Document 9J0MYJ99vdvzDk1dRq9oVx31L
AR226-3395
Repeated Dose Oral Toxicity of 8-2 Telomer B Alcohol Range-Finding Study in Rats
G.L. Kennedy,1 G.S. Ladies,1 J.C. O'Connor,1 S.A. Gannon,1 R. Jung,2 H. Iwai,3 S. Shin-ya4
TRP* Toxicology Program, 'DuPont Haskell Laboratory for Health and Environmental Sciences, Newark, Delaware, USA ^lariant GmbH, Sulzbach, Germany
^aikm Industries, Inc., Osaka, Japan ^sahi Glass, Co., Ltd., Tokyo, Japan
Preliminary to a repeated dose toxicity assessment, a range-finder study involving repeated oral
doses of 8-2 Telomer B Alcohol was conducted in rats to determine the time needed to reach steady-state as determined by total organofluorine blood fluoride levels. Groups of 10 male and 5 female Cri:CD(SD)IGS BR rats each were dosed daily with either 0 (control), 5, 25, or 125 mg 8-2 Telomer B Alcohol/kg/day. A number of toxicology end-points such as body weights, liver and kidney weights were recorded during and at the end of the study. Blood samples were analyzed for total fluoride levels weekly. Steady-state concentrations were reached between test days 60 and 84. At steady-state, pooled plasma samples obtained from males and
females over the duration of the study were analyzed for Telomer 8-2 Alcohol (parent compound), Telomer 8-2 acid, perfluorooctanoate acid (PFOA), and perfluorononanoic acid (PFNA) and total fluorine levels. The level of parent compound detected did not exceed 0.074 ppm in either males or females. In males, PFOA represented approximately 85% of the total plasma fluorine. In females, PFOA represented approximately 5%. The 8-2 acid of Telomer B Alcohol and PFNA were also found in plasma of both males and females.
Significantly lower mean body weights and increased liver weights compared to control were observed in male rats administered 125 mg/kg/day. Based on these data, the following doses were chosen for the 90-day oral toxicity study: 0, 1,5, 25, and 125 mg/kg/day.
*
Telomer Research Program
To determine appropriate dose levels for use in a 90-day oral subchronic study with 8-2 Telomer B Alcohol.
Telomer C8-2 Alcohol
F
F
F
H
F
F
F
C8-2 Acid (M477)
F
0
PFNA
F
F
F
F
F
F
0
PFOA
Test substance, 8-2 Telomer B Alcohol (99.2% pure) Test species: Crl:CD rat (male and female) Standard husbandry, 5-day quarantine Groups: 10 males, 5 females/group [5 males/group allowed 75-day post-dosing recovery
period]. Doses: 0, 5, 25, 125 mg/kg Daily gavage beginning with 7-week-old rats
Doses in methylcellulose suspensions, 5 mL/kg dosing volume. Parameters measured (dosing and during recovery)
Body weights (2 x/week) Cage-side exams (daily) Total fluoride/parent metabolite evaluation
Blood samples collected 1 x pre-dosing weekly during dosing Organ weights - liver, kidney Parent/Metabolite Evaluation
At steady-state, pooled plasma, fat, liver, and kidney samples from each group were analyzed
for Telomer 8-2 Alcohol Perfluorooctanoic Acid (PFOA) Perfluoronanonoic acid (PFNA)
Dose (mg/kg)
0
Finding None
5
None
25
None
125
Striated teeth
Clipped teeth
Sex Incidence
M
10/10
F
5/5
M
10/10
F
5/5
M
10/10
F
5/5
M
7/10*
F
4/5*
M
4/10*
F
0/5
* (p <0.05) different from control
Dose
(mg/kg)
0 5 25 125
After Dosing
(Test Day 81)
Male
Female
594 44 264 45
564 59 302 22
553 34 296 41
509* 55 291 21
After Recovery (Post-Dosing Day 75)
Male
Female
554 100 322 41
595 57 348 29
573 83 549 37
332 50 346 31
*
(p <0.05) different from control
Resttte (Continued)
Dose
Liver
Kidney
(g/lOOgbwt)
(g/lOOgbwt)
(mg/kg) Se Test Day 81 Post-Dosing Day 75 Test Day 81 Post-Dosing Day 75
x
M 3.9(0.28)
F
3.0(0.13) 3.2(0.14)
0.76(0.03)
0.65(0.06) 0.70(0.03)
M 3.7(0.20)
F
3.1(0.14) 3.2(0.33)
0.76(0.06)
0.67(0.03) 0.71/(0.07)
25
M 4.1(0.19
F
2.9(0.13) 3.4(0.37)
0.75(0.04)
0.69(0.05) 0.73(0.06)
125 M 5.5*(0.39)
F
3.1(0.32) 3.6*(0.05)
0.87(0.11)
0.74*(0.07) 0.78*(0.02)
(p 0.05) different from control
Results (Continued) Total Blood Fiu.orlne Analysis
Alcohol
.Results (Continued) Total Blood FIaoriae Analysis
20 -i
Resalts (Continued)
Analysts of 8-2 Teloiaer B Alcohol, PFOA, and PFNA la Seruas aad Selected Tissaes
Dose (mg/kg/day)
0
Male PFOA (ppm)
0.07
MalePFOA
Converted
toppmF
0.05
Male Total Plasma F
(ppm)
NM
Female PFOA (ppm)
0.0
Female PFOA
Converted
toppmF
0.0
Female Total Plasma F (ppm)
NM
5
2.19
1.51
NM
0.08
0.05
NM
25
8.47*
5.83
8.11
0.54*
0.37
5.88
125
65.60* 45.16
53.24
1.85*
1.27
23.20
Determined using Wickbold Torch; * Mean of 2 separate runs.
