-------
6 4
D1benzo-£-d1ox1n Dlbwzofuran
FIGURE 2. Structure of dfoxin and furan
the tetra-, penta-, hexa-, hepta-, and octa-dibenzofurans (Buser and
Bosshardt, 1976). The amount of then chemicals 1n PCP varies with each
industrial batch produced, even when produced by the sane nnufacturer.
Analytical methods for wasuring Individual Isomers require sophisticated
and expensive analytical instrumentation, and standards for the isomers are
not generally available. Until recently, both the dioxins and furans in
PCP have been raaasured as 1someric groups. Table 2 shows the composition
of typical commercial PCP.
The physical, chemical, and toxicological properties of indi-
vidual dioxins and furans are, with one exception, relatively unknown.
The exception is 2,3,7,8-tetr3chlorod1benzo-j£-dioxin. (TCDD), which has
been stown to be one of the most toxic compounds knovn. TCDD is not
fov.id in PCP at a limit of detection less than 0.05 ppm (Johnson et al.,
1973). However, the dioxins in PCP have been shown by Johnson et al.
16
-------
If
tUSLL 2. Composition of cooMrcial pantachlorophgnol
CoBpomat
Pcntachlorophrael
It tradi loropbcnol
Trichloropacool
Cblorinatad Phcnoxyphcao I*
H«t*-dioxioa
H*pta~dioxia*
Oct*-tiioxia
Haxa-foran*
Eapts-furans
Occa-furaa
Dowieide 7
M.4Z
4.4Z
< 0.1Z
< 6.2Z
4 ppa
125 pp.
2500 ppa
30 ppm
80 ppa
80 pp*
2i
Dowieide EC-?
89. 8 S
10.2Z
< 0.1%
-
1.0 ppa
6.5 ppa
15.0 ppa
< 1 PP»
1.8 ppa
< 1 ppa
II Data froo Dow Cheaical Coapitoy.
2/ Total gra«cw th«a lOOt bccicuse nusbcrs ar« rounded off.
17
-------
(1973) to cause cblorecne in rabbits and edeaa in chicks. The only data
available coap axing the toric effect* of individual diozia isoaers were
reported by He Conn*1 tt ml. (1977), and these are shown in Table 3.
These data indicate thac the hexa- and hepta-dioxin isoaers tested vere
less toxic than TCDD in sdce and (oinea pigs; haeerer, they would be
classified as Category I poisons (oral IJ)-50 less than 50 ag/kg).
I/
TABLE 3. Single oral LD-50-30 of dioxin isoaes
Isoaer
1.2,3,4
1,2,3,6
*
1,2.3,7
,7,8-HCDD
,7,8-HCDD
,8,9-flCDD
LD-50-30,
Guinea Pigs'
72.5
2/
70-100
2/
60-10C"
uft/ki
Mice
825
1250
1440
1,2,3,4,6,7,8-BeCDD 7180
I/
TCDD 2 283.7
I/ Data froa HcCoanell et al. (1977).
2j Estiaaced range represent* variability aaoog replicates.
3/ TCDD values are shown for coaparative purposes.
Firestone (1977) detected PC?, individual bexa- and bepta-dioxin
isoosrs, aod octa-dioxin in asaples of coaatrcial gelatin procurrsd fzoa
supsraarbets and in bulk. Gelatin is produced froa pork skioe and catcle
-------
bones and bides, which My be preserved with PCP during processing both in
thia country aad abroad. According to Firestone, the annual consumption
of gelatin in the United State* is 57 million pound* of doasstic production
and 13 million pounda of imports.
Higheat level* of PCP aad total dioxina were found in bulk gelatin
that ma imported from Mexico and produced by a single company. Three
meaaurements of thia gelatin averaged 6.4 pom of PCP, and aix asaaurcments
averaged 26.8 ppb of total dioxina. In contrast, bulk domestic porkskin
gelatin had no PCP and 0.1 ppb of total dioxina (octadioxins) in one of two
•ample •eaaurements. Three conauaer packages of unflavored gelatin purchased
in a supermarket showed 0.2, 0.8, and 3.6 ppb of total dioxins.
0. Regiatered Daea and Production
Pentachlorophenol aad it* derivative* axe among the coat ver-
satile peetisidea now in uae in the Oaited States. This versatility is
due first to their efficacy against a wide variety of pests (bac-
teria, yciac, slime molds, algra, fungi, plants, insects, snails), and
second to their solubility in both organic solvents and water. Thus,
PCP can be applied to a wide spectrun of materials. In various concentrations,
solvents, and formulationa, pentachlorophenola are registered for use on
beans (for replanting purposes only), wood, leather, burlap, sasonry,
cordage, paints, patroleua, pulp and paper mill systems, weeds on seed
crops (preharvost desiccant), secondary oil recovery injection waters, and
corasarcial and industrial water cooling towers and evaporation condensers
(B*-PCP).
19
-------
Approximately 50,000,000 pound* of PC? is produced annually in the
Qaiccd States. Ihf major use of PC? in the Obi ted States is an a wood
preservative. This use COBSUMS approximately 802 of ail PC? produced.
About 111 of the PC? produced is formulated as Ma-PC? and used in the
produc?ioa of pressed and insulation board, and in cooling town. Approxi-
mately 6Z is used in pulp and paper stills to control the growth of slime-
forming bacteria and fungi in paper production; 3Z is used for fan
treatment of fence posts, home .protection against termites, and as a
herbicide and pre-hazvest desiccant. . . ,
The number of federally-registered products coutainitg PC? and
the number of registrants is given in Table 4. In addition, there are 75
State-registered products formulated by 60 registrants.
I/
TAJL£ 4. Federal retiatration of pentactCorophenot"^
PC?
Na-PCP
K-PCP
L-PCP
Ho. Products
578
196.
5
6
No. Registrants
240
88
4
2
; .. • '
I/ Data from computerized Eagistration Division files.
20
-------
E« Regulatory History
Technical PCP was registered for us* as a wood preservative in
1943 by Dow Cheaical Company and Monsanto Agricultural Products Co«pany.
Subsequently, registrations were granted for a vide variety of uses,
including agricultural uses such .as pre- or postharvest weed treatment
and prebarvest dessication of seed crops. Dhtil 1970, regulatory
actions against PCP were confined to these kinds of uses. For example,
in the "USDA Sunasary of Registered Agricultural Pesticide Uses" issued
on August 31, 1968, PCP was registered as a weed killer on alfalfa, cot-
ton, pineapples, and sugarcane. These registrations were car xlied by
Pesticide Regulation (PR) Notice* 69-4 (February 1, 1969) and 70-4
(February 26, 1970) when the concept of zero tolerance was abandoned by
tha Department of Agriculture. Currently, PC? is registered for agri-
cultural u?e only as a seed treatment for nonfood uses on beans, alfalfa,
clover, lespcdeza, and vetch.
On September 28, 1970, US DA published PR Notice 70-22. Although
PCP was oot eentioned by name, the Hotice stated "Appropriate regulatory
action will be taken under the provisions of the Act (FXfBA) if these
chlorodioxins are found in any economic poison." The notice was directed
toward tha presence of 2,3,7,8-tetrachlorodibenzo-jj-dioxin (TCDD) in the
herbicides 2,4,5-trichlorophenoxyacetic acid and silvex; PC? and ics
chlorodiozina wara not eectioeed. The Dow Chenical Cctipacy, hcvaver,
interpreted the Hotice to apply to PCP and took action to reduce chlorodioxin
levels in its technical PCP.
21
-------
At the ti-«» 'die Notice was issued, Methodologies for the analysis
of diesiiia in PCP were not totally reliable. Therefore, there was
disagreeaent within the industry on the actual level* of dioxins in
their products. There were no tozicplogical studies on PCP dioxins, and
toxic effects vere inferred froa chloracne and chick edema effects of
conaercial PC?. These same effects are caused by TCDD. In the absence
of such evidence, regulatory action oc dioxin levels in PC? was not
possible. This situation continued until 1974, when research
involving purified PCP (i.e., relatively free of dioxins), in contrast
to commercial PC?, began to appear in the literature..
II. Suaaa.v of Scientific Evidence Relating to Reouttable Presumption
Criteria
A. Reproductive and Fetotpxic Effects in Mammalian Species
4C CFS 162.1lU)(3)(ii)(B) provides that "a. rebuttable presump-
tion shall arise if a pesticide's iagredient(s)... Produces any other
chronic or delayed toxic effect in test animals at any dosage up to a
level, as dete rained by the Administrator, which is substantially higher
than chat to which humans can reasonably be anticipated to b< exposed,
taking into account ample margins of safety." This section reflects con-
cern thrtt chronic exposure to chemicals may result in injury to the re-
productive system and/or the fetus and provides that a rebuttable pre-
sumption .hall arise if chronic chemical exposure in test anima1* pro-
duces such results, and if human exposure to the chemicals exceed an
ample margin of safety.
