4-chlorotoluene

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

supporting study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: well documented and scientifically acceptable

Data source

Reference

Reference 1

Reference Type:

publication

Title:

Subacute and subchronic oral toxicity of p-chlorotoluene in rats

Author:

Terrill JB, Robinson M, Wolfe GW, Billups LH

Year:

1990

Bibliographic source:

J Am Coll Toxicol 9, 487-495, also in EPA-PB91-233379.

Reference 2

Reference Type:

publication

Title:

Subacute and subchronic oral toxicity of p-chlorotoluene in the rat

Author:

Terrill JB, Robinson M, Wolfe GW, Billups LH

Year:

1990

Bibliographic source:

Toxicologist 10(1), 61 (abstr.)

Materials and methods

Principles of method if other than guideline:

p-Chlorotoluene was administered by gavage for 14 and 90 days to Sprague-Dawley-derived rats at dose levels of 200, 600 and 1800 mg/kg/day and 50, 200 and 800 mg/kg/day, respectively.

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

4-chlorotoluene

EC Number:

203-397-0

EC Name:

4-chlorotoluene

Cas Number:

106-43-4

Molecular formula:

C7H7Cl

IUPAC Name:

4-chlorotoluene

Details on test material:

the purity was determined to be greater than 98 %; 1-Chloro(4-chloromethyl)benzene at 0.5 % was identified as the only impurity

Test animals

Species:

rat

Strain:

Sprague-Dawley

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

90 d

Frequency of treatment:

daily, 7 d/w

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 50, 200 or 800 mg/kg bw/d in corn oil
Basis:

No. of animals per sex per dose:

10 males and 10 females per group

Control animals:

yes, concurrent vehicle

Details on study design:

Post-exposure period: no

Results and discussion

Effect levels

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day (nominal)

Sex:

male/female

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

RS-Freetext:
800 mg/kg bw/d:

-----ANIMAL OBSERVATIONS
mortality:  death of 4/10 males and 2/10 females 
signs of intoxication: languid behabior, prostration,     sensitivity to  touch, tremors, epistaxis, wheezing,     dyspnea and/or polypnea, death
food consumption comparable to controls
body weight:
males: initiation to week 13: statistically significant     decreased  body weight gain, shown in a figure, mean     terminal body weight was  not significantly decreased:     489 g versus 571 g of control 
females: body weight gain: not significnant different to     control;  mean terminal body weight was significantly     decreased: 282 g vers.  321 g of controls 
-----TERMINAL EVALUATIONS 
ophthalmoscopic evaluation: no treatment-related effects      observed
--Hematology:
     values comparable to control values (data not shown)
--Clinical chemistry:
     (significantly changed values vers. controls)
males: 
BUN (33 vers. 11 mg/dl), Creatinine (1.0 vers. 0.5 mg/dl), 
ALP (136 vers. 87 IU/L), Bilirubin (0.23 vers. 0.16mg/dl)
Sodium (139 vers. 143 mEq/L)
females:
female values comparable to respective control values 
--Urinalysis:
pH-values: 
     significantly decreased in males (6.42 vers. 7.50 in      controls)  and in females (6.50 vers. 7.25 in controls)
all other parameteres were comparable to the respective      control  parameters (data not shown)
-----NECROPSY:
--Organ weights:
absolute organ weights [significant changes in organ-to-body weight  ratios(%bw)]  versus controls
-males: 
brain: 2.18g [0.456 %bw] vers. 2.18g [0.386 %bw],
liver: 15.11g [3.134 %bw] vers. 14.97g [2.616 %bw]
kidneys: 4.12g [0.878 %bw]  vers. 3.57g [0.628 %bw]
adrenal: 0.076g(sign.)[0.0164 %bw] vers. 0.059g[0.0104          %bw]
testes: no relevant changes: 
control-high dose (rel weights): 5.26g (0.931 %bw) - 4.96g (1.016 %bw)
-females: 
brain: 2.09g [0.742 %bw] vers. 2.05g [0.643 %bw]
liver: 9.82g [3.481 %bw] vers. 8.83g [2.748 %bw]
lungs: 1.24g(sign.)[0.439 %bw(not sign.)] vers.                    1.41g  [0.441 %bw] relative weights were unaffected
kidneys: 2.35g [0.835 %bw] vers. 2.22g [0.694 %bw]
heart: 1.05g [0.370 %bw] vers. 1.08g [0.377 %bw]
ovaries: no relevant changes: 
control-high dose (rel weights): 0.163g (0.0512 %bw) -  0.0547g (0.0745  %bw)
----gross- and histopathology:
--kidneys: 
males: 
depressed areas, pale areas, mottled appearance, dilated renal pelvis,  and/or granular/pitted/rough texture, 
males and females: 
chronic progressive nephropathy (degeneration and regeneration of the  tubular epithelial cells, interstititial fibrosis, mononuclear cell  infiltrates) in 10/10 treated and in 2/10 control males and in 9/10  treated females but not in control females
--liver: 
males and females: 
centrilobular hypertrophy of hepatocytes
--adrenal gland: 
males and females: 
hyperplasia of the zona fasciculata
--stomach: 
males and females: 
dark areas in the glandular portion, minimal mucosal erosion in the  glandular portion in 2/10 males and 3/10 females
--testes and ovaries: 
no pathological findings.

