Agency practice for other antimicrobial pesticide
chemicals. 

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