22
-------
In the studies summarized below, fatotoxic and teracogenic effects
have be*n reported in rats exposed to purified and commercial grade
PCP. These same effects were obsiirved in rats exposed to a mixture
of two unspecified isomers of HCD1). Specifically, exposure to PCP
and these HCDD isomers .resulted in statistically significant increases
in the incidence of skeletal and noft tissue anomalies, growth-re:arded
fecuses and of embryonic resorption in the lifters of treated dams.
1. Fetotoxicity
a. Studies with TCP
Schwetz et al. (1974) studied the effects of purified and com-
mercial grade PC? on rat embryonal, and fetal development. The Composi-
tions of the two types of PCP are given in table 5. Dosages of ;, 15,
30, and 50 mg/kg/day of both PCP types w«re administered by gavage on
gestation days 6 through 15 inclusive. Their results, shown in able 6,
may be summarized as follows: both purified and commercial PCP caused
statistically significant increases in fetal resorptions at the two higher
doses, as veil as among litters exposed to 15 mg/kg/day of conmer-
cial PCP. Specifically, the resorption rate ranged from 27.1* (64/235) to
lOOZ (229/229) in the two highest (commercial and purified) doie groups, com-
pared to A.22 (15/358) in the control group. At 30 and 50 mg/Kj day,
purified PCP had a sore pronounced effect than commercial PCP. .'-'or example,
at 50 Bg/kg/day, purified PCP caused 100Z fetal resorbtion, while commercial
23
-------
TABLZ S. Composition of pentachlorophenol material* used by Schweti et «1. (1974)
Coaaarcial Grade Purified
identification Lot Ho. MW06210-9822A fttf. Ho. 27-91-1
i/
Phenolics, Z
Pentacalorophenol 88.4 98+
Tecrachlorophanol 4.4 (K27
Tricblorophenol < 0.1 0.05
Higher Chlorinated 6.2 0.5
Fbeooxy phenols
21
Moophenolics, ppn
Di beozo -g^diat i as
2,3,7,8-tetrachlorodibeozo- < 0.05 < 0.05
H«x«chlorodiben2o-2^-dioxin -4 < 0.5
H«ptachlorodibenzo-j£-tiioxin 125 < 0.5
Octachlorodibanzo-£-ttioxin 2500 < 1^0
Dibenzofuricj
Uexachlorodibenzofurmn 30 < 0.5
BeptAcblorodibenzofurui 80 < 0.5
Oct«chlorodibenzofur«n 80- <^ 0.5
JY Deterainsd by gas-liquid chromatography.
II Determined by use of an LK2 9000 gas chrosuitograph-mass spectrometer.
-------
TABLE 6. Effect of pantachlorophenol on the incidence of fetal resorptions and
Test Material
sod Dose,
»S/ kg/day
2/
Vehicle Control
> I/
Pentachlorophenol
Coanercial
4/
5.8
15
6/
34.7
50
Purified
5
15
30
50
on
the s«:x ratio of survivors
Besorptions
4exmi
i
4.2
7.1
8.8
27.2
53. 1
4.2
5.9
97.5
100.0
; Fe tunes
Ho.
15/353
15/212
5/
17/194~
5/
64/235^"
5/
108/186""
8/L89
13/221
5/
233/239
5/
229/229
ABonf
Z
30.3
"
55.6
64.7
94.7
93.3
46.7
38.9
100.0
100.0
Litters
Ho.
10/33
10/18
5/
11/17
5/
18/19"
5/
14/15"
7/15
7/13
5/'
20/20~
3/
19/19
Sex Ratio
M : F
50 50
50 50
52 48
60 40
5/
79 21
48 52
50 50
5/
83 17
_!_/ Adapted frwa Schwetz et al. (1974)
y 2.0 nl/kjt body weight corn oil per day.
_3_/ Doiages cdninistered in 2.0 ml corn oil/kg body weight.
kj Equivalent to 5.0 sig/kg/day ptwified PCP.
_5_/ Indicates values significantly different froa control
values by the binomial expansion test, p < 0.05.
_6_/ Equivalent to 30.0 ag/kg/day purified PCP.
25
-------
KT canoed 5AZ resorptioa. Ac 30 (purified) «ad 50 (couejsrcial)
ag/kg/day, there *«re statistically significant difference* ia the
sex ratio of surviving fetuses; Mica were heavily predonisMt,
Sebvau et al. fouad that adadoistration of FCP daring early
orgaoogeaesis (days 8 through 11 of geatation) had aon prooouacad
tfftetc oa fatal raorptioa than did its adaiaiatxatioa daring lata
orj«no|«n«iis (days 12 through IS) (Table 7).
The no-effect dote for fatal rasorptioaa was 5.8 cosjuarcial
grade PCF/kg/day aod 15 ag purified PC?/kg/day. ttaasurasjents were also
taken on fetal body weight and crovn-rvp length, both of which decreased
with the increase in dosage. The no-effect dose for these parameters
was 15 *g conercial grade or purified KP/kg/day.
1* .
Larsen et al. (1975) fed 60 Mg C-PCP/kg body weight to pregnant
Charles River CD strain rats on day 15 of gestation; They detected neg-
I* . . t
ligible amounts of C-PCP in the placentas and fetuses up to 32 hours
•fter dosage. This indicated that the aaount of PC? that passes through
the placental barrier on day 15 is negligible. la a separate experiment that
used unlabeled KT? and was reported in the saaw paper, single oral doses
of 60 ag/kg adainistered to separste groups of aniuls on days 6, 9, 10,
11, 12, or 13 of gestation had no statistically significant effect on
tha rate of reoorpcioa of the teat anisuls as cosiparttd to control*.
However, statistically significant reductions in fetal weight were
reported in days 9 and 10.
26
-------
TAIL! 7. Effect of adaiaiatrai:ion of peatachloropbanol auriaa. early or late
orgaso^eeasis
Teat Material
and Dose,
•tt/kt/day
on the incidence of fetal resorptioea «
ratio of offspring
Raaorptions
Aaoaii Fetuaes Avont Litters
t Bo. I Bo.
•d on the sax
Sex Batio
M : f
MTS eMl OF GZSTATXOM
Vehicle Control
Pentachloropbenol
2/
Coanercial 34.7
Purified 30.0
7.6 13/172 53.3 8/15
3/ 3/
45.3 105/232" 94.7 18/19"
3/ 3/
91il 163/179" 100.0 l6/lo"
53 47
55 45
62 38
DATS 12-15 OF CESTATI08
Vehicle Control
Pent ach loropoenol
2/
Coocrcial 34.7 ;
Purified 30.0
4.2 11/259 40.9 9/22
6.1 13/213 58.8 10/17
4.5 11/244 45.0 9/20
46 54
52 40
49 51
II Adapted from Scteratz *c al. (1974).
2/ Equivalent to 30.0 mf/kf/day purified PCP.
T/ Values significantly diffartat fro* control values by tha
binooial axpancion case, p < 0.05.
27
-------
•iakla (1973) reported ea the fstotosic effecta ef PC? ia cha
G»Um Syriaa baas* tar. Afcar doaea of 1.25. 2.5. 5. 10, and 20 at/kg
war* c£ai&iLater«d by gavaga oa day* 6 through 10 of gestation, ha retorted
•a differoecaa bacvaen control end CMC aaiaala in cha«a aarsjaarers:
••canal barfy weight, fatal miffec, liccar aixa, aad Mater of laaorpciow.
Xaeraaaaa coxieicy vaa aocarf at cka fe*o aichaat aoaaa, tac tkaaa iacraaaas
«Jbra "miaiatl ia o«kar." »a aataor aCacad that PC? vu foaad la aacaccabla
aaooau (oaapacifiad) in eba oacraacad aniaals a* wall as in chair diac.
Fabric (1978), in a §ta4y Co ba daacriaad in asra aacail ia
Section III. B.. obaarrad oacraaaaa in littar aixa afcar iajaccion
of SO aod 100 agna PCF/kg body vaifhc into cba paritonaal cavity of
prcgaaoc aica ac day can of gaacacioo. Control mca, oa tba avaraga.
arodncad 6.4 fatuaac/doB. Littar aixa vaa radwcad at cha 50 at/kg
doeo to 3.67 fecaaM/daB, aad co 3.92 facvaaa/dav ac cha 100 ag/kg doaa.