200 mg/kg bw/d:
-----ANIMAL OBSERVATIONS
no mortality, no signs of intoxication were reported
food consumption comparable to controls
body weight development comarable to respective controls, including  terminal body weights
-----TERMINAL EVALUATIONS 
ophthalmoscopic evaluation: no treatment-related effects      observed
--Hematology:
     values comparable to control values (data not shown)
--Clinical chemistry:
     values comparable to control values
--Urinalysis
pH-values: 
     significantly decreased in males (6.80 vers. 7.50 in      controls)  and in females (6.35 vers. 7.25 in controls)
all other parameteres were comparable to the respective      control  parameters (data not shown)
-----NECROPSY:
--Organ weights:
     values comparable to respective control values
--gross- and histopathology:
stomach: 
males and females: 
dark areas in the glandular portion, 
female only: 1/10 with minimal mucosal erosion in the glandular portion 

50 mg/kg bw/d:
-----ANIMAL OBSERVATIONS
no mortality, no signs of intoxication were reported
food consumption comparable to controls
body weight development comarable to respective controls, including  terminal body weights
-----TERMINAL EVALUATIONS 
ophthalmoscopic evaluation: no treatment-related effects      observed
--Hematology:
     values comparable to control values (data not shown)
--Clinical chemistry:
     values comparable to control values
--Urinalysis
pH-values: 
     increased in males (7.75 vers. 7.50 in controls) and      decreased  in females (6.85 vers. 7.25 in controls)
all other parameteres were comparable to the respective      control  parameters (data not shown)
-----NECROPSY:
--Organ weights:
female: 
lungs abs weight significantly decreased when compared to the respective  control:1.28g vers. 1.41g; relative weights were unaffected      
all other values of organ weights were comparable to respective control  values
--gross- and histopathology:
stomach: 
males and females: 
dark areas in the glandular portion, 
female only: 1/10 with minimal mucosal erosion in the glandular portion

Applicant's summary and conclusion

Executive summary:

p-chlorotoluene was administered by gavage for 90 days to Sprague-Dawley-derived rats at dose levels of 50, 200 and 800 mg/kg/day. In the 90-day study, 4 of 10 males and 2 of 10 females in the high-dose group died due to treatment; survivors exhibited an adverse effect upon body weight, languid behavior, prostration, tremors, sensitive to touch, epistaxis and respiratory distress. In

the 90-day study, increases in alkaline phospthaase and creatinine (males on1y) , and increases in adrenal (absolute and relative,

females), kidney (relative, both sexes) and liver (relative, both sexes) weights were noted.

Histopathology findings of centrilobular hepatocellular hypertrophy, adrenal cortical hyperplasia and exacerbation of chronic progressive nephropathy confirmed the clinical laboratory and organ weight results. Animals receiving 50 or 200 mg/kg/day (90 days) did not exhibit treatment-related findings.