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Repeated dose toxicity: inhalation

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Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
26/08/1985 - 13/05/1986
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: - scientifically sound study - generally guideline compliant - missing urinalysis, clinical chemistry and haematology are covered by respective experiments in DOW HET-K-002524-004 with the same animal strains

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1986
Report Date:
1986

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
Deviations:
yes
Remarks:
: no haematology examinations, only limited biochemical and urinalysis examinations
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): 1,2,3-Trichloropropane
- Substance type: chlorinated organic solvent
- Physical state: liquid, colorlessprior to initiang the exposures, Bartels, M. J. (1985). Analysis o f 1,2,3-Trichloroporpane (Lot #TB-83120210), analytical data sheet HET K-002524-006-1, The Dow
Chemical Company, Midland, M I 48674.
- Purity test date: 1985, see above
- Lot/batch No.: Lot BTB-831202-10)
- Stability under test conditions: stable
- Storage condition of test material: not reported

Test animals

Species:
other: rat and mouse
Strain:
other: Fischer 344 rats and B6C3F1 mice
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc. (Kingston, NY and Portage, MI, U.S.A. )
- Age at study initiation: 6-8 wk
- Weight at study initiation: rats: 211.1 g (male), 140.1 g (female); mice: 24.6 g (male), 23.3 g (female)
- Fasting period before study: not reported
- Housing: housed singly in stainless steel cages with wire bottoms
- Diet (e.g. ad libitum): Purina Certified Rodent Chow (Ralston Purina Co., St . Louis, MO), ad libitum
- Water (e.g. ad libitum): tap water, analyzed periodically by the City o f Midland, MI
- Acclimation period: 7 d


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22.2
- Humidity (%): 50
- Air changes (per hr): not reported
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: not precisely reported

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure:
whole body
Vehicle:
other: unchanged (no vehicle)
Remarks on MMAD:
MMAD / GSD: not applicable
Details on inhalation exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 4.1 m³ stainless steel and glass chambers
- Method of holding animals in test chamber: Exposures were conducted i n the
same cages used for housing the animals.
- Source and rate of air: 800 L/min;
- Method of conditioning air: air supplied to the chambers controlled by a system designed to maintain temperature at approximately 21°C and relative humidity at approximately 50%; temperature and relative humidity recorded at the end of each exposure period.
- System of generating vapour:
metering the liquid test material at controlled rates into vaporization tubes as described by Miller et. al. (Miller , R. R., Letts, R. L.. Potts, W. J. and McKenna, M. J. (1980) Improved methodology for generating controlled test atmospheres. Am. Ind. Hyg. Assoc. J. 41:844-846.).
Vapors swept into the exposurechamber inlet ducts with compressed air and mixed and diluted with incoming air by turbulence.
compressed air supply to the vaporization tubes preheated (100°C) to facilitate complete vaporization of the liquid test material.
- Temperature, humidity, pressure in air chamber: 21 °C, 50 %, pressure not noted
- Air flow rate: 800 l/min
- Air change rate: 11.1

TEST ATMOSPHERE
- Brief description of analytical method used: GC-FID
- Samples taken from breathing zone: yes


Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The actual concentration in each chamber was measured approximately 1-2 times/hr by gas chromatography (peak height) using a Varian Model 1400 gas chromatograph with flame ionization detector using a 6'x1/8" stainless-steel column (142°C) packed with 8% Triton X-305 on 100/120 CW-HP.
The analytical equipment was standardized daily by vaporizing measured volumes o f the test substance i n Saran bags filled with a measured volume (100 L) of air. The concentration o f TCP in each chamber was then determined by interpolation from a standard curve.
Duration of treatment / exposure:
4 h/d,
Frequency of treatment:
5 d in the first week, 4d in the second week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 6, 18 or 60 mg/m³ (0, 1, 3 or 10 ppm)
Basis:
nominal conc.
No. of animals per sex per dose:
5
Control animals:
other: yes, but not reported whether sham-exposed or not treated
Details on study design:
- Dose selection rationale: based on study Miller (1986 A) where 0.08 mg/L air (13 ppm) was a LOAEL
- Rationale for animal assignment (if not random): random
Positive control:
no

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: complete check: after each exposure period; check for mortality and water and food supply only: daily on weekends
- complete check: any changes in appearance were noted and recorded



BODY WEIGHT: Yes
- Time schedule for examinations: prior to the 1st , 3rd, 5th and 9th exposures.