PC? vac tdai.nistared in a 102 solution of diaathylforpaadda; a vaaicla
control vas not raportad. Littar siza calotlationa incladad daaa chat
had no litters.
The Schwacs at al. study citad earlier eftablishea that iagettioo
of PCP by pregnant rats during organoganasis produces lethal and
•"• '\
toxic effects sach as fetal resorpcion and reduced body sixe. Coapereble • **
effects were DOC observed when larger but single doses were adadaistered
to rata during org&eeserasis (Larsen, 1975), nor whan single doses
vcrc ciaiaistored to hesators (Biakle. 1973).
2B
-------
Fable 8. Effect of traatiaant with chlorinated iJibenco-p-J ioxin on aatarnal and fatal body aaasureaMBta ami th«
incidence of fetal retorption—
M fatal body
2/ Ho. Maternal waijfhtja^in^s^ 4/
lost Compound littara Deya 6-11 Day a 13-21 Deyt 6-21 weight if
Control 30 36 *. 2 101 *_ 6 137^8 3.68 *. 0.05
Ha«echloro<)ibanso-£-
dioxin (4)
0.1 ug/kg/day 19 28 * 2 102 + 5 130 + 5 5.73 + 0.04
1 ug/kg/day 19 27 * 3.. 99 7 5 126 * 6 3.93 * 0.16..
10 ug/kg/day 19 22 * 3y/ 97 + 3.. 119 +• 6,. 3.12 * 0.05-^
100 ug/kg/day 19 6*^2^ 13 _» 7-^ 19^9^ 3.65 7 0.28^
~~.
Oc t «ch 1 or od I ben«o-p_-
dioxin (5)
100 «£/kg/day 12 32 * 2 100 * 8 131 * 7 3.73 + 0.09
500 aig/kg/day 17 35 _* 3 115 ± 4 150 _» 5 5.69 7 0.05
I/ Adapted froa Schvets at al. (1973).
?/ Hexachlorodibenco-j^-diozin aaaipla: purity " >99X; two unapacifiad iaoaMra
Fetal
crown-
~4/ Fatal Beaorptioa, t
runp length (M 5J
mm Populatioa
44.5 *.
43.8 *
45.7 7
42.6 7
35.2 *,
43.6 4
44.5 T
in ratio
0.1 7(22/337)
0.1 5(10/217)
0.3,, 9(20/218)
o!7^23(S7/229)
I/
83(194/227)
0.4 8(11/131)
0-2 5(9/199)
of
Utter
47(14/30)
47(9/19)
74(14/19)
94(17/18)
7/
100(19/19)
42(3/12)
41(7/17)
89:11. All scaplei adotiniatared on daya 6-15 of gestation aa a corn oil. -acetone
(9:1) aotution. Octachlorodibenio-j>-dioxin aaatplaa: purity • 98.862.
)/ Mean _*_ etandard error for various gaatation tinea.
£/ Mean of litter cs«n« • atkndard arror.
f/ % (number raaorptiona/nmbair implantation*).
?/ X (nuBber littara with at leaat one raaorption/nuaiber littera).
F/ Significantly different froa control by an analyaia of varianca and Tukey'a
or the 2x2 contingency tabla (reaoiptiona) , p < 0,05.
test
29
-------
b. ltK*)M9 VJtk
SctMts at «l. (1973) atdaiaia tared parifiad k*xacaloro-£-«ib«aco-
dioxiaa (ICSD) (two eaapecified iaoaars) cad oc tackier o-g-dioxia (OCSO)
by gawaga ^ •**•«*»* Sprajoe-Bawiey rat* OB 4ays 6 chroafB 13 of (••ca-
tion. DCMMC were 0.1. 1, 10. or 100 eg/kg/day 1CDO aad 100 or 500 a*/
kg/day OCOD.
The result* of taeae st»diaa en •hov» ia Ta*l« f. For KCDO,
tb«r« were statistically sicaifieamt iacr*a*«a over eootrols ia fatal
r««orptiooa at th« 10 and 100 af/kg/das? doa«a. aa wtll aa oacr*aa«> ia
fetal body waighc cod fetal crowa-ruBp laagta. Ia contract, OCDD at both
dose lava Is (100 azta 500 aig/ kg/day) prodocod ao fatal rcaorptioaa or othar
effaces accept for aa increase in the iacideace of subcataneous edesu at
the hieh dose leval.
The EO)D need ia this experiaeat vaa reported by the authors to
have a purity in excess of 99Z, aad to consist of two iaoaors ia the
ratio 89:11. The presence of HCDD in PC? aad the low BCDD doses
producing fetotoxic effects in pregnant rats strongly suggests taat ex-
posure to HCDD via exposure to PC? caa cause chronic effects as defined
in 40 CPE 162.11(a)(3)(ii)(B).
2. Teratology
*• Studies with PC?
Schwetz at al. (1974*) also investigated the teratoganic effects
of PC? oa rats. In this study they observed fetal anoswlies produced by
oral adnioistratioa (gssrege) of 5.8, 15, 34.7, and 50 ag/kg/day of c cause r-
cial grade PCP, and 5, 15, and 30 Bg/kg/day of purified PC?. In one
experiment, they administered these amounts of PCP during days 6 through
30
-------
XABU 9.
ef pantacfeloropfeaool on tba
of fetal accBalies
Peatachloropbeaol (sx/ki/day)
Vehicle
Control
••••MBBHOMSIBV
SOFT TlSSCtt A00eiALZ£S
Ka. of kitten 33
Stabcata»eou« Idea* 18
i
Dilated Ureter* 0
SFET-TTAL ANOMALIES
Bo. of Litters 31
Skull (delayed ossification) 19
> - *
Laa&ar Sr-'ars • 13
Elba (sap«CTs&Qtrary, 1 tartar, 0
or ftued)
Vertebrss (saparaosMrary, 19
* b sorea! shape, delayed
ossification, sussing or
uafiuad canters of ossi-
fication)
Stsmsbre* ( tcps rawer ary , 16
delayed or unrusad centers
of ossification, fused or
etcg£9red)
Cooaercial Grade
5.8 15 34.7 50
18 16 19 13
Fercant of Litters
27 27 27
11 5
-------
orgMOj
axa on cna utciaanca 01 zacai sjaoMiu
Days 8-11 of Cantatioo Days
w
12-15 of
Captation
Paatacaloropbaaol
Aaossaliaa
SOFT TISSUE ANOMALIES
86. of Lit tar*
Subcutsnaous cdeaa
SKELETAL AMOHALIES
80. of Litters
ffthicl* Coamrcial Purifiad fahiela O
34.7 30
MBarcial
34.7
Coatrol •kykx/dar •ir/kc/day CoaCrol at/kayday
15 17 4 22 17
Parcaat of Littara Affactad
2/ 2/
7 82" 100~ 59
15 18 6 22,
Parcaat of. Lit tars
35
17
Affactad
PttTifi^i
30
ax/kc/day
20
21
95
20
27 2/
1QO 100
2/ 37
100~ 100
36
0
*i
0
Skull (dalcyad 33 33 17 36 4. 70~
ossification)
Ribs (saptrauaarary 0
or fuaad)
Vertebraa (superauaarary, 27
abnoraal shape, dalayad
oaeif icacioo, fucad,
•iwing or ua fused
cantata of ossification)
Slaroabraa (dalayad or 47 VT 100~ 50
ua fuaad caatars of
ossification, fuasd
or stages r«l)
21
21
21
82
21
21
85"
JY /^riiaietarssd po in corn oil during aarly or laca organo(aa«
-------
15 of gescatioa; statistically nigaificaat iacr*es«* in skeletal defects
of til* rib*, steraebree cad vertebrae war* observed ia tetla treacaaat group*
(Table 9). Xa a aeceai experieunt, they gevo 30.0 (purified) aad 34.7
(conBareial grada) Kg/kg/day rC? oo day* 8 through 11 of gestation to one
group of eaisMla, *ad oa day* 11 through 15 to • second group; statistically
significant iaer*a**s ia abaorsttl staraebrae sed skulls were observed ia
eaiaals treated with purified Kf and abooraal steraebrae ia aaiaals
treated with eosiBMreial r<7 (Table 10).
These results establish that the higher doses of PC? produce
fetal aaoMlies ia the rat. At the 30 «g/kg/day dose the effects
of purified PC? were sore pronounced than tbose of the equivalsnt of coaaer-
cial grade POP.
b. Stuaiea with Dio«ias
Ia the 1973 paper cited above, Scbwetx et al. reported tsrato-
geaic effects fooa the dioxins found ia PCP. they adxiaistercd doses of
0*1, 1, 10, and 100 ug HGDD/kg/day to pregnant Sprague-Dawley rat* oa days
6 through 15 of gestation. Thfy found statistically sigsificaac increases over
the controls ia all of the terstogenic parameter* observed at 100 ug/kg.
