Registration Dossier

Administrative data

Endpoint:
sub-chronic toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
comparable to guideline study

Data source

Reference
Reference Type:
publication
Title:
Subchronic Inhalation toxicity study of 1,3-dichloro-2-propanol in rats
Author:
Kim H-Y et al
Year:
2007
Bibliographic source:
Ann. Occup. Hyg. 51 (7) pp 633-643

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 413 (Subchronic Inhalation Toxicity: 90-Day Study)
Deviations:
not specified
GLP compliance:
not specified
Limit test:
no

Test material

Reference
Name:
Unnamed
Test material form:
liquid
Specific details on test material used for the study:
purchased from Acros Organics (Fisher Scientific Japan)

Test animals

Species:
rat
Strain:
Fischer 344
Details on species / strain selection:
Standard rat strain used in toxiciology studies
Sex:
male/female
Details on test animals and environmental conditions:
Forty-eight 5-week-old Fischer 344 rats of each
gender were obtained from a specific pathogen-free
colony at Charles River Japan Inc. (Kanagawa,
Japan) and used after 10 days of quarantine and acclimatization.
The animals were housed in a room
maintained at a temperature of 22 – 3C and a relative
humidity of 50 – 20% with artificial lighting
from 08:00 to 20:00 and with 12–15 air changes
per hour (Industrial Chemicals Research Center,
Korea Industrial Safety Corporation, Daejeon,
Republic of Korea). The animals were housed individually
in wire-bottomed stainless steel wire mesh
cages that were placed in exposure chambers and
were allowed sterilized tap water and commercial rodent
chow (LabDiet 5002, PMI Nutrition, USA) ad
libitum. The Institutional Animal Care and Use Committee
approved the protocols used in this animal
study, and animals were maintained in accordance
with the Guide for the Care and Use of Laboratory
Animals (NRC, 1996).

Administration / exposure

Route of administration:
inhalation: gas
Type of inhalation exposure:
whole body
Vehicle:
air
Details on inhalation exposure:
Whole-body exposure chambers (Shibata Co., Japan) including a gas generator (Shibata Co.) were used to expose the rats to 1,3DCP.
The test animals were exposed to 5, 20 or 80 ppm 1,3-DCP or fresh air for 6 h/day, 5 days/week
for 13 weeks. The inhalation exposure was carried out from 10:00 to 16:00 in a stainless-steel chamber
(1000 l). The experimental design was based on the usual working schedule for workers, as well as the
major exposure route for the test chemical.
Temperature, relative humidity, pressure and air ventilation in the chambers were recorded using an
environmental controller (Shibata Co.). The temperature and relative humidity were maintained at 23.3–
23.7C and 55.9–60.5%, respectively.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
23.7C and 55.9–60.5%, respectively. The concentrations of 1,3-DCP in the chambers were calibrated
with a standard chemical (Acros Organics Co., UK), air pump (Iwaki Co., Japan), gas meter (Shinagawa
Co., Japan) and Teflon bags. The conditions used for detecting 1,3-DCP by gas chromatography
(Shimadzu Co., Japan) were as follows: detector, flame ionization detector; column, silicon DC-200
15% chromosorb with mesh of 80/100 and a 0.5-m length; detector temperature, 150C; oven temperature,
100C; injector temperature, 150C; and injection volume, 1 ml of gas sample. The 1,3-DCP
vapor concentrations in the chambers were measured every 15 min during exposure and were controlled
to be within –5% of the target concentration using a personal computer. The mean concentration measured
every 30 min for 6 h was taken as the value on a given day. This was then averaged over the 13week
exposure period in order to obtain the mean and standard deviations, and the daily gas concentrations
in the three chambers were measured at 5.3 – 0.78, 20.8 – 1.86 and 79.0 – 4.53 ppm,
respectively.
Duration of treatment / exposure:
6 hours/day
Frequency of treatment:
5 days/week for 13 weeks
Doses / concentrationsopen allclose all
Dose / conc.:
5.3 ppm (analytical)
Dose / conc.:
20.8 ppm (analytical)
Dose / conc.:
79 ppm (analytical)
No. of animals per sex per dose:
10 animals per sex per dose
Control animals:
yes, concurrent vehicle
Details on study design:
Prior to testing, rats were evaluated by clinical observations and body weight determinations during
a 7-day quarantine period to assure freedom from potential confounding variables. Forty males and 40 females
were randomly assigned to four experimental groups: three treatment groups receiving 5, 20 and
80 ppm 1,3-DCP and a vehicle control group. Each group consisted of 10 rats of each gender. All of
the rats were sacrificed after treatment for 13 weeks. The experimental concentrations were selected based
on the results of a preliminary dose-range finding study. Groups of five rats of each gender were exposed
to 1,3-DCP via whole-body inhalation at concentrations of 10, 33 and 100 ppm for 2 weeks. Both
males and females showed a moderate-to-severe reduction in body weight gain and food intake at 100
ppm. Accordingly, 80, 20 and 5 ppm were selected as the high, medium and low doses, respectively,
using a scaling factor of x4.
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
All animals were observed twice daily (before and
after exposure) throughout the study period for any
clinical signs of toxicity, and mortality.