FOOD CONSUMPTION: No


FOOD EFFICIENCY: No


WATER CONSUMPTION: No


OPHTHALMOSCOPIC EXAMINATION: No


HAEMATOLOGY: No


CLINICAL CHEMISTRY: No, as no significant findings were reported for higher concentrations in a preceding study with the same animal strains and the same study design


URINALYSIS: Yes, in rats only
- Time schedule for collection of urine: at the morning prior to the 9th exposure
- Metabolism cages used for collection of urine: No data
- Animals fasted: No data
- Parameters checked: bilirubin , glucose, ketones, occult blood, pH, protein, urobilinogen using chemstrip 7 (Bio-Dynamics/Div. o f BMC, Indianapolis, IN, U.S.A.) and specific gravity (American Optical Co., Keene, NH)


NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes: rats were fasted overnight prior to the scheduled sacrifice; mice were not fasted prior to the sacrifice
Weights recorded of brain, heart, liver , kidneys, thymus (rats)
HISTOPATHOLOGY: Yes: tested tissues:
liver
pancreas
peripheral nerve
adrenals
small intestine
mesenteric lymph node
epididymides
prostate
oviducts
urinary bladder
salivary glands
mediastinal lymph node
thyroid gland
larynx
eyes
lacrimal/harderian glands
oral tissues
heart
brain
spinal cord
kidneys
cecum
mesenteric tissues
seminal vesicles
uterus
cervix
lungs
thymus
aorta
parathyroid glands
skin
tongue
auditory sebac gland
gall bladder (mice only)
spleen
pituitary
bone marrow
stomach
large intestine
testes
coaguiating glands
ovaries
vagina
skeletal muscle
mediastinal tissues
esophagus
trachea
mammary gland
nasal tissues
bone
Statistics:
Body weights, absolute and relative organ weights and urinary specific gravity were evaluated by Bartlett's test for equality of variances. Based on the outcome of Bartlett's test, exploratory data analysis was performed by a parametric or non-parametric analysis of variance (ANOVA), followed respectively by Dunnett's test or Wilcoxon Rank-Sum test with a Bonferroni correction for multiple comparisons.
Statistical outliers were identified by a sequential test and excluded at the discretion of the study director.
The nominal alpha levels to be used and test references were as follows:
Bartlett's test (Winer, 1971) a = 0.01
Parametric ANOVA (Steel and Torrie, 1960) u = 0.10
Non-Parametri c ANOVA (Holl ander and
Wolfe, 1973) a = 0.10
Dunnett's test (Winer, 1971) a = 0.05, two-sided
Wilcoxon Rank-Sum test (Hollander and
Wolfe, 1973) a = 0.05, two-sided
Bonferroni correction (Miller, 1966)
Outlier test (Grubbs, 1969) a = 0.02, two-sided
Since multiple, interrelated parameters were statistically compared in the same group of animals, the frequency of false positive errors may have been much greater than the nominal alpha level. Thus, in addition to statistical analyses, the final toxicologic interpretation of the data includes factors such as dose-response relationships and whether or not the findings appear to be plausible and consistent in the light of other biologic findings.

Results and discussion

Results of examinations

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
not examined
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
not examined
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
no effects observed
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
no significant effect in any dose group
not examined

BODY WEIGHT AND WEIGHT GAIN
no significant effect in any dose group

FOOD CONSUMPTION
not examined

FOOD EFFICIENCY
not examined

WATER CONSUMPTION
not examined

OPHTHALMOSCOPIC EXAMINATION
not examined

HAEMATOLOGY
not examined

CLINICAL CHEMISTRY
not examined

URINALYSIS
no significant effect in any dose group

NEUROBEHAVIOUR
not examined

ORGAN WEIGHTS
no significant effect in any dose group

GROSS PATHOLOGY
no significant effect in any dose group

HISTOPATHOLOGY: NON-NEOPLASTIC
rats: - very slight exposure related degenerative changes and inflammation in the olfactory epithelium of male and female rats in the 60 mg/m³ (10 ppm) group, and the thickness o f the olfactory epithelium was very slightly decreased in male and female rats in the 18 mg/m³ (3 ppm) group
- no effects on nasal tissues in the 6 mg/m³ (1 ppm) group
mice: - inflammatory reaction in the olfactory epithelial region of 60 mg/m³ (10 ppm) exposed mice, confined to the mucosa and associated with the focal change in thickness
- no effects on nasal tissues in the 16 mg/m³ (3 ppm) group