For «aae?l«, cleft pelete wee observed in 471 (6/17) of tht fetuses
exposed to HCDD, coopered to none (0/156) io the coot roll; 121 (2/17) of
rhe treeted fetoseo had dilated renal pelvis compared to 0.6Z (1/56) in
tbe ccntrols; and J1Z (5/16) oi: the treated fetuses had abnorxal verte-
brae cospar*d to 6X (9/158) in the controls. Subcutaneous cios* was
o6aorvcd &t all doeas except 0..1 ug/kg/dey, which was coasidered tfae no-
effect dose. In contrast, OCD1) did not cease teratogenicity at 100
c$/kg/day; doses of 500 ns/kg/ciay caused stibcutaneous cdeea, trat no other
effects.
33
-------
Table 11 MaatriMi the reeults of treacsjeat vick ICDO.
3« fcnoeure Analysis
In order to attenine whether • »res«ption sboald b« issued
based oa reproductive and fatotoxic effects, pursuant to Section
162.11(a)(3)(ii)(B). the Agency suet dctersdae whether or not aa
anpla margin of aafeey exists between Cke level* of Kf which produce
reproductive and fetotoxic efface*, aod the laral(«) to •bica cfae popole-
^ioa at tick (woveo of chile-beari>| age) eaa reasonably be amticipetad
to be expoaed.
This section orescats eacisutes of dietary, inhalatioa aod derail
exposure to PCP eod HCDD oo a "worst case" basis. These estimate* art o»»«a
oa the exposure of a pregnant woaan in the BOB* and at work at aiajor PCP and
IU-PCP use work sites, i.e., wood preaerring plants, cooling towers, tanneries,
and construction sites, this approach to PCP exposure analysis is taken because
of the fetotoxic end taratogenic effects of PC? described in Section II.A.I and
II.A.2 and because of the continued •oveneoc of woawn into all areas of the labor
force. Estimates are coopuced on Che basis of 60 kg prignaoc wooan, 100* absorp-
tion via dietary and inhalation exposure, and 102 adsorption via deraal contact
for both PCP and tts-PCP. lharr Is no data available on denutl absorption of
PCP.by pregnant woven; the 10Z estimate is baaed oo the penetration v*lu«
of 7-151 of several chlorinated hydrocarbons, reported by Hcibach and
3
Folds*n (1974). A noraal breathing rate is defined as 1.8 n /hour at work,
3
and 1.0 u /hour in the bone*
Isnalat^en of water vapor cootailing He-PC? ic an exposure route
for workers in industrial cooling towers, paper palp Bills end tanneries.
Appendix I shews the calculations used to derive estimate? of PCP in
water vapors at these sites.
-------
TAUI£ 11. Hffect of treatment with hexachlorodibenzo-p-dioain on the incidence
of fetal flncnu
y
iliOB
Incidence of Annual ies After Treatment on Days 6-15 of Gestation
SOFT TISSUE ANnHM.lES
Cleft Palate
Dilated Renal Pelvis
Subcutaneous Bdesa
SKL1&TAI, A&XM.IES
Split Vertebral
Centra
Sp 1 i t S temebrae
Delayed Ossification
of Sternebrae
3/
L
P
L
P
L -.
P
L
P
L
P
L
0
0
0.6
4
5
21
6
19
0.6
4
11
44
Control
(0/156)
(0/28)
(1/156)
(1/28)
(B/1S6)
(6/28)
(9/158)
(5/27)
(1/158)
(1/27)
(18/158)
(12/27)
0.1 uj/ky/day
1 (1/104)
5 (1/19)
0 (0/104)
0 (0/19)
6 (6/104)
12 (6/19)
2 (2/101)
5 (1/19)
1 (1/103)
5 (1/19)
28 (29/103)
74 (14/19)
1 ugAq/day
0 (0/99)
0 (0/19)
2 (2/99) >-
5 (1/19)
35 (54/99)
100 (19/19)
VM
1 (1/99)
6 (1/18)
2 (2/99)
11 (2/18)
12 (12/99)
50 (9/18)
10 u^/kq/day
0 (0/86)
0 (0/18)
6 (5/86)
17 (3/18)
100 (86/86)
100 (18/18)
7 (6/86)
29 (5/17)
2 (2/86)
12 (2/17)
34 (29/86)
71 (12/17)
100 uq/kq/day
47 (8/17)
73 (8/11)
12 (2/17)
18 (2/11)
100 (17/17)
4/
100 (11/11)
31 (5/16)
56 J5/9)
31 (5/16)
56 (5/9)
56 (9/16)
56 (5/9)
j/ Adapted frcro Sclwatz et al. (1973).
2/ Incidence anony fetal population: * (rxsiix>r of affected fetuses/mniier
fetuses examined). *
3/ Incidence cnvong litters: % (ntf^«r of affected iittbrs/nurber litters
S iyn if leant ly different (van control by 2 x 2 contingency table, p < 0.05.
35
-------
Exposure to BCDD is developed using the same base* as for PCP. In
addition these assumptions are made: that the HCDD content of most technical
PC? and Na-PCP in the market place is 4 ppm (Table 2) and that assimilation
of HCDD is identical to that of PCP and Ha-PCP. Using these assumptions,
-b
exposure -3 BCDD is equal to the exposure to PCP times the factor 4 X 10
(4 ppm).
a. Dietary Exposure
Although PCP has no registered uses on any food commodity,
PCP residues have been measured in foodstuffs (Table 1), and therefore
there is exposure to PCP in the diet. Using the data in Table 1 and the
average daily intake of the commodities which have been found to contain
PCP, it is possible to obtain an estimate of PCP exposure from foodstuffs.
Table 12 displays these results,' computed for average and •«••»•?««• PCP intake
per day. For a 60 kg pregnant woman, the intake would be:
0.0015 mg/day/60 " O.C2S ug/kg/day average,
or 0.0181 mg/kg/day/£G » 0.302 ug/kg/day maximum.
For HCDD, intake would be:
-6 -6
0.1 X 10 ug/kg/day average, or 1.21 X 10 ug/kg/day maximum.
b. Dermal Exposure
i. Homeowners
PCP is sold in retail stores for treatment of wood to prevent
rot and decay in boats, masonry, fences, and other sites.' Common directions
call for tvo coats of 52 PCP in mineral oil or a 3 to 30 minute soak.
Assuming that a 60 kg applicator spills enough of the solution to cover
one hand (10 ml or about 10 grams), the exposure would be:
(10 gms x 0.05 x O.D/60 - 0.833 mg/kg/day.
-6
For ECDD, exposure would be 3.33 X 10 og/kg/day.
36
-------
Table 12. Estimated Average and Maximum Daily Intake of PCP in the Diet
I/ 2/
Commodity
Dairy Products
Grains and
Cereals
Root Vegetables
Fruite
Sugars and
Adjuncts
Average
Intake
kg /day
0.477
0.181
0.261
0.261
0.135
Average
PCP Residue
">g/kg
0.0005
0.001
0.001
Trace
0.006
Max iraura
PCP Residue
wg /kg
0.01
0.013
0.010
0.011
O.U4
Average
PCP Intake
nig/day
0.0002
•0.0002
0.0003
f~~ ' ,
0.0008
Maximum
PCP Intake
mg/day
0.0048
0.0024
0.0026
0.0029
0.0054
Totals
0.0015
0.0181
1 From Agricultural Handbook No. 62, August 1961, p. 42
2 From Table 1 (Johnson and Manske, 1977)
37
-------
ii. Construction Barken
PCF-treated wood i» used Co construct platforms, fences, porches,
aad other structures. It is estimated that 6 months after treatment, PC?
will be present on the wood surface at about 0.5 mg/ square foot (Koppers
Chemical Company, 1978). Denial exposure occurs if workers handle wood
without wearing gloves. Assuming that die worker actually handles wood
40 times during an 8-hour period, aad that the ana of the hands averages
0.23 sq. ft., then exposure would be:
(40 x 0.5 mg/sq.ft. x 0.25 sq.ft./operation x O.D/60 - 8.3 ug/kg/aay.
-6
For HCDD, exposure would be 33.2 X 10 ug/kg/day.
iii. Cooling Tower Workers
Na-PCP is used to control the growth of algae, bacteria and
fungi in water cooling systems. Formulations typically contain SOX
Na-PCP, and are added to the system at concentrations of 60 ppm for
initial cleaning, then reduced to 30 ppa to maintain control. A worker
could be exposed dermally to 100 al of cooling water containing
80* x 60 ppn formulation, or 48 ppm (48 mg/liter), of Na-?CP. (Shamaiengar,
1978). Exposure would then be:
(48 mg/1 x 0.1 liter x O.D/60 kg - 0.008 mg/kg/aay.
