ACUTE ORAL TOXICITY STUDY
OF PENETRON IN SPRAGUE-DAWLEY RATS
Submitted to:
- ICS/Penetron International Ltd.
- 45 Research Way
- Suite 203
- East Setauket, NY 11733
-
- FDRL Study No. 8375A
Date: December 26,
1984
FDRL Study No.
8375A
Acute Oral Toxicity Study
in Rats (FHSA) FDRL Test Article ID: 84-0909 Sponsor Test
Article ID: Penetron
SUMMARY
The above referenced test article was
evaluated for acute oral toxicity in male and female Sprague-Dawley rats. The
test article was administered by gauge to each of ten rats at a level of 5.0
g/kg body weight.
One animal died on day 7 following
administration of the test article. According to 16 CFR 1500, the above
referenced test article is not considered to be toxic and does not require
cautionary labeling.
FDRL Study No.
8375A
Acute Oral Toxicity
Study
Purpose:
To determine
the acute oral toxicity of the test article following a single dose by gauge to
male and female Sprague-Dawley rats.
Compliance with
Government Regulations:
This study was conducted in accordance with
the regulations for Good Laboratory Practice as described by the FDA (21 CFR
Part 58), 16 CFR 1500.3 and FDRL Standard Operating Procedures. All data and
pertinent records have been retained by FDRL and are available upon request.
Experimental Design:
Animals and Animal Care
Ten young adult Sprague-Dawley rats were obtained from Charles River
Breeding Laboratories, Inc., Wilmington, MA.
All housing and care conformed to the
standards established in the "Guide for the Care and Use of Laboratory Animals"
DHEW Publication No. (NIH) 78-23. Animals were individually housed in wire mesh
bottom cages in environment-controlled rooms and provided food and water ad
libitum.
Procedure
After an
acclimation period of at least 5 days, animals were assigned to the test. Food
was withheld the night prior to dosing on the first day of the study, animals
received a single oral dose by gauge of the test article at a level of 5.0 g/kg
body weight.
Observations
Animals were weighed prior to dosing,
at termination of the study or at necropsy. They were observed frequently on the
day of dosing and daily thereafter for a total of 15 days. All external signs of
toxicity or pharmacological effects were noted.
Necropsy
All animals that died during the study
were subjected to a gross necropsy and abnormalities were recorded.
FDRL Study No.
8375A
Table 1 Mortality
|
|
Dosage
Level
G/kg |
No.
Rats
Dosed |
No. of Animal Deaths on
Day |
|
|
1 |
2 |
3 |
4 |
5 |
6 |
7 |
8 |
9 |
10 |
11 |
12 |
13 |
14 |
15 |
Cumulative Mortality
|
|
5.0 |
10 |
0 |
0 |
0 |
0 |
0 |
0 |
1 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
0 |
1/10 |
|
Percent Mortality
10% |
95% Confidence
Intervala 0 to 40%
|
|
a E. L. Crow Biometrika 43,
423-435 (1956).
Table 2 Mean Body
Weight Dataa |
|
|
Dosage
Level
G/kg |
Body Weights (g)
|
|
Initialb
|
Day 15
|
|
Males
5.0 |
225.4
+/-10.8(5) |
322.4
+/-15.2(5) |
|
Females
5.0 |
211.0
+/-9.7(5) |
254.8
+/-18.5(5) |
a Values are means +/- S.D. for the
nuinber of observations in ( ).
b Fasted body weight.
FDRL Study No.
8375A
Table 3 Incidence of
Daily Observations |
|
|
Dosage
Level
g/kg |
Observations
|
No. Affected/No.
Examined |
|
Males |
Females
|
|
5.0 |
- Ataxia
- Decreased activity
- Diarrhea
- Gasping
- Rales
- Salivation
- Wet - abdomen
- Deaths
|
- 0/5
- 0/5
- 0/5
- 0/5
- 0/5
- 0/5
- 0/5
- 0/5
-
|
- 1/5
- 2/5
- 2/5
- 1/5
- 1/5
- 2/5
- 3/5
- 1/5
-
|
Table 4 Incidence of Gross
Necropsy Findings |
|
|
Dosage
Level
g/kg |
Findings |
No. Affected/No.