DETAILED CLINICAL OBSERVATIONS: Not specified

BODY WEIGHT: Yes
The body weights of each rat and food consump-
tion were measured at the beginning of exposure
and once a week during the exposure period. The
amounts of food were calculated before they were
supplied to each cage, and their remnants were measured
on the next day in order to calculate the difference,
which was regarded as daily food consumption
(g/rat/day).

FOOD EFFICIENCY: no

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study): No


OPHTHALMOSCOPIC EXAMINATION: Yes
External eye examination on all males and females
was carried out shortly before the beginning of the
experiments and in the last week of the exposure period.
The ocular fundus was examined during the last
week of the exposure period using an indirect binocular
ophthalmoscope (IO-H, Neitz Instruments Co.,
Japan). The conjunctiva, sclera, cornea, lens and iris
of each eye were also examined.

HAEMATOLOGY: Yes
- Time schedule for collection of blood: prior to necropsy
- Anaesthetic used for blood collection: Yes (pentobarbital)
- Animals fasted: Yes
- How many animals: all groups
- The following parameters were determined: red blood cell (RBC, erythrocyte) count,
hemoglobin concentration, hematocrit (HCT), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin
concentration (MCHC), platelets (PLTs), white blood cell (WBC, leukocyte) count and differential WBC count.

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood:
- Animals fasted: Yes
- How many animals: all groups
- Blood samples were centrifuged at 3000 rpm for 10 min within 1 h after collection. The sera were stored at <80C in a freezer prior to analysis. The following serum biochemistry parameters were evaluated using an autoanalyzer (Shimadzu CL-7200,
Shimadzu Co.): aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), blood urea nitrogen (BUN), creatinine (CRTN), GLU, lactate dehydrogenase (LDH), total cholesterol (T-CHO), total bilirubin (T-BIL), total
protein (TP) and creatine phosphokinase (CPK).

URINALYSIS: Yes
- During the last week of exposure, urinalysis for
five males and five females per group was carried
out with fresh urine to determine the specific gravity,
pH, protein, glucose (GLU), ketone body, occult
blood, bilirubin, urobilinogen, nitrite and leukocyte
contents by using a Uriscan S-300 urine chemistry
analyzer (Yeongdong Electronic Co., Republic of
Korea).

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No


OTHER:
Sacrifice and pathology:
Gross findings
At the end of experiments, all surviving animals
were anesthetized by an intraperitoneal administration
of sodium pentobarbital (50 mg kg body
weight) for blood sample collection. The rats were
then sacrificed by exsanguination from the abdominal
aorta. Complete gross postmortem examinations
were performed on all terminated animals.