During routine maintenance, this would drop to 0.004 ng
-6
Na-PCP/kg/day. For HCDD, exposure would be 0.032 I 10 «g/kg/day for
-6
initial cleaning, and 0.016 X 10 lag/kg/day during routine maintenance.
iv. Paper/Pulp Mill Workers
To control slime, algae and bacteria, Na-PCP is added to the
paper-pulp slurry during the manufacturing process. A typical product
contains 452 active ingredients of which 252 is Na-PCP. The concentration
of the product used is 450 ppa, of which 113 ppa (113 mg/1) is Na-PCP.
-------
During tfce process, copies of pulp •lurry are taken periodically. If
• worker Cakes samples hourly (8 i:iaes/day) and wees one hand with 10 ml
of the slurry (International Paper Company, 1978), the exposure voula be:
(8 z 0.01 liter x 113 mg/JL z O.D/60 kg •
0.015 mg PCP/kg/day
-6
For HCDO, exposure would be 0.060 Z 10 af/kg/day.
v. Tannery Workers
A typical product used to control growth of sliae and fungi contains
12.92 PCP. With a use concentration of 1:4,000, the solution would contain
1 gin/4,000 gn 'rater or 250 ppn of product. If a worker were exposed during
normal operations, she'could demally receive about 1400 ml of solution daily
on her exposed arms and neck (Shasiaiengar, 1978). Exposure here would be:
(1.4 liter x 250 otg/1 x 0.129 z O.D/61 kg -
0.075 mg Na-PCP/kg/day
! -6
For HCDD, exposure would be 0.3 X 10 «g/kg/day.
vi. Workers ia Pressure-Treatment Planes
Although data id not available on dermal exposure at these sices,
it can be assuaed that this exposure is at least equal to exposure at
construction sites. Freshly treated wood can be expected to contain
teore PC? on its surface than wood used at construction sites, the latter
having been subjected to weathering, i.e., leaching, vaporization, etc.,
in the interval between pressure treatment at the plant and use at
construction tites. Therefore, dermal exposure at pressure treatment
plants is taken to be at least the saae as that at construction sites.
39
-------
i/
Table 13. Pentnchlorophenol Concentrations in Air et a Pressure Treatment
Plant.
Kcppert Company, Incorporated
North Little Rock, Arkansas
February 24, 1976
**Concentrut ions
Sample No
Al
A3
AS
A6
A7
AB
A9
A10
A2/12
A4/14
Ar«rican
Threshold
Sampling
. Operation Period (oin)
Hand Nix Oper.
Hand Nix Oper.
Sampling Nan
Asst. Treater
Laborer
Laborer
Treating Oper.
Locoootive Oper.
Hand Nixer
Hand Mix Oper.
Conference on Governmental
112
112
442
445
43tt
437
339
110
112
Industrie I
*Type of
Sanple
GA
CA
EQUIPMENT
P
P
r
?
P
P
CA
Hygieniats,
3
(*K/M )
0.01)4
0.004
FA I LIKE - VOID
0.001
0.001
0,006
0.001
-------
Table 11 itwimnriirtu t«e results of treatment with 1CDD.
3. Exposure Analysis
In order to detenus* whether a prestsaption should be issued
based on reproductive «ad fetotoxii: effects, pursuant to S«ctioa
162.11(a)(3)(ii)(B), the Agency mast determine whether or Dot aa
••pi* margin of safety exist* betwiea the levels of PCP which produce
reproductive end fetotozic effects, end the level(s) to which the popula-
fion at risk (women of child-bearing age) can reasonably be «iticipatad
to be exposed.
This section presents estisuttes of dietary, inhalation and denul
exposure to PCP and HCDO on a "voruc case" basis. These estiaates art basea
on the exposure of a pregnant woven in the hoae and at work at major PCP and
Ha-PCP use work sites, i.e., wood preserving plants, cooling towers, tanneries,
and construction sites. This approach to PCP exposure analysis is taken beceuse
of the fetctoxic and taratogeaic effects of PC? described in Section II.A.1 and
II. A. 2 and because of the continued snvesttnt of woven into all areas of the I sis or
force. Estimates are computed on iihe b*si»'of 60 kg pregnant wooan, 10U« absorp-
tion via dietary a?d inhalation exposure, and 101 adsorption via der&al contact
for both PCP and Ha-PCP. There is no data available on deraal absorption of
PCP.by pregnant woaen; the 10Z estimate is based on the peaetration value
of 7-151 of several chloriuated hydrocarbons, reported by Haibach cod
3
Feldnsn (1974). A noraal breathing rate is defined as 1.8 n /hour at work,
3 •
and 1.0 01 /hour in the hoe*.
Inhalation of water vapor containing Ma-PC? is an exposure route
for workers in industrial coo ling towers, paper pulp mills and tanneries.
Appendix I shows the calculations used to derive ettisatcs of PC? in
water vapors at these sites.
34
-------
3
the daily exposure of a 60 kg worker at • Moderate breathing race (1.8 • /hr)
would be:
3 3
(8 ug/» z 1.8 • /hr s 8 hours)760 • 1.92 ug/kg/day.
-6
For HCDD, exposure would be 7.68 X 10 ug/kg/day.
la the abeeace of data on PC? cooceatraciona in the air at
construction sites, these values for PC? and HCDO are taken as
worst case estimate* at the** sites.
iii. Cooling Towers
Son persons working near cooling towers can be exposed by
inhalation of vapors and drift containing Ma- PC?. The relative
amounts of Ma-PC? aad water evaporating from the cooling water is a
function of their Molecular weights and vapor pressures, and is esti-
3
aaccd to be 0.02 ug PC?/« (Appendix 1). Exposure therefore would be:
3 3
(0.02 ug/n x 1.8 • /hr x 8 hr)/60 - 0.004 ug Ha-PCP/kg/day.
-6
For BCDD, exposure would be 0.016 X 10 ug Ea-PCP/kg/day.
Drift is the entrained water carried from the tower by the exhaust
air. In an average cooling tower, approximately 12 of the cooling fluid is
lost to drift. For a properly fv.-.ctioning cooling tower, the ratio of vatec.
to air voight should be unity in order to insure y^in""** heat exchange. At an
average cooling rcte of 300 gallons/minute, this weight of water is equivalent
3
£0 tha veight of 880 • of air. The drift (3 gallons or 11.355 liters), distri-
buted in this volust- of air, gives an Ha-PCP concentration of:
3 3
(11.355 1 X 45 mg/l)/880 m - 0.6 eg Ha-PCP/m .
-------
* would than b«:
3 3
(0.6 ag/a x 1.8 • /hr x 8 hrs)/60 - 0.15 &g Na-iCP/kg/day
-6
For QCDD, exposure would be 0.60 X 10 nrj/kg/day.
iv. Papgr/Pulp Mills
Inhalation «posure in based on a concentration of 0.047 ug Na-PCP/
3
a (se« Appendix 1), vhidi cc«put*s to:
3 .3
(0.047 ug/ta x 1.8 m /hr x 8 hrs)/60 » 0.01 ug Na-PC?/tog/day.
-6
For HCDD, exposure would be 0.04 X 1U ug/tog/day.
v. Tanneries
3
Inhalation exposure is based -on a concentration of 0.013 ug/m (see
Appendix 1} so that exposure is: "
3 3
(0.013 ug/to x l.fc m /hr x 8 hr3)/60 leg » 0.003 ug m-PCP/)cg/d<^
-6
For HCDD, exposure would be 0,012 X 10 ug/kg/day.
4. Conclusions ; • ; ; ,
Table 14 sunnarizes the exposure estimates for PCP and HCDD deve-
loped in Section II.A.3. Table 15 gives the ratios of the no effect
dose level to total exposure.to PCJP and HCDD of the major use sites.
Cie foregoing discussion establishes that PCP and possibly its HCDD
contaminants cause teratcgenic and fetotoxic effects in test animals. The
adverse effects observed among the injured fetuses include distorted sax
ratios, increased incidences of. resorbed embryos, steletal anomalies arid
subcutaneous edsna. The no-effect levels are 5.8 mg/kg/day for PCP ard
1 ug/kg/day for HCDD. In addition, PCP contains other dioxin contaminants
which have not been fully characterized toxicologically, and which vary
quantitatively fron batch to batch.