Examined |
|
Males |
Females
|
|
5.0 |
Intestines: contain blood like viscous liquid |
N/A |
1/1
|
DOSING SCHEDULE
Study Title: Acute Oral FDRL Study No.:
8735A
Instructions: FHSA Design FDRL Test
Article
Species: S.D. Rats I.D. No.: 84-0909
C.R. 11/7/84
Test Article
Diluent:Dist./Deionized H20
Density: N/A
Concentration: 95% Form:
Suspension |
|
|
Animal Number & Sex
|
Time Dosed
|
Body Weight (g) At Day
|
Level Dosage G/KG
|
Dose ML (total)
|
Date of Death
|
Comments
|
|
1 |
|
15 |
WAD |
|
D0750031M |
1:26 |
227 |
|
303 |
|
5.0 |
1.19 |
|
DAW- Debbie Webster |
|
0032 |
|
208 |
|
322 |
|
5.0 |
1.09 |
|
NT
- Nancy Trout |
|
0033 |
|
224 |
|
313 |
|
5.0 |
1.18 |
|
SB
- Shirley Bennit |
|
0034 |
|
236 |
|
341 |
|
5.0 |
1.24 |
|
|
|
0035 |
|
232 |
|
333 |
|
5.0 |
1.22 |
|
|
|
|
|
|
|
|
|
|
|
|
|
0036F |
|
202 |
|
245 |
|
5.0 |
1.06 |
|
|
|
0037 |
|
216 |
-- |
-- |
147 |
5.0 |
1.14 |
11/25 DAW |
|
|
0038 |
|
223 |
|
274 |
|
5.0 |
1.17 |
|
|
|
0039
|
|
200 |
|
234 |
|
5.0 |
1.05 |
|
|
|
0040 |
|
214 |
|
266 |
|
5.0 |
1.13 |
|
|
|
|
|
|
|
|
|
|
|
|
|
Initials
& Date |
NT DAW
11/19/84 |
DAW
11/19/84 |
|
SB
12/3/84 |
|
|
|
|
|
|
Reviewed by: BR Date:
12/3/84 TEST ARTICLE PREPARATION DATA
Study Title: Acute Oral
FDRL Study No.: 8735A
Species: Rat
FDRL Test Article I.D.: 84-0909
Concentration Prepared: 95%
Test Article Density: N/A gm/ml
Diluent: Destilled/Deionized H20
Total Amount Dispensed: 25.0
Prepared Physical State: Susspension
PREPARATION
PROCEDURES
( ) Test article dispensed
undiluted.
( X ) Weighed 23
75 gm test article, Q.S. to 25.0 ml with diluent
( ) Test article ground
with rnortar and pestle.
( ) Test article blended at
______ speed for ______
DOSING INFORMATION
Level
Coefficient a
Level
Coefficienta
5.0g/kg
5.26
Special Instructions:
Shake prior to dosing
Comments
Calculations:
LW 11/19/84
Preparation: DS 11/19/84
Initials/Date
Initials/Date
Review SB 11/19/84 BS
12/3/84
Initials/Date
a Coefficient x kg body weight =
dose
N/A = Not Applicable
Study Title: Acute Oral FDRL Study No.:
8375A
FDRL Identification No.:
84-0909 Balance Calibration And Work Log
|
|
|
Date
|
Weight
|
Difference
|
Scale No.