Organ weights
The absolute and relative (organ-to-body weight
ratios) weights of the following organs were measured:
liver, right kidney, lung, heart, thymus, right
testis and/or right ovary.
Other examinations:
Histopathology
The following tissues were obtained from all animals: abnormal lesions, skin, mammary gland,
spleen, pancreas, jejunum, stomach, duodenum, ileum, cecum, colon, mesenteric lymph node, salivary
gland, submandibular lymph node, ovaries, uterus, vagina, urinary bladder, epididymides, prostates,
seminal vesicles, rectum, kidneys, adrenal glands, liver, sternum, thymus, heart, lung, trachea, esophagus,
thyroids (including parathyroids), tongue, aorta, sciatic nerve, skeletal muscle, femur, thoracic spinal
cord, Harderian glands, brain, pituitary gland, eyes, testes, nasal cavity, nasal turbinates and Zymbal
glands. Eyes and testes were preserved in Davidson’s fixative and Bouin’s fixative, respectively. Other
tissues were fixed with a 10% neutral buffered formalin solution. The tissues were routinely processed,
embedded in paraffin and sectioned at 3–5 µm. The sections were stained with hematoxylin–eosin stain
for microscopic examination. The nasal passages and nasal turbinates were decalcified prior to being
embedded and sectioned. The nasal cavity was sectioned at levels posterior to the upper incisors,
the incisive papilla, the second palatine ridge and the first molar teeth . All organs and tissues
taken from all animals in the vehicle control and the high-dose groups were examined microscopically.
All gross lesions, as defined by the study pathologist, were also included in the examination.
Statistics:
Data are presented as means – SDs. The variance of numerical data was checked using Barlett’s
(1937) test. If the variance was homogeneous, data were subjected to one-way analysis of variance
(ANOVA), and if the variance was not homogenous, data were analyzed by Kruskal–Wallis (1952) non-
parametric ANOVA. If either of the tests showed a significant difference among the groups, the data
were analyzed by the multiple comparison procedure of the Dunnett (1964) post-hoc test. Clinical signs,
necropsy findings and histopathological findings were represented as frequencies and were subjected
to Fisher (1970) exact probability test when necessary.
All statistical analyses were conducted with Statistical Analysis Software (SAS, NC, USA). The
significance of the differences from the control group was estimated at the probability levels of 1% and 5%.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Description (incidence and severity):
No treatment-related toxic symptoms or mortality
were observed in any of the animals treated with 1,3DCP
during the study period.
Mortality:
no mortality observed
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
The body weight gain of male rats was statistically significantly suppressed in the
80-ppm group on Days 7 through 90 of treatment compared with that of the control group.
The body weight gain of female rats was also significantly lower in the 80-ppm group from Day 7
of treatment to termination compared with the control group. Although the difference was not statistically
significant between the groups, food consumption
was also slightly lower in the 80-ppm groups of both
genders from Day 1 of the test to termination compared
with that of the control group (data not shown).
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Description (incidence and severity):
Although the difference was not statistically
significant between the groups, food consumption
was also slightly lower in the 80-ppm groups of both
genders from Day 1 of the test to termination compared
with that of the control group
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
no effects observed
Description (incidence and severity):
Ophthalmologic examinations did not show any
treatment-related ocular lesions in any of the animals
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
In males, MCV was significantly decreased in the 5-ppm group when compared with the control group.
HCT and MCV were significantly decreased in the 20-ppm group, and MCHC was significantly increased
in the same dose group in comparison with that of the control group. Hemoglobin (HB), HCT,
MCV, MCH and WBC were significantly decreased, while the PLT count was significantly increased in
the 80-ppm group when compared with that of the control group. In females, HB was significantly
decreased in the 5-ppm group compared with the control group. RBC, HB, HCT and MCV were significantly
decreased, while MCHC and PLT count were significantly increased in the 20-ppm group when
compared with the control group. The 80-ppm group showed statistically significant decreases in the HB,
HCT, MCV and MCH and a statistically significant increase in the PLT count compared with the controls.
Clinical biochemistry findings:
effects observed, treatment-related
Description (incidence and severity):
In males, statistically significant decreases in AST, ALP, BUN, LDH and CPK were observed in the
5-ppm group in comparison with the control group. The 20-ppm group showed statistically significant
decreases in ALP, BUN, T-BIL and CPK and statistically significant increases in serum GLU and TP
when compared with the control group. The serum levels of ALP, BUN, CRTN and T-CHO were significantly
decreased, while AST, ALT and TP were significantly increased in the 80-ppm group as compared
with those of the control group. In females, statistically significant decreases in ALP and BUN were
observed in the 5-ppm group compared with those of the control group. The 20-ppm group exhibited statistically
significant decreases in ALP, BUN, CRTN and T-BIL compared with those of the control group. The
80-ppm group showed statistically significant decreases in ALP, BUN and CRTN and statistically significant
increases in AST, ALT and TP compared with the findings for the control group.
Urinalysis findings:
effects observed, treatment-related
Description (incidence and severity):
In the male 80-ppm group, a statistically significant increase in urine protein was observed.
In the female 80-ppm group, significant increases in urine protein and leukocyte counts were observed.
The other urinary parameters tested in both sexes were not significantly
different between the treatment groups and controls.
Behaviour (functional findings):
not examined
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
In males, the liver weight in all of the treatment groups and kidney weight in the 20- and
80-ppm groups were significantly increased in a dose-dependent manner compared with those of
the control group. The weights of testis and heart in the 80-ppm group were also significantly increased
in comparison to the control group. In females, the liver weight in all of the treatment groups and the
kidney weight in the 20- and 80-ppm groups were significantly increased in a dose-dependent manner
compared with those of the control group. Heart weight in the 80-ppm group was also significantly
heavier than that of controls.
Gross pathological findings:
no effects observed
Description (incidence and severity):
At the scheduled necropsy, there were no treat-
ment-related gross findings in any of the treated
animals.
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
In males, 10 cases of multifocal necrosis, 4 cases of inflammation, 10 cases of pigmentation,
8 cases of biliary hyperplasia and 1 case of the foci of cellular alteration were observed in
the livers of the 80-ppm group. Ten cases of chronic nephropathy were also found in the 80-ppm group.
One case each of multifocal necrosis and inflammation was found in the 20-ppm group. Chronic nephropathy
was noted in 4 cases of the 20-ppm group. In females, 10 cases of multifocal necrosis,
7 cases of inflammation, 10 cases of pigmentation, 1 case of biliary hyperplasia and 6 cases of the foci
of cellular alteration were observed in the liver of the 80-ppm group. Four cases of chronic nephropathy
and 2 cases of renal protein cast were also observed in the 80-ppm group. Hepatic inflammation
occurred in 2 cases in the 20-ppm group. The incidences of these findings were significantly higher
in the 80-ppm group than those in the control group, but not in the 20-ppm group. The severity of the histopathological
changes was slight in the 20-ppm group, but moderate-to-severe in the 80-ppm group.
The other histopathological findings observed in both genders of the treatment groups were also found in the
control group or were determined to be spontaneous changes without any dose–response relationship.
Histopathological findings: neoplastic:
not specified

