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Toxicological information

Repeated dose toxicity: oral

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Administrative data

Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
March - June 1979
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: comparable to guideline study with acceptable restrictions
Cross-reference
Reason / purpose:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1986
Reference Type:
secondary source
Title:
1-chlorobutane, CAS No. 109-69-3
Author:
OECD SIDS
Year:
1997
Bibliographic source:
SIDS Initial Assessment Report for SIAM 6

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 408 (Repeated Dose 90-Day Oral Toxicity in Rodents)
Deviations:
yes
Remarks:
only necropsy and histologic examination were performed, other observations (e.g. food consumption, haematology, clinical biology) are not regarded; administration five days per week
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): n-butyl chloride
- Storage condition of test material: in the dark at 0 °C

Test animals

Species:
rat
Strain:
other: F344/N
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Breeding Laboratories, Portage, USA
- Age at study initiation: 7 weeks
- Weight at study initiation: males: 23 g; females: 18-19 g
- Housing: five per cage in polycarbonate cages (Lab Products, Rochelle Park, NJ, USA); Bedding: Aspen bed hardwood chips (American Exelsior Co., Baltimore,MD, USA) or Chips hardwood chips (Agway Inc., Syracuse, NY, USA)
- Diet: ad libitum Wayne Lab Blox pellets (Allied Mill, Chicago, IL; USA)
- Water: ad libitum (Automatic watering system; Edstrom Industries, Waterford, WI, USA)
- Acclimation period: 18 days


ENVIRONMENTAL CONDITIONS
- Temperature: mean 21.8 °C
- Humidity: 5% - 74% (average 40%)
- Air changes (per hr): 10
- Photoperiod: 12 hrs dark / 12 hrs light ( fluorescent light)


IN-LIFE DATES: March - July 1979

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:
Preparation were hand agitated for 10 sec and sealed in serum vials. Dose mixtures were stored at 4 °C for a maximum of 10 days.

VEHICLE
- Amount of vehicle (if gavage): 5 mL/kg bw/d
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Periodic analyses for n-butyl chloride in corn oil were performed by the testing and analytical chemistry laboratories. Duplicate 1 mL samples were extracted with methanol containing 2 mg/mL of n-amyl alcohol as an internal standard. Samples were analyzed by GC-FID. Individually spiked portions of undosed corn oil (5 or 6 concentrations bracketing the specified concentration range of the referee sample) were used to obtain standard data. The samples were determined from the linear regression equation computed from the standard data (peak area analysis).
Analyzed mixtures were within +/- 10% of the target concentration.
Duration of treatment / exposure:
13 weeks (90d)
Frequency of treatment:
5 d/w
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 30, 60, 120, 250 and 500 mg/kg bw/d
Basis:
actual ingested
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
- Dose selection rationale: Doses selected for the 13-week studies were based on weight gain depression and clinical signs observed in the 14-days studies.


Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: two times per day

CLINICAL SIGNS
- Time schedule: recorded once per week

BODY WEIGHT: Yes
- Time schedule for examinations: once per week

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: No
- Compound intake calculated as time-weighted averages from the consumption and body weight gain data: No

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

OPHTHALMOSCOPIC EXAMINATION: No

HAEMATOLOGY: No

CLINICAL CHEMISTRY: No

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No


Sacrifice and pathology:
GROSS PATHOLOGY: Yes

HISTOPATHOLOGY: Yes

The following tissues were examined: gross lesions and tissue masses, mandibular lymph node, mammary gland, skin, salivary gland, sternebrae, thyroid gland, small intestine, colon, liver, prostate/testes or ovaries/uterus, lungs and bronchi, heart, esophagus, stomach, brain, thymus, trachea, pancreas, spleen, kidneys, adrenal glands, urinary bladder, pituitary gland, spinal cord (if neurologic signs present) and eyes (if grossly abnormal).

Tissues were preserved in 10% neutral buffered formalin, embedded in paraffin, sectioned and stained with hematoxylin and eosin.
After completion of the pathology examination, the slides, individual animal data records and summary tables were sent to an independent quality assurance laboratory for evaluation.
Statistics:
Data recording:
Data were recorded in the Cacinogenesis Bioassay Data System (Linhart et al., 1974). The data elements include the recommendations by the International Union Against Cancer (Berenblum, 1969)

Survival analyses:
The probability of survival was estimated by the product-limit procedure of Kaplan and Meier (1985) and is presented in the form of graphs. Statistical analyses for a possible dose-related effect on survival used the method of Cox (1972) for testing two groups for equality and Tarone's (1975) life table test for a dose-related trend. All reported P values for the survival analysis are two-sided.

Results and discussion

Results of examinations

Details on results:
CLINICAL SIGNS AND MORTALITY
6/10 males that received 500 mg/kg bw/d n-butyl chloride died before the end of the study, three of these because of gavage accidents.
Hyperactivity and convulsion on one or more occasions in male and female animals of the 250 and 500 mg/kg bw/d groups (250 mg/kg bw/d: 5/10 males and 2/10 females; 500 mg/kg bw/d: 9/10 males and 8/10 females). No animals of the lower dose group were hyperactive or convulsed.

BODY WEIGHT AND WEIGHT GAIN
The final mean body weights of males of the 250 and 500 mg/kg bw/d dose group were 11% or 20% lower than those of the vehicle control group. Females exposed to 250 and 500 mg/kg bw/d were 6% or 10% lower than that of the controls.

GROSS PATHOLOGY
Mild to moderate compound-related extramedullary hematopoiesis in the spleen in 3/10 males were observed that received 500 mg/kg bw/d. In two rats the severity was mild and in a third animal moderate. This lesion was not examined in the verhicle control group.

HISTOPATHOLOGY:
no histopathologic changes





Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
120 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Dose descriptor:
LOAEL
Effect level:
250 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: clinical signs; mortality; body weight;

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Body weights of rats in the thirteen-week gavage studies of n-butyl chloride

Dose

(mg/kg bw/d)

Mean body weights (g)

Final weight relative to vehicle controls (%)

initiala

final

changeb

Males

0

131 +/- 2

299 +/- 4

+168 +/- 3

---

30

131 +/- 2

300 +/- 5

+169 +/- 5

100

60

130 +/- 2

290 +/- 4

+160 +/- 3

97

120

131 +/- 2

285 +/- 3

+154 +/- 4

95

250

131 +/- 2

265 +/- 4

+134 +/- 3

89

500

131 +/- 2

240 +/- 10

+113 +/- 9

80

Females

0

103 +/- 1

181 +/- 8

+78 +/- 6

---

30

102 +/- 1

177 +/- 3

+75 +/- 2

98

60

103 +/- 1

176 +/- 2

+73 +/- 1

97

120

103 +/- 2

174 +/- 1

+71 +/- 1

96

250

103 +/- 1

171 +/- 2

+68 +/- 2

94

500

103 +/- 1

163 +/- 2

+60 +/- 2

90

a: Initial means group body weights +/- standard error of the mean. Subsequent calculations are based on those animals surviving to the end of the study.

b: Mean body weight change of the survivors of the group +/- standard error of the mean. Final body weights were taken during week 12 of the study.

Applicant's summary and conclusion