|
Technician
Inititals |
|
Applied
|
Read
|
|
11/19/84 |
200/500 |
200/500 |
0/0 |
1 |
DAW 8:30
|
|
11/25/84 |
200/500 |
200/500 |
0/0 |
1 |
DAW 8:20
|
|
12/3/84 |
200/500 |
200/500 |
0/0 |
1 |
SB 11:00
|
|
|
|
|
|
|
|
|
|
|
|
BR 12/3/84
|
Study Title: Acute Oral FDRL
Study No.: 8375A
Dose Level: 5.0 g/kg
Dosed: 11-19-84
Species: S.D. Rats FDRL Test Article I.D. No.: 84-0909
DAILY OBSERVATIONS |
|
|
Animal No. 0031M
|
Animal No. 0032M
|
Animal No. 0033M
|
Animal No. 0034M
|
Animal No. 0035M
|
Initials/ Date
|
| Day 1 -
Initial |
/ |
/ |
/ |
/ |
/ |
NT DAW 11/19
|
| Day
1 |
Dosed late
|
No |
2nd
|
obs
|
|
|
| Day 1
3:12 |
/ |
/ |
/ |
/ |
/ |
DAW 11/19
|
| Day 2
8:36 |
/ |
/ |
/ |
/ |
/ |
NT 11/20
|
| Day 2
3:14 |
/ |
/ |
/ |
/ |
/ |
DAW 11/20
|
| Day
3 |
/ |
/ |
/ |
/ |
/ |
DAW 11/21
|
| Day
4 |
/ |
/ |
/ |
/ |
/ |
DAW 11/22
|
| Day
5 |
/ |
/ |
/ |
/ |
/ |
NT 11/23
|
| Day
6 |
/ |
/ |
/ |
/ |
/ |
DAW 11/24
|
| Day
7 |
/ |
/ |
/ |
/ |
/ |
DAW 11/25
|
| Day
8 |
/ |
/ |
/ |
/ |
/ |
SB 11/26
|
| Day
9 |
/ |
/ |
/ |
/ |
/ |
SB 11/27
|
| Day
10 |
/ |
/ |
/ |
/ |
/ |
SB 11/28
|
| Day
11 |
/ |
/ |
/ |
/ |
/ |
SB 11/29
|
| Day
12 |
/ |
/ |
/ |
/ |
/ |
SB 11/30
|
| Day
13 |
/ |
/ |
/ |
/ |
/ |
NT 12/1
|
| Day
14 |
/ |
/ |
/ |
/ |
/ |
NT 12/2
|
| Day
15 |
/ |
/ |
/ |
/ |
/ |
SB 12/3
|
|
Reviewed By: BR Date:
12/3/84
Study Title: Acute Oral FDRL
Study No.: 8375A
Dose Level: 5.0 g/kg
Dosed: 11-19-84
Species: S.D. Rats FDRL Test Article I.D. No.: 84-0909
DAILY OBSERVATIONS | |
|
Animal No. 0036F
|
Animal No. 0037F
|
Animal No. 0038F
|
Animal No. 0039F
|
Animal No. 0040F
|
Initials/ Date
|
| Day 1 -
Initial |
/ |
Sal.
|
Sal. |
/ |
/ |
NT DAW 11/19
|
| Day
1 |
Dosed late
|
No |
2nd
|
obs
|
|
|
| Day 1
3:12 |
/ |
/ |
/ |
/ |
/ |
DAW 11/19
|
| Day 2
8:36 |
/ |
Rales, Ad
|
/ |
Ad |
/ |
NT 11/20
|
| Day 2
3:14 |
/ |
ClearRales, G, Ad
Wetm-6 |
/ |
Ad Wetm-6
|
Di |
DAW 11/20
|
| Day
3 |
/ |
NC |
/ |
NC |
Clear Di
Wetm-6 |
DAW 11/21
|
| Day
4 |
/ |
G, Ad, Wetm-6,/Di
|
/ |
Clear Wetm-6
& Ad, V |
Clear Wetm-6
|
DAW 11/22
|
| Day
5 |
/ |
Clear Wetm-6,/Ad, G,
Di |
/ |
/ |
/ |
NT 11/23
|
| Day
6 |
/ |
Ad, G, Di
|
/ |
/ |
/ |
DAW 11/24
|
| Day
7 |
/ |
DEAD
|
/ |
/ |
/ |
DAW 11/25
|
| Day
8 |
/ |
|
/ |
/ |
/ |
SB 11/26
|
| Day
9 |
/ |
|
/ |
/ |
/ |
SB 11/27
|
| Day
10 |
/ |
|
/ |
/ |
/ |
SB 11/28
|
| Day
11 |
/ |
|
/ |
/ |
/ |
SB 11/29
|
| Day
12 |
/ |
|
/ |
/ |
/ |
SB 11/30
|
| Day
13 |
/ |
|
/ |
/ |
/ |
NT 12/1
|
| Day
14 |
/ |
|
/ |
/ |
/ |
NT 12/2
|
| Day
15 |
/ |
|
/ |
/ |
/ |
SB 12/3
|
|
Reviewed By: BR Date:
12/3/84
Study Title: Acute Oral FDRL
Study No.: 8375A
Dose Level: 5.0 g/kg
Dosed: 11-19-84
Species: S.D. Rats FDRL Test Article I.D. No.: 84-0909
DAILY OBSERVATIONS | |
|
Animal No. 0036F
|
Animal No. 0037F
|
Animal No. 0038F
|
Animal No. 0039F
|
Animal No. 0040F
|
Initials/ Date
|
| Day 1 -
Initial |
/ |
Sal. |
Sal.