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
< 5.3 ppm (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
haematology
clinical biochemistry
urinalysis
organ weights and organ / body weight ratios
histopathology: non-neoplastic
Dose descriptor:
LOAEL
Effect level:
ca. 5.3 ppm (analytical)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
body weight and weight gain
haematology
clinical biochemistry
urinalysis
organ weights and organ / body weight ratios
histopathology: non-neoplastic

Target system / organ toxicity

open allclose all
Critical effects observed:
yes
Lowest effective dose / conc.:
5.3 ppm (analytical)
System:
haematopoietic
Organ:
blood
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes
Critical effects observed:
yes
Lowest effective dose / conc.:
5.3 ppm (analytical)
System:
hepatobiliary
Organ:
liver
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes
Critical effects observed:
yes
Lowest effective dose / conc.:
5.3 ppm (analytical)
System:
urinary
Organ:
kidney
Treatment related:
yes
Dose response relationship:
yes
Relevant for humans:
yes

Any other information on results incl. tables

Table1.Urinary analysis i nmale and female rats after inhalation of 1,3 -DCP for 13weeks

 

Parameters

Dose(ppm)

 

 

0

5

20

80

No.of rats

5

5

5

5

Male

 

 

 

 

Ketone(mg per 100ml)

10.00–0.00

6.00–5.48

9.00–2.24

8.00–4.47

Protein(mg per 100ml)