43
-------
i/
TABLE 14. Estimates of Huatn Exposure to PC? >nd liCDD
Site
ug/kg/day
HCDD
-6
ug x 10 /kg/day
Home
Construction
Sites
Cooling
Towers
Psper Pulp
Hills
Tanneries
Dietary
0.025 av
0.302 max
0.025 av
0.302 max
0.025 av
0.302 max
0.025 av
0.302 MX
0.025 av
0.302 max
Pressure Treat-0.025 av
mcnt Plants
0.302 MX
Dermal
833
8.33
2/
8
3/
4
15
75
8.33
Inhalation
53.3
1.92
0.004
4/
150
0.01
0.003
1.92
Total
886.32
886.60
10.28
1U.55
5/
158.03
5y
154.31
15.04
15.31,
75.03
75.31
10.28
10.55
Dietary
0.1 av
1.21 MX
0.1 av
1.21 MX
1
0.1 av
f 1.21 MX
'.
O.I av
1.21 MX
0.1 av
1.21 MX
0.1 *t
1.21 MX
Dermal
3330
33.2
U
32
3/
16
60
300
33.2
Inhalation
213.3
7.68
0.016
4/
600
0.04
0.012
7.68
Total
3)43.40
3544.)!
40.98
42.09
5/
632.02"
5/
617.23"
60.14
61.25
300.11
301.22
40.98
42.09
\j Based on a 60 kg pregnant woman
27 Initial Treatment
_3/ Routine Treatment
4/ Cooling Tower Drift
2/ Inhalation of cooling tower drift
f PCP vapors + dermal and dietary
exposure
-------
Data available to the Agency indicate that the physical and rhaaical
properties of PCP, and its ccaaercia.1 uses and distributions lead to
substantial hsan and erwironeental 'exposure to this pesticide. In this
regard, several factors arc significant;
- Currant KP production apprcads*tes 50,000,000 pounds
per year and production is expected to inciease to
80.000,000 pounds par ytsr in tti« naar future (Josephson,
1977). If PCP is squally distributed asoog the total
U.S. population, ssauairq 60 kg body might for each
individual exposed, the theoretical exposure potential
for each parson in the general population is 5 ng/kg/day.
- Although PCP is registered! seunly for non-agri culture!
uses, the cbeaical is widely distributed in the environ-
ment and in huean tissues. It is present in the blood
and urine of persons not Jmown to be exposed to the
pesticide. It has been found in the drinking water of
80% of 108 cities sespled,, in rainwater in Hawaii, and
at low levels in food coeiDdities such as sugars, root
vegetables, and grain and c-ireal products (Table 1).
- PCP is registered for hosn and industrial uses. As a
result, hoaieoMnara, workaacs using PCP in leather, wood,
and paper processing plants, and others using products
containing PCP are exposed to the chemical, toe Agency
estimates that user exposure levels range from appratioately
0.9 ng/kg/day for hone uses to less than 0.01 ag/kg/day at
construction sites (Table 14).
- Bcsss, tanneries, wood pressure treatment plants,
pulp mills, and cooling towers are major use sites presen-
ting significant exposure potential, particularly since
PCP bea been shown to be absorbed through the skin. These
uses cay involve denial as well as inhalation contact with
the pesticide. Further, since 80% of the annual PCP pre-
diction is used for wood preservatives, substantial numbers
of. people who spray, dip, and pressure-treat wood at plants
Eay bs exposed to the pesticide. In addition, workers
using PCP-traated wood at: construction sites can be exposed.
The Agency's pre-KPAR review of pesticide exposure is based on
data about the chenical under reviisw, other pesticides, general
assumptions, end other relevant information. The Agency recognizes
that the exposure data available is sketchy and incomplete. The Agency
suppleaoented this data with reasonable worst case assumptions, which by
45
-------
/I /2
Tattle 15. Ratio of No Effect DOM to Stood Exposure Estimates
for PCP ted BCDD
Site PCP BCDD
Bane 6.55 282
Construction Sites 557 24073
Cooling Towers 37.2 1602
Paper Pulp Mills 382 16477
Tanneries 77.2 : 3327
Pressure Treatment -
Plants 557 24073
1) No Effect Doses are 5.8 ng/ug/day for PCP and
1 ug/fcg/day for BCDD.
2} Averages of Total Exposures from Table 14.
their nature are conservative. Nevertheless, uncertainty remains as to
the validity of the preliminary exposure estimates derived froc the data
and the assumptions. Therefore, in determining whether an adequate
Bargin of safety exists, the Agency considers it prudent public policy
to utilize greater safety factors for PCP than it would in situations
where it had greater confider-s in the underlying exposure data and
assumptions.
40 CHI 162.11(a)(3)(ii}(B) provides that a rebuttable presurption
shall arise if a pesticide produces ery "chronic or delayed toxic effect
in test znimals at any dosage up to a level. . . which is substantially
higher than that to which nunans can reasonably be anticipated to be
46
-------
cqposed, taking into account acple xargins of safety . . . .• KP
produces teratoganic and fetotcxic effects in test enianls, and workers
using KP in connection with tannery, hcae, pressure treatment, paper
pulp processing, cooling fewer and all other uses Kay be esgposad to PQ>,
with levels at Major use sites ranging from 0.01 to 0.9 Kg/kg/day, B>e
Agency has concluded that the difference between these huun exposure
levels and the no-effect level in test aniaal* eay not constitute an aspic
amrgin of safety. Accordingly, the Agency has concluded that all POP
registrations exceed this risk criterion.
The Agency invites registrants to provide data and infatuation
to confirm, refine, or rebut the information upon which the exposure
; . ' '.?.-.
estimates are based. The Agency will use the new data to determine
whether or not the presvapticn has been rebutted and in asse&sirsg the
risks which FCP uses nay present to health and the envircnaent.
ni. Studies Relating to Possible Adverse Effects
ISnis section describes stiadies on PCP ,v*iich do not meet the cri-
teria outlined in 40 CFR Section 162.11. It is intended to provide
information on other toxic effects of FCP, including those resulting
from misuse, with the exception of the discussion of oncogenicity
and inategenicity, the studies prisented were chosen as exaoplcs of these
effects; other r^xjrts are availiible in the scientific literature.
A- Oncogfenic Effects in T^st Aninals
In 19©, Irrses et al. adoijustered FCP (Dowicide 7) by gavsge to
slice at doses of 46.4 eg/kg on days 7-28 of age and at 130 ppn (17 mg/
kg/day) in the diet for the following 17 months. 'Say report ad that
this reginss erased no significant increase in bznor incidence in test
aninals es oxtpared to the control eniraals. In 1976 Schwetz et si. in en
47
-------
unpublished •tody submitted Co EPA, reported that dietary regimes of
Dowicide EC-7 at 1, 3, 10, and 30 mg/kg/day for 22 and 24 Months for
male and female rate, respectively, did not increase tumor incidence
over control animals. The cosmosition of toe PCP products used in
these studies was similar to those shown in Table 2.
Boutvell and Bosch (1959) tested a series of phenolic chemicals
for their ability to induce skin tumors in mice. In these experiments
a simple application of 6.3* dimethylbenzanthracene (CUBA) in benzene was
first applied to shaved back skin as an initiator. Subsequently, 202
PCP, the promoter, was applied in benzene to the back skin of each test
animal twice weekly for IS weeks. In this short-term study the investi-
gators reported a survival rate of 82.9Z (29/35) in the test animals and
a r».te of 752 (15/20) in control animals treated with benzene only after
the initial exposure to "DHBA. The average number of papillomas per sur-
vivor in the test group vac 0.04, slightly less than the 0.07 observed
in the controls; the percent of survivors with papillonas was fc.02 as
compared to 72 in the control group.
i
These papers hove been reviewed by the EPA Carcinogen Assessment
Croup and were found to be negative with respect to oncogenie effects
of PCP (Albert, 1978).
B. Mutagenic Effect*
Fahrif (1974) induced mi totic gene conversion at
the ade 8 and trp 5 loci of Saccharomyces cerevisiae. Using a con-
centration of 0.19 millimoles (50 ppm) PCP in 12 dimethyl sulfoxide
5
for 6 hours, he found 6.62 ade 2 convertant* per 10 survivor*
48
-------
5 . 5
(control: 0.45 per 10 survivors) and 4.31 trp 5 convert ants per 10
5
survivors (control: 0.36 per 10 survivors). Fahrig did not report on
the statistical reliability of thtse data.
In a later report, Fahrig (1978) studied the mutagenic
properties of certain chlorophenols, including PCP, in yeast and mice
("mammalian spot test"). He used £. cerevisiae MP-1, a diploid multipurpose
strain for screening intergenie recombination (mitotic crossing over),
intragenic recombination (mitotic gene conversion) and forward mutation.
o
He incubated cell suspensions at 25 C with 400 Kg/liter PCP foi 3.5 hours.