HISTOPATHOLOGY: NEOPLASTIC (if applicable)
no significant effect in any dose group

Effect levels

open allclose all
Dose descriptor:
NOAEC
Effect level:
6 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
other: rat: based on the absence of any adverse effects, especially absence of effects on nasal tissues
Dose descriptor:
NOAEC
Effect level:
18 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
other: mouse: based on the absence of any adverse effects, especially absence of effects on nasal tissues
Dose descriptor:
LOAEC
Effect level:
18 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
other: rat: thickness o f the olfactory epithelium was very slightly decreased in both sexes, degenerative changes and inflammation in this tissue at higher concentrations
Dose descriptor:
LOAEC
Effect level:
60 mg/m³ air (nominal)
Sex:
male/female
Basis for effect level:
other: see 'Remark'

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

- table 1: exposure concentrations and chamber conditions

Target Conc. (ppm)

Analytical concentration

Nominal Concentration

Temp. (°C) (c)

 

Analytical concentration (a)

Coefficient of variation (b)

Rangeof

Mean ± SD

Rangeof

Max.

Min.

Rel. Hum. (%) (c)

0

 

 

-

 

 

21.1

19.6

64.7

1

1.0±0.0

0%

0

0.9±0.1

0.8- 1.0

20.2

21.4

66.3

3

2.9±0.2

7%

2.5-3.2

2.6±0.2

2.3- 2.7

20.0

21.0

68.6

10

9.7±0..3 (d)

3%

9.2-10.0

12.1±0.9

11.0-13.2

20.6

21.6

69.3

(a) Numbers are X ± SD daily time-weighted average (TWA) values for 9 exposures.

(b) Coefficient of variation is the SD of the daily TWA measurements divided by X (X100).

(c) X ± SD of daily measurements for 9 exposure days.

(d) On day 8, the 10 ppm exposures were conducted for. only 4.5 hours instead of 6 hours as a result of an operational error.

- None

Applicant's summary and conclusion

Conclusions:
1,2,3-Trichloropropane was tested in a 14 d repeated dose inhalation study (exposure: 5d/ wk, 4 h/d) following generally TG OECD 412. Clinical chemistry and haemotological examinations were not conducted no effects were found even at higher concentrations in an accompanying study (Miller 1986 A). Histopathological changes in the nasal tissues of rats and mice were found leading to NOAECs of 6 mg/m³ (1 ppm) for the rat and 18 mg/m³ (3 ppm ) for the mouse.
Executive summary:

The present study DOW HET-K-002524-006 / (F344 rat and B6C3F1 mouse, 14d repeated dose inhalation toxicity lower doses) was a follow up study to DOW HET-K-002524-004 / (F344 rat and B6C3F1 mouse, 14d repeated dose inhalation toxicity, higher doses) and conducted to asses the NOAEC for 1,2,3 -Trichloropropane for rats and mice after repeated inhalation exposure (4 h/d, 9 exposures in 14 d, concentrations: 0, 6, 18 or 60 mg/m³ (0, 1, 3 or 10 ppm)). NOAECs of 6 mg/m³ (1 ppm) for the rat and 18 mg/m³ (3 ppm ) for the mouse were found, the corresponding LOAECs are 18 mg/m³ (3 ppm) for the rat and 60 mg/m³ (10 ppm) for the mouse.

Male and female Fischer 344 rats and B6C3F1 mice were analyzed daily for clinical signs, expect on weekends. Body weights were measured prior to the 1st , 3rd, 5th and 9th exposures. In rats urinalysis was conducted at the morning prior to the 9th exposure. At the end of the study the animals were sacrificed and subjected to gross necroscopy and histological analysis of various tissues.

Body weights, organ weights and urinalyses were unaffected by the TCP exposures. Histopathologic examinations of the nasal tissues revealed very slight exposure-related changes in the olfactory epithelium of rats in the 3 ppm and 10 ppm groups, as well as in mice in the 10 ppm group. Similar effects on the olfactory epithelium had previously been found in rats and mice exposed to 13 ppm TCP vapors in a previous study; more pronounced effects on nasal tissues occurred in animals exposed t o 40 or 132 ppm (DOW HET-K-002524-004 / (F344 rat and B6C3F1 mouse, 14d repeated dose inhalation toxicity, higher doses)).