22.00–10.96

36.00–37.15

24.00–13.42

86.00–31.30**

pH

Leucocytes (WBC/µl))

6.70–0.27

19.00–8.22

6.70–0.27

19.00–8.22

6.80–0.45

32.00–24.90

6.50–0.00

130.00 -207.97

Female

 

 

 

 

Ketone(mg per 100ml)

7.00–4.47

4.00–5.48

9.00–2.24

2.00–4.47

Protein(mg per 100ml)

8.00–13.04

2.00–4.47

0

20.00–14.14*

pH

Leucocytes(WBCll1)

6.10–0.22

7.00–10.95

6.60–0.22

17.00–11.51

6.50–0.5

12.00–12.55

6.50–0.35

65.00–22.36**

Values are presented as means–SDs.

* Indicates significant difference at P<0.05 compared with the control group.

** Indicates significant difference at P<0.01 compared with the control group.

Table 2: Hematological results in male and female rats after inhalation of 1,3 -DCP for 13 weeks

Parameters

Dose(ppm)

 

 

0

5

20

80

No.of rats

10

10

10

10

Male

 

 

 

 

RBC(x10e12 /l)  

HB(g/dl )

8.36–0.40

15.73–0.55

8.46–0.54

15.25–0.58

7.82–0.57

15.32–0.26

7.86–0.46

13.77–0.92**

HCT(%)

38.94–2.42

38.21–1.97

34.35–1.82**

33.50–2.66**

MCV(fl)

46.81–0.51

44.40–1.06*

43.91–1.30**

40.90–0.53**

MCH(pg)

18.84–1.15

17.77–1.00

19.67–0.45

17.22–1.25*

MCHC(g/dl)

40.28–2.43

40.01–2.40

44.83–1.10*

41.37–4.60

PLT(10e9/l)

WBC(10e9/l)

675.80–44.46

4.43–1.07

724.10–44.91

4.35–0.60

740.70–83.18

4.25–2.42

899.10–219.70**

3.14–0.27**

Female

 

 

 

 

RBC( 10e12/l)

HB(g/dl)

7.62–0.50

14.99–0.48

7.21–0.74

14.42–0.43*

6.77–0.65*

14.11–0.35**

7.21–0.53

12.98–0.41**

HCT(%)

38.52–2.66

36.00–3.86

33.61–3.28**

32.49–2.14**

MCV(fl)

50.58–0.37

49.94–0.45

49.60–0.40*

45.08–0.94**

MCH(pg)

19.74–1.27

20.20–2.16

20.99–1.71

18.07–1.24*

MCHC(g/dl)

39.06–2.65

40.48–4.59

42.29–3.55*

40.06–2.35

PLT(  10e9/1)

632.00–35.20

699.80–44.04

727.30–49.24**

755.80–87.37**

WBC (10e9/L)

 3.49 -0.49

 2.97 -0.43

 3.02 -0.63

 3.25 -0.31

Values are presented as means–SDs.

* Indicates significant difference at P<0.05 compared with the control group.

** Indicates significant difference at P<0.01 compared with the control group.

Table3.Serum biochemical findings in male and female rats after inhalation of 1,3 -DCP for 13weeks

 

Parameters

Dose(ppm)

 

 

0

5

20

80

No.of rats

10

10

10

10

Male

 

 

 

 

AST (IU/l)

151.20–39.00

89.89–7.77**

103.60–20.60

219.10–123.1*

ALT (IU/dl)

73.67–21.05

47.44–5.48

51.80–13.05

485.57–246.7**

ALP (mg/dl)

266.89–19.73

230.11–15.67*

193.44–48.28**

221.90–19.78*

BUN (mg/dl)

17.78–1.43

15.91–1.50**

16.19–0.72*

15.48–0.77**

CRTN (mg/dl)

0.72–0.06

0.62–0.16

0.68–0.04

0.60–0.00*

GLU (mg/dl)

139.44–26.43

165.22–8.61

171.78–15.34**

151.10–15.64

LDH (IU/l)

1901.11–514.8

1380.05–422.4*

1598.70–370.1

1444.18–387.7

T-CHO (mg/dl)