7
He spread aliquots of the suspensions, approximately 3x10 cell;, on solid
nutrient-deficient (intragenic recombinants and mutants) or complete
o
(intergenic recombinants) 'media and incubated at 25 C for 4 and 8 days
respectively. Fahrig reported statistically significant (p<0.001)
increase* is fovard mutation and mitotic gene conversion. Table 16 contains
the results of this experiment.
In the mammalian spot test, he mated females of inbred C57£L/6JHan
strain mice to males of rotation bred 7-stock. The progeny of this combination
are susceptible to color spots in the adult coat if a mutagenic agent is
injected into the peritoneal cavity of the dam during the tenth day of
fetal development. The incidence of color spots in untreated mice bred
as described was 0.1Z. A dosage of 50 mg/kg PCP to pregnant mice produced
color spots in 0.6* of the progeny; a dosage with 100 mg/kg resulted in a
1.32 incidence of spots. Fahrig did not give the statistical significance
of these data.
49
-------
TABLE 16. Induction of forward mutation, intragenic and intergenic recombination in
S. cereviaiae HP-1 in vitro with pentachlorophenol at » treatnmnt time of
T7
3.5 hours
Experiment
Control
t of Concen-
Genetic Experi- tration
Colonies of
Genet ica 1 ly
Colonies of,
I of Genet ically
2/
Altered Cells Experi- Altered Cells
Alteration ments (mg/1) Survival Per Survivor
Mutation 4
Intergen.
Rec.
400 59 ± 8 2.00 _* 0.22 (216)
(10813)
0.47 + 0.14 (50)
ments Per Survivor ' Significance
4 0.61 _f 0.07 (113) < 0.001
0.49 + 0.08 (91) > 0.8
In ^agen.
Kec.
?.64 + 0.45 (*
2.93 + 0.10 C542) < 0.001
1. Adapted from Fahrig et al.. (1977>
2. Control Survival - IOOX
3. Miitants, Convertants (Intragenic Recombination)/10 surviviors,
2
Hecombinanta (Intergenic Recombination)/10 survivors
The numbers in parenthesis give the actual numbers of colonies counted.
50
-------
A geneticist and statistician assigned to EPA have reviewed the Fahzig
et al. paper (1978). In the opinion of the geneticis*- is study does not
provide evidence of the mutagenicity of PCF. This op: . was based on the face
that the experiment has certain shortcomings. Among these are absence of
information on the controls as well as on maternal toxicity (Mauer, 1978). Only
two animals were affected at each dose level; the EPA statistician has found that
this response is not statistically significant at the 0.05 level (Rossi, 1978)
using the chi-square test. -. : -
For these reasons, the reviewers did not consider the mammalian spot
test to be sufficient evidence of matiigenicity, and the criteria of multitesc
evidence of 40 CFR Section 162.11 (a) (3)(ii')(A) are not met.
It should be noted that outagenicity tests on PCP were negative with
the Aiaes test (Andersen et al.' 1971) , the host-mediated assay (buselmaier
et al. 1973), and the sex-linked recessive"lethal test on Drosophila
(Vogel and Chandler, 1974). -'"••' '
C. Chloracne
Chloracne ("chlorine acne") is a human skiri disorder characterized
by distention of hair follicles by horny cutaneous tissue, and by a de-
crease or absence of the sebaceous glands in the area of infection.
This condition has been observed 'in workers in" PCP manufacturing plants
and wood preserving operations (Baader and Bauer, 1951). Chloracne can
arise in these workers weeks or months after exposure, and a!: first was
51
-------
thought to be due to PCP itself. However, using the rabbit eat test,
Jones et ml. showed in 1962 that the acnegenic agent in the herbicide
2,4,5-T was its contaminant TCDD. Further study of the acnegenic effects
of pare and coraercial grade PCP identified its dioxin contaminants as
the causative agent (Johnson et al., 1973).
D. Hepatic Effects
Goldstein et al. (1976) fed pure and technical grade PCP to female
Sherman rats for 8 months at dosages of 20, 10ft, and 500 ppn. Technical
PCP produced hepatic porphyria at 100 and 500 ppn, and all doses caused
.increased hepatic aryl hydrocarbon hydroxylaje activity, glucuronyl trans-
ferase activity, liver weight, cytochrome P-450-, and aicrosoaal hene.
N-deaethylase activity was not affected. In contrast, pure PCP had no
significant effect on these parameters, except for .increasing glucuronyl
transferase at 500 ppsn. Both PCP types decreased the rate of body weight
gain at 500 ppn. The technical PCP used contained 8 ppm hexa-, 520 ppm
hepta-, and 1380 ppm octachlotodibenzodioxin. Pure PCP contained less
than C.I ppm each of these contaminants.
Kimbrough and Linder (1975) fed 1000 ppm "relatively pure" PCP and
technical PCP to male rats for 3 months. All of, the animals were reported to
have statistically significant enlargement of the liver when compared to the
controls. Histological examination of the liver using the light microscope
showed that the rats fed technical PCP had foany cytoplasm or pronounced vaciro-
lation of the hepatocytes, inclusions, single hepatocellular necrosis, inter-
stitial fibresis, and a brown pigment in macrophages and Kupffer cells.
52
-------
Examination with the electron microscope (bowed an increase in (Booth
endoplasmic reticulum, many lipid vacuoles, and atypical mitochondria.
Livers of rats fed the relatively pure PCP showed enlarged hepatocytes,
and many cells contained inclusion* in their cytoplasm. Electron micro-
scope studies showed a slight increase in smooth endoplasmic reticulua,
atypical mitochondria, and some lipid vacuoles. Livers of control rats
were normal. Kimbrough and Linder did not report the amount of dioxin
contaminants in the pure and technical PCP which was used in the study.
In 1976, Schwetz et *1. observed discoloration of the liver in
fenale rats fed 10 or 30 ng/kg/day PCP* Histological examioacicn re-
vealed pigmented material in the hepatocytes-.surrounding the central
veins with smaller amounts present in the reticuloendothelial cells.
Hepatocytes in the centrilobular region alsq contained pigmented mater-
ial but were not necrotic. The PCP used in this study was representa-
tive of Cow's product and contained approximately 30 ppm total dioxins.
E. Toxicity to Humans t, ...-•-,
There are reports of deaths caused by industrial or accidental
exposure to PCP. In most cases exposure occurred by dermal contact,
either to PCP in solution or to materials treated with PCP. Bergner
et al. (1965) described five cases ofrPCP intoxication in Winnipeg in
1963. The one fatality involved a worker in a wood treating
plant who, using his bare hands, dipped wood into a vat containing a so-
lution of &.1J PCP in petroleum solvent. A similar incident had pre-
viously been reported in 1952 in France by Truhaut et al. IE this case
two workers were immersing wooden planks in a 32 aqueous solution of a
-------
mixture of 802 Na-PCP and 202 •odium tetrachlorophenate. The worker*
plunged their hands and forearms into Che liquid bath to remove the
planks. After 6 days of this work, both Men becane ill and ultimately
died. In all three cases, the initial symptoms cf intoxication were
profuse sweating and elevated temperatures.
These saw symptoms were observed in an incident involving nine
neonates in a nursery for newbora infants in St. Louis. Kobson et al.
(1969) reported these and other symptom* in these infants, two of whom
died. Other symptoms reported were increased pulse rate ( > 150/minute),
hepatomegaly, and respiratory distress* "Of the seven survivors, six
received exchange blood transfusions, and one received only supportive
therapy. Exposure was proven to be via percutaneous absorption
of Na-PCP which had been mistakenly used to launder'the infants'
diapers and bed linsns. -
In a followup paper, Armstrong et al. (1969) measured PCP levels
in samples of these diapers and linens, in autopsy tissues, and in the
serum of a surviving infant. They detected the following PCP residues:
six diapers, 2.64 to 17.20 ing/100 g; two shirts, 7.38 and 7.90 mg/100 g;
two shirt backs, 22.40 and 195 mg/100 g; two crib pads, 4.89 and 17b.70
ag/100 g; one mattress pad, 14 mg/100 g; one pillow case, 6.25 mg/100 g;
and two muslins, 1.15 and 2.80 mg/100 g. In autopsy tissues, PCP measure-
ments were: kidney, 2.8 mg/100 g; adrenal, 2.7 mg/100 g; heart and blood
vessel, 2.1 mg/100 g; fat, 3.4 mg/100 g; and connective tissue, 2.7 mg/100 g.