|
/ |
/ |
NT DAW 11/19
|
| Day
1 |
Dosed late
|
No |
2nd
|
obs
|
|
|
| Day 1
3:12 |
/ |
/ |
/ |
/ |
/ |
DAW 11/19
|
| Day 2
8:36 |
/ |
Rales, Ad
|
/ |
Ad |
/ |
NT 11/20
|
| Day 2
3:14 |
/ |
ClearRales, G, Ad
Wetm-6 |
/ |
Ad Wetm-6
|
Di |
DAW 11/20
|
| Day
3 |
/ |
NC |
/ |
NC |
Clear Di
Wetm-6 |
DAW 11/21
|
| Day
4 |
/ |
G, Ad, Wetm-6,/Di
|
/ |
Clear Wetm-6
& Ad, V |
Clear Wetm-6
|
DAW 11/22
|
| Day
5 |
/ |
Clear Wetm-6,/Ad, G,
Di |
/ |
/ |
/ |
NT 11/23
|
| Day
6 |
/ |
Ad, G, Di
|
/ |
/ |
/ |
DAW 11/24
|
| Day
7 |
/ |
DEAD
|
/ |
/ |
/ |
DAW 11/25
|
| Day
8 |
/ |
|
/ |
/ |
/ |
SB 11/26
|
| Day
9 |
/ |
|
/ |
/ |
/ |
SB 11/27
|
| Day
10 |
/ |
|
/ |
/ |
/ |
SB 11/28
|
| Day
11 |
/ |
|
/ |
/ |
/ |
SB 11/29
|
| Day
12 |
/ |
|
/ |
/ |
/ |
SB 11/30
|
| Day
13 |
/ |
|
/ |
/ |
/ |
NT 12/1
|
| Day
14 |
/ |
|
/ |
/ |
/ |
NT 12/2
|
| Day
15 |
/ |
|
/ |
/ |
/ |
SB 12/3
| |
Reviewed By: BR
Date: 12/3/84 Abbreviations and Symbols used in Recording
Observations | |
| AD – accidental
death
Ad – activity decreased
Ai – activity increased
Al – hair loss
An – anorexia (loss of appetite)
At – ataxia, wobbly gait
B – blood
C – clinicals
COP – corneal opacity
Cy – cyanosis
D – died
DB – dried blood (give location)
DME – dark material around eyes
DMN – dark material around nose
Di – diarrhea
Em – emaciated
FD – found dead
G – gasping
Lac – lacrimation greater than normal
(tearing) -
NC – no change |
/ –
normal
Nd – nasal discharge
M – respiratory rate decreased
Ri – respiratory rate increased
Ppp – pin point pupils
S – sacrificed
Sal – salivation
Sb – appears to have blood in
stools
Sh – shallow breathing
SM – sacrificed moribund
SS – soft stools
T – tremors
Ub – appears to have blood in
urine
Us – urine stain (state location)
V – vomiting
X – escaped, lost, missing
NNf – no noteworthy
findings. |
|
Use L – left, R – right, M – middle
plus numbers 1-12 for locations of nodules or other conditions where
appropriate. Use +1, +2, +3 after appropriate abbreviations to indicate degree
of severity of that condition (+1 – slight, +2 – moderate, +3 – .extreme), i.e.
moderately increased activity would be Ai +2.
Appendix II Labeling
Requirements Labeling Requirements* Acute Oral
Toxicity
If 50% or more of the animals die when
given a single dose of 50 mg/kg or less, then the test article is considered
"highly toxic" and appropriate cautionary labeling is required.
If 50% or more of the animals die when
given a single dose greater than 50 mg/kg up to and including 5.0 gms/kg, then
the test article is considered "toxic" and appropriate cautionary labeling is
required.
If less than 50% of the animals die
when given a single dose of 5 grams/kg or greater, then the test article is not
considered to be toxic and does not require cautionary labeling.
As defined in 16 CFR 1500.3
This final report was reviewed as
required by Good Laboratory Practice Regulations for non-clinical laboratory
studies, 21 CFR Part 58 and the study protocol. Inspections were accomplished as
noted, and reported to the study director and inanagement immediately following
their completion. Based on these inspections and the review of the report, this
study was conducted and reported in conformance with the Good Laboratory
Practice regulations.
| |