67.00–7.21

66.10–6.38

62.60–6.59

55.70–5.46**

T-BIL (mg/dl)

0.26–0.10

0.20–0.07

0.15–0.08**

0.19–0.01

TP (g/dl)

6.93–0.86

7.59–0.09

7.70–0.18**

7.88–0.28**

CPK (IU/l)

1233.25–380.6

695.75–165.2**

929.38–329.1

874.80–337.1

Female

 

 

 

 

AST (IU/l)

90.90–13.83

86.50–14.82

80.70–8.83

163.67–110.6*

ALT(IU/dl)

42.33–3.81

38.56–5.08

36.67–6.42

274.78–252.6*

ALP (mg/dl)

271.69–18.18

208.40–16.02**

179.11–15.31**

217.00–16.79**

BUN (mg/dl)

20.69–0.87

17.53–1.13**

18.27–1.03**

15.36–1.28**

CRTN (mg/dl)

0.73–0.05

0.69–0.06

0.64–0.05**

0.61–0.03**

GLU (mg/dl)

125.00–9.78

129.89–15.37

122.10–16.85

144.00–12.33

LDH (IU/l)

910.70–322.6

793.10–363.4

655.20–255.4

896.30–417.1

T-CHO (mg/dl)

80.78–6.08

83.40–14.47

95.80–14.44

72.20–20.32

T-BIL (mg/dl)

0.32–0.08

0.27–0.05

0.24–0.05*

0.27–0.05

TP (g/dl)

6.83–0.18

6.93–0.41

7.10–0.81

8.04–0.35**

CPK (IU/l)

666.50–268.3

765.30–278.4

506.67–185.6

534.00–309.5

Values are presented as means–SDs.

* Indicates significant difference at P<0.05comparedwith the control group.

** Indicates significant difference at P<0.01 compared with the control group.

Table4.Relative organ weight of male and female rats after inhalation of 1,3 -DCP for 13weeks

 

Parameters

Dose(ppm)

 

 

0

5

20

80

No.of rats

10

10

10

10

Male

 

 

 

 

Liver

2.69–0.15

3.12–0.18**

3.54–0.21**

4.26–0.48**

Kidney:right

0.29–0.02

0.33–0.03

0.35–0.04**

0.41–0.04**

Testis:right

0.48–0.02

0.48–0.03

0.50–0.03

0.56–0.03**

Lung

0.43–0.06

0.39–0.04

0.41–0.03

0.47–0.05

Heart

0.29–0.02

0.31–0.01

0.32–0.03

0.34–0.03**

Thymus

0.09–0.01

0.10–0.01

0.11–0.01

0.10–0.02

Female

 

 

 

 

Liver

2.49–0.21

2.92–0.14**

3.37–0.16**

4.98–0.35**

Kidney:right

0.31–0.02

0.33–0.02

0.36–0.02**

0.42–0.02**

Ovary:right

0.03–0.006

0.03–0.006

0.03–0.006

0.03–0.006

Lung

0.51–0.12

0.50–0.07

0.57–0.07

0.59–0.07

Heart

0.34–0.02

0.33–0.02

0.36–0.03

0.39–0.03**

Thymus

0.14–0.02

0.13–0.01

0.14–0.01

0.14–0.02

Values are presented as means–SDs.

* Indicates significant difference at P<0.05comparedwith the control group.

** Indicates significant difference at P<0.01 compared with the control group.

Parameter

Male

 

 

 

 

Female

 

 

Dose(ppm)

 

 

 

 

Dose(ppm)

 

0

5

20

80

 

0

5

20

80

No.of rats

10

10

10

10

 

10

10

10

10

Liver

 

 

 

 

 

 

 

 

 

Multifocal necrosis

0

0

1

10*

 

0

0

0

10*

Inflammation

0

0

1

4

 

0

0

2

7*

Pigmentation

0

0

0

 

 

 

 

 

10*

Biliary hyperplasia

0

0

0

8*

 

0

0

0

1

Foci of cellular alteration

0

0

0

1

 

0

0

0

6

Kidney

 

 

 

 

 

 

 

 

 