C8-2A (ppm)
Fat
Liver Kidney
PFOA (ppm)
Plasma Fat Liver Kidney
PFNA (ppm)
Fat Liver Kidney
8-2 Telorner B Alcohol (mg/kg/day)
5
25
125
0.07(0.01) 0.02(0.00)
NM
0.34(0.13) 0.13(0.03) 0.01(0.00)
1.37(0.55) 0.77(0.53) 0.07(0.07)
2.19 0.09(0.04) 6.96(1.94) 1.64(0.83)
8.47 0.35(0.12) 18.68(10.38) 8.43(4.14)
65.60 1.90(1.66) 30.69(20.68) 29.11(17.38)
0.00(0.00) 0.51(0.09) 0.00(0.00)
0.00(0.00) 0.91(0.23) 0.11(0.09)
0.01(0.01) 1.19(1.25) 0.86(0.62)
NM = not measured.
Results (Continued)
Plasma PFOA Concentration in Male Rats
-0 mg/kg/day
-5mg/hg/day -25rrg/kg/day -125 mg/kg/day
Plasma PFOA Concentration in Female Rats
35-,
30
=> 25
0) 20
3
'S' 15
10-
5
--a--i^4^ 0
C 3
7
14 21 28
A
---- 0 mg/kg/day
5 mg/kg/day --A-- 25 mg/kg/day
X 125 mg/kg/day
M-1l--t=:::^1S--r--r-^--
35 42 49 56 63 70 77 84 Test day
ResaSts (Continued) Plasma 8-2 Telomer BAIcohol Concentration in Male Rats
- 5 mg/kg/day - 25 mg/kg/day -125 mg/kg/day
Plasma 8-2 Telomer BAIcohol Concentration in Female Rats Test Day
- 5 mg/kg/day - 25 mg/kg/day
-125 mg/kg/day
ResttBts (Continued)
2.00-,
Plasma PFNA Concentration in Male Rats
- 0 mg/kg/day - 5 mg/kg/day - 25 mg/kg/day -125 mg/kg/day
2.00-i
^ 150-
|
0)
3. i.oo-
o o
0
0.50 -
0.00
Plasma PFNA Concentration in Female Rats
- 0 mg/kg/day - 5 mg/kg/day - 25 mg/kg/day -125 mg/kg/day
Resalts (Continued)
Plasma Met477 Concentration in Male Rats
20000000 -i
18000000 -
16000000 -
14000000 -
12000000
10000000
< 8000000
6000000 4000000 2000000
Q
^-X---~^ X -{ y^^'^^'^'^,
'^r-^r-ir^r^ --- -
X----X---x--^^^ Ar
-
.
.
.
*
-----------f
T--------=F----------i----------------------T----------i----------=r--------=r----------.----------i
0
7
14 21 28 35 42 49 56 63 70 77
Test day
---- Series2
--A-- Series3 --X-- Series4
20000000 -, 18000000 16000000 14000000 12000000 10000000 -
<
8000000 6000000 4000000 2000000 -
0
Plasma Met477 Concentration in Female Rats
- 5 mg/kg/day - 25 mg/kg/day -125 mg/kg/day
C'oraelttslons
Doses of Telomer 8-2 Alcohol were well tolerated; number of endpoints were altered at
125 mg/kg.
Steady-state blood fluorine levels were attained between weeks 8 and 13 of dosing; males
reached higher levels than females.
Telomer 8-2 Alcohol was extensively metabolized by both sexes of rats.
The 90-day toxicity study would employ dose levels ofO, 1, 5, 25, and 125 mg/kg.