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Toxicological information

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:
other information
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline Study

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1994
Reference Type:
publication
Title:
Unnamed
Year:
2006

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 412 (Subacute Inhalation Toxicity: 28-Day Study)
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
99.4% 2-Chloro-4-to1uidine (mind. 98%)
0.23% p-toluidine
0.01% 4-Chloro-3-toluidine
0.01% 2-Chloro-4-nitrotoluene
0.03% 6-Chloro-3-toluidine
0.09% 2,5-Dichloro-4-toluidine
0.13% 3,4-Dichloroaniline/2,6-Dichloro-4-toluidine
N.N. < 0.01% 4-Formylamino-2-chlorotoluene
0.05% unknown compounds (2 compounds)

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
inhalation
Type of inhalation exposure:
nose/head only
Vehicle:
other: unchanged (no vehicle)
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
6h/d
Frequency of treatment:
5d/week, 4 weeks
Doses / concentrations
Remarks:
Doses / Concentrations:
19.1, 115.1 and 702.3 mg/m3 air
Basis:
analytical conc.
No. of animals per sex per dose:
10
Control animals:
yes

Results and discussion

Effect levels

Dose descriptor:
NOAEC
Effect level:
ca. 19.1 mg/m³ air
Sex:
male/female
Basis for effect level:
other: predominant atrophic changes of the olphactory epithelium and the minimal to borderline erythrocytotoxic effecs at 115.1 mg/m³.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

In the 19.1 and 115.1 mg/m³ dose group no clinical symptoms or mortality was observed. In the 702.3 mg/m³ dose group the rats showed unspecific neurocentral symptoms (diminuated motility, piloerection, unkempt fur, atony, inactivity), signs of transient hypoxia, bradypnea, breathing sounds, serous exsudate of nostris) All signs were more severe in female rats. Bodyweights were signifficantly diminuated in the 702.3 mg/m³ dose group. Organ weight-bodyweight-rlelation was was statistically changed in 115.1 mg/m³ female dose group and in both sexes of the 702.3 mg/m³ dose group. In the 115.1 mg/m³ air dose group in both sexes a diminuated weight of the thymus was observed. In the 702.3 mg/m³ group a toxicologically signifficant heightening of reticulocytes, bilirubin and methemoglobin and a diminuation of hematocrit, hemoglobin and erythrocytes. Hematological changes (hemosiderose of spleen, diminuation of hemoglobin, increase of reticulocytes) was found in female rats from 115.1 mg/m³ air.

Applicant's summary and conclusion

Executive summary:

In a subacute inhalation study in male and female Wistar rats performed according to OECD TG 412 the test substance was tested in followng doses: 19.1, 115.1 and 702.3 mg/m3 air, 6 hours per day, 5 days per week for 4 weeks.

The bodyweight was checked before the first exposition and than twice weekly. Appearance and behaviour were checked, also following symptoms were judged:

Appearance of mucosa (eye and respiratory tract); Snout skin, pinna, and general condition of fur, grooming activities; Breathing; Circulation; Somatomotoric and behavioral pattern; neurocentral and autonome symptoms; cageobservations (urination, diarea, polydipsie, general vigilance of animals); rectal temperature (weekly); Clinical-chemical blood parameter; Clinical-chemical analysis-organs and urine, eye observations, section (organ weight of brain, heart, testicles, liver, lung, spleen, adrenal gland, kidney, ovaries, thyroid, thymus), histological analysis (Aorta descendens, eyes incl. lid, epididymis, brain, skin, urinary bladder, heart, testicles, pituitary gland, intestin, femur, bonemarrow, head, larynx, liver, lung, lymph node, mamma, spleen, muscle [M.quadriceps femoralis], paratyroid, adrenal gland, nervus ischiadicus, kidney with pelvis, esophagus, ovaries, pancreas, prostate, spinal cord, seminal vesicle, salivary gland, sternum, trachea, lacrimal gland, thyroid, thymus, uterus, vagina, tongue.

Rats exposed for 4 weeks to 702.3 mg/m³ displayed characteristic signs of toxicity that included cyanosis, respiratory distress, and signifficantly decreased body weights. Rectal temperatures were significantly decreased at 115.1 mg/m³ and above. dark and enlarged spleens occured at 702.3 mg/m³. At this concentration, prominent treatment related effects included methemoglobiemia, reticulocytosis, red blood cells with Heinz bodies, decreased hemoglobin, hematocrit, and red blood cell counts. Borderline evidence of erythrocytotoxicity was noticed at 115.1 mg/m³ (based on a minimal increase in Heinz bodies). Spleen and liver weights were signifficantly increased at 702.3 mg/m³, whereas the thymus weight was decreased at 115.1 mg/m³ and above. Microscopic changes were found in the spleen (hemosiderosis) at 702.3 mg/m³. An atrophy of the olfactory epithelium in the nasal cavities occurred at 115.1 mg/m³ and above. Clinical pathology revealed changes pathognostic of hepatic effects, although microscopic examinations did not reveal any specific changes. The NOAEC was 19.1 mg/m³ and is based on the predominant atrophic changes of the olphactory epithelium and the minimal to borderline erythrocytotoxic effects at 115.1 mg/m³.