Chronic nephropathy

0

0

4

10*

 

0

0

0

4

Protein cast

0

0

0

0

 

0

0

0

2

Heart

 

 

 

 

 

 

 

 

 

Cardiomyopathy

2

1

2

1

 

1

0

0

0

Pituitary gland

 

 

 

 

 

 

 

 

 

Pseudo cyst

0

1

0

0

 

0

0

0

0

Submandibular lymph node

 

 

 

 

 

 

 

 

 

 

 Focal hyperplasia                             

1

0

2

1

 

0

1

0

1

Pancreas

 

 

 

 

 

 

 

 

 

Vacuolation

0

0

1

0

 

1

1

0

0

Ovary

 

 

 

 

 

 

 

 

 

Angiectasis

1

1

0

0

 

Lutealcyst

1

1

0

0

 

Clitorialgland

 

 

 

 

 

 

 

 

 

Inflammation

0

1

3

1

 

* Indicates significant difference at P<0.05 compared with the control group.

Applicant's summary and conclusion

Conclusions:
Tthe 13-week repeated inhalation exposure of rats to 1,3-DCP resulted in decreases in HB
and MCV and an increase in the relative liver weight at >5 ppm; decreases in the HCT and PLTs and increases
in the relative kidney weight and histopathological alterations including hepatic necrosis, hepatic
inflammation and chronic nephropathy at .20 ppm; as well as decreases in the body weight gain, MCH
and WBC and increases in the urine protein, leukocyte, AST, ALT, histopathological alterations such as multifocal
necrosis, inflammation, pigmentation, biliary hyperplasia and foci of cellular alteration of the liver, and
chronic nephropathy and protein cast of the kidney at 80 ppm. The target organs were determined to be the
liver, kidney and blood cells in rats. The no-observed-adverse-effect level was considered to be <5
ppm/6 h/day, and the low-observed-adverse-effect level was believed to be 5 ppm/6 h/day in rats. The
present results are expected to provide some information on the general toxic effects and target organ toxicity
of 1,3-DCP via repeated inhalation exposure, which can aid in the process of risk assessment.
Executive summary:

The subchronic toxicity of 1,3-dichloro-2-propanol (1,3-DCP) was investigated in Fischer 344

rats after 13 weeks of repeated, whole-body inhalation exposure. Groups of 10 rats of each

sex were exposed to 1,3-DCP vapor by whole-body inhalation exposure at concentrations of

0, 5, 20 or 80 ppm for 6 h/day, 5 days/week for 13 weeks. All of the rats were sacrificed at

the end of the treatment period. During the test period, clinical signs, mortality, body weights,

food consumption, ophthalmoscopy, urinalysis, hematology, serum biochemistry, gross findings,

organ weights and histopathology were assessed. At 80 ppm, a decrease in the body weight

gain, an increase in the urine protein and leukocyte counts and an increase in the liver and kidney

weights were observed in both genders. Hematological and serum biochemical investigations

revealed decreases in hemoglobin (HB), hematocrit (HCT), mean corpuscular volume

(MCV) and mean corpuscular HB, as well as increases in the platelet (PLT) count, serum

aspartate aminotransferase and alanine aminotransferase. The number of white blood cells

was significantly lower in males than in controls, but this was not the case in females. Histopathological

alterations included an increase in the incidence of multifocal necrosis, inflammation,

pigmentation, biliary hyperplasia and the foci of cellular alteration of the liver and chronic nephropathy

and protein cast of the kidney. At 20 ppm, decreases in HCT and MCV and increases

in the liver and kidney weights were observed in both genders. A decrease in the HB of females

and an increase in the PLT count of females were also observed. Histopathological alterations

included slight increases in the incidences of hepatic necrosis, hepatic inflammation and

chronic nephropathy. At 5 ppm, we found decreases in the MCV of males and the HB of females,

as well as an increase in the liver weight of both genders. In the present experimental

conditions, the target organs were determined to be the liver, kidney and blood cells in rats.

The no-observed-adverse-effect level was considered to be <5 ppm/6 h/day and the low-

observed-adverse-effect level was believed to be 5 ppm/6 h/day in rats.