Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
supporting study
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
limited documented study report (e.g. no individual data availabe for organ weights), with methodological deficiencies (e.g. particle size distribution: only <2% of particle-size range within the recommended range of 1.5 to 3.0 µg and whole body exposure); thus the exposure of all relevant regions of the respiratory tract is questionable.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1979
Reference Type:
publication
Title:
Monsanto Chemical Co. (1976) unpublished study Project No. BT-76-142. Cited from BUA Report 208, 1996
Author:
BUA Report
Year:
1996

Materials and methods

Principles of method if other than guideline:
Method: other subacute dust inhalation toxicity study
GLP compliance:
no
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
N-1,3-dimethylbutyl-N'-phenyl-p-phenylenediamine
EC Number:
212-344-0
EC Name:
N-1,3-dimethylbutyl-N'-phenyl-p-phenylenediamine
Cas Number:
793-24-8
Molecular formula:
C18H24N2
IUPAC Name:
N-(1,3-dimethylbutyl)-N'-phenylbenzene-1,4-diamine
Details on test material:
Santoflex 13, Lot no. KD03-017

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female

Administration / exposure

Route of administration:
inhalation
Vehicle:
other: unchanged (no vehicle)
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
4 weeks
Frequency of treatment:
6 h/d and 5d/w
Doses / concentrations
Remarks:
Doses / Concentrations:
51, 247, 498 mg/m3
Basis:

No. of animals per sex per dose:
5 per dose and sex
Control animals:
yes, concurrent no treatment
Details on study design:
Post-exposure period: no data

Results and discussion

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
51 mg/m³ air
Sex:
male/female
Basis for effect level:
other: hypoactivity of treated animals at exposure day 8, decrease in hemoglobin value (13%) and hematocrit value (9 %) in females
Dose descriptor:
LOAEL
Effect level:
247 mg/m³ air
Sex:
male/female
Basis for effect level:
other: hypoactivity, swollen snout, scratching, changes in hematology parameters, increased liver weights males

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Particle size distribution:

Sample of airborn dust was collected weekly from the test atmosphere for conducting microscopic determination of particle size distribution. Particles were counted with respect to four size ranges: 5 microns or smaller, 6 to 10 microns, 11 to 25 microns and larger than 25 microns.

Particle size distribution:

 Particle size range µm

          Percent of total counted

week

 low dose  1  2  3  4
 1 to 5  1.9  0.9  2.3  0.9
 6 to 10  12.1  9.5  10.9  4.3
 11 to 25  31.5  28.5  29.8  20.4
 > 25  54.5   61.1   57.0  74.3
 mid dose        
  1 to 5  1.8  1.1  1.0  1.3
  6 to 10  12.3  10.0  7.5  8.9
  11 to 25  36.2  25.0  20.0  37.8
 high dose  1.9  1.3  0.9  0.8
   1 to 5  7.7  12.6  11.4  11.4
  6 to 10  17.3  31.2  36.8  37.6
  11 to 25  73.1  55.0  50.9  50.2

total number of particle count for week 1 through 4 were (low dose): 257, 221, 265 and 230, respectively.

Mortality: one male from the mid dose died during the investigation period

Clinical signs: hypoactivity was noted in all test groups. Animals from the mid and high dose groups exhibited swollen snouts and scratching. One male of the mid dose showed a cylindrical fleshy structure (approx. 1 mm in diameter and 3 mm in lengh) on the middorsal region.

Mean body weight gains: treated animals were comparable to control

Organ weights (no individual data available, no statistical summary tables were availabe for this data,data for organ weight ratios calculation are incomplete):

Kidney(no single organ weights availabe): low dose females exhibited significant (P<0.05) higher organ to brain weight ratio than control; mid dose females exhibited significantly (P<0.05) higher organ weights and organ to body weight ratios than control females

Liver (no single organ weights available): low and mid dose males exhibited significantly (P<0.01) higher organ weights than control males; high dose males exhibited significantly (P<0.05) higher organ weights than control males; mid dose males exhibited significantly (P<0.05) higher organ to body weight ratios than control males

Low dose females exhibited signifcantly (P<0.05) higher organ weights than controls; mid and high dose females exhibited significantly higher organ weights (P<0.01) as well as higher organ body and organ to brain ratios than control females.

Lung( no single organ weights availbale): High dose males exhibited signifcantly lower organ weights (P<0.01) as well as lower organ to body and organ to brain weight ratios (P<0.05)than control males; mid dose females exhibited significantly (p<0.05) lower organ weights and organ to brain weight ratios than control females.

Spleen(no single organ weights availabe): mid dose males exhibited significantly (P<0.05) higher organ weights

and organ to body weight ratios than control males

There were no signifcant differences between test and control animals with respect to brain, gonads and heart weight data.

Gross or histopathologic alterations:

No gross or histopathologic alterations attrinutable to the effects of the test material were observed in any of the treated rats examined. Cornealopacities were observed in one female rat in each of the mid and high dose treatment groups. histopathologic evaluation of the affected eye from the rat in the high dose group revealed it to be histologically normal.

Haematology:

Changes in haematology was noted in treated animals.

A dose-dependent decrease in hemoglobin and dose-dependent increase in leukocytes were noted in treated females. A decrease in the erythrocyte count and hematocrite value were noted in treated males and females (not dose dependent). A dose dependent decrease in MCV(Mean corpuscular volume)and MCH

(Mean corpuscular hemoglobin)was noted in treated males.

Clinical Chemistry:

BUN (Blood urea nitrogen):

Values for the mid dose males were significantly higher (P<0.05%) than control.

SGPT (Serum Glutamic pyruvic transaminase):

the values for the mid and high dose males were signifcantly lower (P<0.05) than control; in the absence of histopathologic alterations attributable to the test material the meaning of these changes are unclear.

Urinalysis:

Mean values for content of blood, ketones, glucose and protein of urine, for pH and for microscopic constituents of urinary sediments determined in samples obtained from treated rats were normal when compared to the values for control rats.

Applicant's summary and conclusion