An infant who survived through exchange transfusion, had PCP levels of 11.8
mg/100 ml before, 6.5 mg/100 ml curing, and 0.2 eg/mi after the transfusion.
54
-------
F. Toxicity to Aniatals
Toxicological data oc PCP are complicated by the presence of vary-
ing quantities of tetrachlorophencls, dioxins, and furan* in the technical
material. Table 17 suaaarizes the available toxicity data for PC? on var-
ious mamalian species.
There are reports of fatalities to far* animals following exposure
to PCP. Spencer, in 1957, described the deaths of two Hereford cows within
24 hours after drinking a 52 solution of PCP in kerosene. Blevins (1965)
reported on the death of a litter of ten pigs kept in a farrowing house
i
whose floor had been overly treated with PCP dissolved in used crankcase
oil. They theorized that the pigs; were triply exposed by direct adsorp-
tion through the skin, frost the silk of the gilt, and through inhalation
of PCP "aerosol." The gilt recovered when it was Moved outside the far-
rowing house.
Adelman et al. (1976) established the LC-50's for Ma-PCP as 0.21
ng/liter for fathead minnows, and 0.22 Big/liter for goldfish. Holnberg
et al. (1972) found that the.eel [Anguilla anguilla.L) did not survive
5 days of exposure to 0.1 ppm Na-?CP in fresh water. Eanec et al. (1968)
found that the LC-50 for coho salmon. (Onchorynchus kisutch) is 0.15 ng/
liter of K-PCP.
The Public Health Service of DHEW has reportt on numerous fish
kills from 1964 to 1970 that were caused by effluents froa wood treatment
plant washing into fresh water. Since 1970, the Pesticide Episode Review Systess
(PEES) fans recorded only four incidents involving fish kills. This indicate*
either that wood preserving practices with effluents hitve becooe no re stringent,
or that incidents are not being reported to PEES.
55
-------
TABLE 17. Toxicity of pentachlorophenol to memmala"
I/
Organii*
(Sen, Strain)
Route of
Administration
Dose or
Concentration
Reference
Wiatar Rats
Albino Rats (H)
Albino Spraguc-
Davley Rats (M,F)
Albino Wistar
Rat* (F)
Sherman Rata (H,F)
(F)
(M)
(F)
Oral (0.5* in
Stanoflex fuel oil)
SubcutaneouR (2Z
in water)
Oral (IX in olive oil)
Oral (21 in water)
tntraperitoneal
o
Intraperitoneal 8 C.
Intrapcritoneal 26 C
o
Intraperitoneal 36 C
Percutaneous (dermal)
/iOX w/v in glycerol
formaldehyde
Oral (in peanut oil)
Oral "
Dermal "
Dermal "
27.3 mg/kg
66.3 mg/kg
77.9 mg/kg
210.6 mg/kg
56 mg/k| /
620 otf/kg (LD-100)
420 Big/kg (LD-100)
120 mg/kg (LD-100)
149 mg/kg
146 mg/kg
175 mg/kg
320 mg/kg
330 mg/kg
Uclchmann et al. (1942)
Deichmann et al. (1942)
Deichmann tt al. (1942)
Deichmann et •!. (1942)
Furquharaon et •!. (1942)
Keplinger et «1. (1969)
Keplinger et •!. (1969)
Keplinger et al. (1969)
Noaket and Sanderson (1969)
Caiuea (1969)
Uaittea (1969)
Gainea (1969)
Cainea (1969)
56
-------
I/
* I
TABLE 17. Toxicity of pentachlorophenol to mamma Ia (Continued)
Organism
(Sex. Strain)
Route of
Administration
Dose or
Concentration
Reference
Sprague-Dswley
Rata (H)
White Mice
Rabbits
Sheep
Calves
Inhalation 80 ml/mtn
Intraperitoneal
Subcutaneous
Oral
Percutaneous
Cutaneous
Subcutaneous
Intraperitoneal
Oral
Orii (5% PCP in
sawdust)
Oral (5X PCP in
sawdust)
11.7 mg/kg
29 »g/kf,
63 Big/kg
130 mg/kg
261 mg/kg
512.5 «g/kg (LB-100)
275.0 mg/kg (LB-100)
135.5 mg/kg (LD-100)
550.0 mg/kg (LD-100)
Hoben et at (1976)
Pleskova and Benct« (1959)
Pleskova and B«ncte (1959)
Pleskova and Bencie (1959)
Pleskova and Bencce (1959)
HcCavack et al. (1941)
HcCavack et al. (1941)
McUavack et al. (1941)
HcCavack et al. (1941)
120 ng/kg (LD-100) Harrison (1959)!
140 mg/kg (LD-100) Harrinon (1959)
\J All values represent the LD unless otherwise noted.
50
57
-------
C. Effects of Tetrachlorophenol
As stated previously, th* presence of tetrachlorophenols in «11
PCf products raises the possibility that adverse effects of PC? could
be attributed to these compounds. The toxicological properties of tetra-
chloroDheaols have not been studied extensively. The "Registry of Toxic
Effects of Cb.esu.cal Substances," published by th* Rational Institute of
Occupational Safety aad Health, DHEW, lists the oral LD for the rat as
i ' 50
140 eg/kg, both for tetrachlorophenol (presiaubly mixed isomers) and for
2,3,4,6—tetrachlorophenol.
Schwetz et al. (1974*) evaluated toe effects of purified and com-
mercial grade tetrachlorophenol on rat embryonal and fetal development.
They fed pregnant Sprague-Dawley rats 10 and 30 mg/kg/day on days 6-15
inclusive of gestation. These doses hid no effect on resorptions, fetal
body weight, or fetal crown-rump length. At 30 mg/kg/day, there were
stati tic ally significant increases in delayed ossification' of the skull
boner for both tetrachlorophenol types. Schvetz'et al. observed subcu-
taneous edena at 10 mg/kg/day with both compounds, but not with the 30
ng/'kg/day doses. Since this effect was not dose-related, the authors
speculate thai it may have been due to chance.
58
-------
Appendix 1
Ha-PC? Content in Uat«r Vapor
Ha-PCP is registered for use as a slinicide in cooling cowers, paper pulp
mills and canneries. In these uses, Na-PCP is normally found in water
aC concentrations of 48, 113 and 32 mg/liter respeccively. The huaidity
in the work areas at these sices can approach 1002, due to vaporiza-
tion froa Che large volumes of water required. Na-PCP can also vaporize
i.
froa solution, and Che amounts of Ha-PCP in Che vapor can be estimated.
1 ' ,T< • - . -
In Che following calculations, ic is assumed that Che Na-PCF/water solution
!
is an ideal binary system. The following constants will be required:
At 1002 humidity and 20*C,
3
weight of water vapor • 17.3 gms/m
vapor pressure of water »*17.54 mm
Vapor pressure of Na-PCP -4
(assosing same volatility as PCI1),* 4.7 X 10 mm
Molecular weight of water » 18
Molecular weight of Na-PCP - 269 '
In 1 liter of solution, at 48 mg/1 Na-PCP, there are approximately
-4
.048/289 - 1.7 X 10 moles Na-PCP Jind 1000 gms/18 - 55.5 moles
water. According to Raoult's Lav, the partial pressure (p*) of each
component in a binary system equali; Che mole fraction M (moles of component/
f
- * ' ' , . ' -*<
total moles present) multiplied by the Vapor pressure of Che component (VP ):
•. - - c
p* - K X VP ..,:...•
f C
59
-------
Then:
-4 -4-9
f Ha-PCP • (1.7 X 10 755.5) (4.7 X 10 ) - 1.4 X 10
P* Watar - (55.5/55.5) (17.54) - 17.54 •*
The mole fraction of Na-PCP vapor in the air can be calculated using the
f oral a:
mole fraction Ha-PCP » p* Ha-PCP
p*^ Water * p* Ma-PCP
-9
- 1.4 X 10
' ' -9
17.54, t 1.4 X 10
or aoles Na-PCP in v*r^ -11
noles water in vajs. r • 8 X 10
The aoles of water on the vapor is
3 3
17.3 gas/a - 0.96 Holes water'n
18
Therefore
3 -11
moles Na-PCP " 0.96 noles water/a X 8 X 10
-11 3
- 7.7 X 10 noles/m
and
-11 3
Crams Na-PCP - 7.7 X 10 noles/m. X 298
-3
- 0.02 ug/m
These same calculations apply for vapors in pulp mills ana .anneries,
and using the concentrations of Na-PCP specified earlier, tnese
calculate to:
3
Pulp mills: Na-PCP - 0.047 ug/m
3
Tanneries: Na-PCP - 0.013 ug/m
60
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I/
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K U)
-------
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