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Diss Factsheets

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
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: well documented and scientifically acceptable

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1974
Reference Type:
secondary source
Title:
Unnamed
Year:
1974

Materials and methods

Principles of method if other than guideline:
Four dogs/group were given daily oral doses of 5, 20, or 80 mg/kg bw of o-chlorotoluene (OCT). The control group was given 5% aqueous acacia solution, 0.5 ml/kg. Daily doses were administered for 3 month by capsule. A general observation, body weight changes, hematology, clinical biochemistry, and urinalysis were performed. Organ weights, bone marrrow and hepatic microsomal activity was examined and pathological findings were evaluated.
GLP compliance:
no

Test material

1
Chemical structure
Reference substance name:
2-chlorotoluene
EC Number:
202-424-3
EC Name:
2-chlorotoluene
Cas Number:
95-49-8
Molecular formula:
C7H7Cl
IUPAC Name:
1-chloro-2-methylbenzene

Test animals

Species:
dog
Strain:
Beagle
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Purebred yound adults:
- Age at study initiation: 10 - 14 months
- Weight at study initiation: 7.1 - 12.7 kg
- Fasting period before study: no, capsules were administered in the morning shortly aftzzer dogs were fed
- Diet: Wayne dog food 300 g/d (Allied Mills Inc., CHicago, Illinois, USA)
- Water: ad libitum

Administration / exposure

Route of administration:
oral: capsule
Vehicle:
other: 5 % aqueous accacia solution
Details on oral exposure:
Due to the very high volatility of the test substance difficulty was experienced in measuring the material gravimetrically. This problem was avoided by using emulsions which were freshly prepared each day with a 5% aqueous acacia solution. Based on the specific gravity of thew test substance and the oncentration of the solvent desired in a stock emulsion, the neceasary amounts of OCT and the acacia solution were measured volumetrically and placed in a Sorvall container, and then blended with a mixer a for 30 aeconds. Dilutions of the stock emulsion were prepared in a similer mannor, i.e., by blending a sufficient quantity of the stock emulsion with the needed amount of acacia olution for 30 seconds.
The concentration of the test substance was adjuated so that dogs at each treatment level reveived 0.5 ml/kg. The daily dose for each deg (approximately 5 ml) was conveniently adminiatered in 2 gelatin capsules. The dose was given in the morning, shortly after the dole were fad.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
3 months
Frequency of treatment:
daily
Doses / concentrationsopen allclose all
Dose / conc.:
80 mg/kg bw/day (nominal)
Dose / conc.:
20 mg/kg bw/day (nominal)
Dose / conc.:
5 mg/kg bw/day (nominal)
Dose / conc.:
0 mg/kg bw/day (nominal)
No. of animals per sex per dose:
4 males and 4 females/dose
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: no
Positive control:
No

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: weekly

OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: before study initiation, at 1, 2, 4 weeks and monthly thereafter, and before sacrifice
- Dose groups that were examined: all

HAEMATOLOGY: Yes
- Time schedule for collection of blood: before study initiation, at 1, 2, 4 weeks and monthly thereafter, and before sacrifice
- Anaesthetic used for blood collection: Not specified
- Animals fasted: Not specified
- How many animals: all

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: before study initiation, at 1, 2, 4 weeks and monthly thereafter, and before sacrifice
- Animals fasted: Not specified
- How many animals: all

URINALYSIS: Yes
- Time schedule for collection of urine: before study initiation, at 1, 2, 4 weeks and monthly thereafter, and before sacrifice
- Metabolism cages used for collection of urine: Not specified
- Animals fasted: Not specified

NEUROBEHAVIOURAL EXAMINATION: No

IMMUNOLOGY: No
Sacrifice and pathology:
Organe weights of , liver, kidney, heart, spleen, thyroid, adrenal, and testen or ovaries were recorded.
Sections of these tissues and of colon, duodenum, ileum, jejunun, Jungs, lymph node, mammary, pancrean, parathyroid, prostate, salivary gland, skin, stomach, striated muscle, thymus, urinary bladder, and uterus were submitted for histopathological examination.
Other examinations:
Bone marrow, obtained from the costa, was counted to determine myeloid/erythroid
cell ratio. A section of this tissue was submitted for microscopic examination.

A liver sample from each dog was used to determine microsomal processing enzyme activity.
Statistics:
Statistical ex aminations were made of the following data:
hematocrit, hemoglobin, red blood cell count, white blood cell count, prothrombin time, platelets, mean corpuscular volume, calcium, serum glucose, blood urea nitrogen, total bilirubin, alkaline phosphatase, and serum glutamic oxalacetic tranoaminase.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
Excepting for one holiday when no treatment was given, the male dogs were treated for 97 and the fermales for 96 consecutive days, thus the dogs received a total of 96 and 95 doses respectively.

A female, in the high exposure group vomited 3 times between test days 10 and 17, and during the 3rd treatment week; red blood was observed in this animal's feces. During test week 2 the dog lost approximately 1 kg body weight, but regained this weight during test weeks 3 and 4. One male in the high exposure group lost approximately 1 kg during test weeks 1 and 2, but recovered
this weight during week 3.
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:
no effects observed
Haematological findings:
effects observed, non-treatment-related
Description (incidence and severity):
A statistically significant increase in platelets in female was noted in the highest dose in the second, third, and fourth bleedings. In the final bleeding the platelets
returned to their pretreatment level.
Clinical biochemistry findings:
no effects observed
Endocrine findings:
not examined
Urinalysis findings:
effects observed, non-treatment-related
Behaviour (functional findings):
no effects observed
Immunological findings:
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Neuropathological findings:
not examined
Histopathological findings: non-neoplastic:
effects observed, non-treatment-related
Description (incidence and severity):
The gross examination of the organs and the histological study of the slides of the dogs showed no pathological alteration induced by the drug.
The parasitosis, branchial rest, pericholangitis, nephrocalcinosis, and dystrophic calcification found are common findings in the strain of dog used.
Histopathological findings: neoplastic:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
Normal variations without treatment related changes were observed in the ratios of the myelocytic vs. erythrocytic cell series.

Effect levels

Dose descriptor:
NOEL
Effect level:
20 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
clinical signs
Remarks on result:
other: Dogs which received daily oral doses of 5, 20, or 80 mg o-chlorotoluene were similar in all respects to the controls. The save level was 20 mg/kg.

Target system / organ toxicity

Critical effects observed:
no

Any other information on results incl. tables

All dose groups: no effects on behaviour, survival, eyes, haematology, clinical chemistry, bone marrow; no findings in the histopathological examinations attributable to treatment.
80 mg/kg bw/d: 1/4 females vomited 3 times between test day 10 and 17 and during the 3rd treatment week, red blood was observed in this animal feces (no further information).


For details on body weight, clinical and haematological values see illustration below.

Applicant's summary and conclusion

Conclusions:
Under the conditions of this oral sub-chronic toxicity study in male and femals Beagle dogs, a NOEL of 20 mg/kg bw/d based on clinical findings in the highest dose group was identified. This was the only signficant effect observed in this study.
Executive summary:

Four dogs per dose group were given daily oral doses of 5, 20, or 80 mg/kg bw of the test substance. The control group was given 5% aqueous acacia solution, 0.5 ml/kg bw. Daily doses were administered for 3 month by capsule. A general observation was performed, body weight changes recorded, hematology analysis, clinical biochemistry, urinalysis and a histopathological evaluation of several organs were performed. Organ weights, bone marrrow and hepatic microsomal activity was examined and pathological findings were evaluated.


NOEL = 20 mg/kg bw/d based on clinical signs at 80 mg/kg bw/d in one animal.