Document ID: EPA-HQ-OPP-2007-0339-0011
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2008-05-28T04:00Z

Memorandum

To:	Risk Assessment Document for Dichlobenil, Fluopicolide and BAM 

From:	Mary Manibusan, Co-chair of ROCKS

Date:	May 12, 2008

RE:	Comparative Toxicity using Derek analysis for Dichlobenil,
Fluopicolide and BAM

DP#:	7E7172, DP 352656.

Dichlobenil and Fluopicolide are pesticides that share a common
metabolite BAM. BAM is a metabolite and/or environmental degradate of
both the fungicide fluopicolide and the herbicide dichlobenil.  Based on
the rat metabolic pathway, BAM is not formed in vivo or at very minimal
amounts (0.09% of the total administered dose in rats) therefore, it is
assumed that neither toxicological profiles for dichlobenil nor
fluopicolide would be reflective of the toxicity specific for BAM.  This
Derek  analysis is therefore focused on the structural similarities of
these compounds to determine whether the  relative toxicity predictions
would be different based on structural alerts.  

Derek Analyses for Fluopicolide, Dichlobenil and BAM (2, 6
Dichlorobenzamide)

Comparative Toxicity

Overall, Derek is confirmatory of the animal data for fluopicolide and
dichlobenil, which forms the bases for the toxicity prediction for BAM. 
Based on the available animal data and Derek analyses, BAM does not
appear to cause different organ specific toxicities compared to
fluopicolide and dichlobenil.  The kidney and liver toxicities are
common to all three compounds.  With respect to relative toxicity,
conclusions from the evaluation of the animal studies appear to confirm
that both fluopicolide and dichlobenil appear to be more or equally
toxic compared to BAM.  Based on the Derek evaluation, Derek did not
appear to distinguish fluopicolide toxicity compared to BAM based on
alerts issued only for the benzamide (BAM) portion of the structure,
indicating that the remaining pyridine structure would not contribute
significant biological activity.  Derek also confirms the liver toxicity
profile and slight to minimal kidney effects evident in the empirical
data for all three compounds.

Olfactory Toxicity

Based on dermal and inhalation exposures to dichlobenil and i.p.
administration of BAM, olfactory toxicity was determined to be a target
organ effect.  The BAM-mediated olfactory toxicity was observed only in
one study collected from open literature (Brittebo et al., 1991) at a
dose (100 mg/kg) eight times higher than that which caused the same
effect using dichlobenil (12 mg/kg i.p.).  No olfactory effects were
reported for Fluopicolide.

All three compounds are structurally similar based on sharing the
2,6-chlorinated benzene structure; the 2,6-positioning of chlorines in
combination with an electron-withdrawing group in the primary position
of the benzene ring is an arrangement that appears to facilitate
olfactory mucosa toxicity (Carlsson et. Al. 2005).  Based on this rule
based reasoning, the nitrile group on the dichlobenil is a better
electron withdrawing group than the amide group on BAM, which is equal
or less than the pyridine group on fluopicolide.  This ranking is
reflective of the potency of olfactory toxicity exhibited in the animal
studies (dichlobenil>BAM>Fluopicolide).

While the olfactory effects are relevant for i.p., inhalation and
dermal, these effects may not be directly relevant for the oral route. 
No oral studies, to date, have reported olfactory toxicity for these
compounds.  For example, a chronic dietary dog study on dichlobenil that
assayed for olfactory histopathology did not observe effects on the
nasal epithelium from long term exposure.  Therefore, based on the
different routes of exposure and the negative long term oral study in
the dog, these data indicate that olfactory effects may only occur when
by-passing the liver metabolism.  

Neurotoxicity

Evidence of potential neurotoxicity in reduced muscle tone were reported
in the 90 day rat study at day 4 in males and days  91 and 92 in females
at a dose of 49 mg BAM /kg/day and this was used to establish the
incidental oral  short and intermediate term endpoint.  Lethargy and
ataxia were observed in a dose-range finding pilot study in mice, but
effects were resolved after 24 hours.  In addition, a two week dietary
study reported clinical signs of neurotoxicity in mice at 375 mg/kg/day,
a dose much higher than that established in the 90 day rat study. 
Furthermore, fluopicolide was tested in both acute and subchronic
neurotoxicity studies and no neurotoxicity findings were reported.    

Based on the totality of the data supporting the potential olfactory and
potential neurotoxic effects for BAM,  the composite uncertainty factor
appears to be more than adequate.

References:

Brittebo EB, Erkisson C, Feil V, Bakke J, Brandt I. 1991. Toxicidty of
2,6-dichlorothiobenzamide and 2,6-dichlorobenzamide in the olfactory
nasal mucosa of mice. Fundam Appl Toxicol. 17(1):92-102.

Carlsson C., Harju M, Bahrami F, Cantillana T, Tysklind M, Brandt I.
2004. Olfactory mucosal toxicity screening and multivariate QSAR
modeling for chlorinated benzene derivatives. Arch Toxicol.
78(12):706-15