Registration Dossier

Administrative data

Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: subacute feeding study done under GLP, compared to guideline study with acceptable restrictions (e.g. no haematology, clinical biochemistry and histopathology conducted)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1988
Report Date:
1988

Materials and methods

Principles of method if other than guideline:
other: subacute feeding study
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Type:
Constituent
Details on test material:
Santoflex 14, purity: 96.2%

Test animals

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

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: 7PPD contained in the diet
Analytical verification of doses or concentrations:
yes
Duration of treatment / exposure:
28 days
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 500, 750, 1500 and 3000 ppm (ca. 0, 36.7, 51.8, 101.2, 186.9 males; 0, 39.8, 58.2, 134.3, 199.6 females); 5 per sex and dose group
Basis:

No. of animals per sex per dose:
5 per sex and group
Control animals:
yes, plain diet

Results and discussion

Effect levels

open allclose all
Dose descriptor:
NOAEL
Effect level:
1 500 ppm
Sex:
male/female
Basis for effect level:
other: slight effects on body weights
Dose descriptor:
LOAEL
Effect level:
3 000 ppm
Sex:
male/female
Basis for effect level:
other: effects on body weights and liver weights

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Analysis of Test Material and Diets

Results of analyses for test material stability conducted over a span of time approximately equal to the study length indicated the test material was stable. The homogeneity of the diet mixtures was determined to be adequate for study use. The stability of the test material/diet mixture was demonstrated for the low and high levels; stored in open containers at room temperature for 7 and 14 days. Weekly analyses of SANTOFLEX 14 antiozonant in the diet were performed on all levels for the first week of the study, and on at least

one level per week thereafter.

The following table shows the overall averages (uncorrected for quality control results):

            Test groups
   T1  T2  T3  T4
 Target exposure (ppm)  500  750  1500  3000
 Study mean (ppm)  450  660  1300  2800
 Standard deviation (ppm)  20  -  -  71
 Study average (% target)  90  88  87  93

Mortality

There were no deaths during this study.

Clinical Signs

There were no adverse clinical observations seen during the study.

Body Weight

Males and females at the highest dietary level had a decrease in group mean body weight by the end of the first week of dosing. Additionally, reduced weight gains were observed in males and females at all but the lowest level for the remainder of the study. Females at the lowest dietary level were slightly (about 10%) lighter in group mean body weight at the end of testing, while there were no significant differences in the lowest level males at any time during the study, when compared to controls. Group mean body weight data are shown in the following table:

 Group  Study mean (g)  % difference from control (study mean)  % difference from control/final body weight)  Overall % gain from initial
 Males        
 Negative control  335.3  -  -  63.6
 T1  333.2  -0.6  -1.1  60.5
 T2  317.0  -5.4  -7.8  48.3
 T3  311.8  -7.0  -7.9  50.9
 T4  289.2  -13.7  -15.9  36.7
 Females        
 Negative control  209.0      41.0
 T1  195.8  -6.3  -9.9 28.7
 T2  192.7  -7.8  -12.6  24.0
 T3  197.6  -5.5  -10.2  27.2
 T4  185.2  -11.4  -16.4  19.5

Food Consumption

Food consumption was reduced on a grams of food per day (GM/DAY) basis for males at all but the lowest level and females at all

dietary levels, as compared to their respective controls the first week of testing and continued to be reduced for most groups during the remainder of the study. T. Overall group mean food consumption data are summarized in the following table:

Food consumption

      g/day     g/kg/day
 Group  Study Mean  % Difference from control (study mean)  Study mean  % Difference from control(study mean)
 Males        
 Negative control  76.3  -  27.0  -
 T1  73.3  -3.9  25.8  -4.4
 T2 69.0   -9.6  22.9  -15.2
 T3  67.5  -11.5  22.1  -18.1
 T4  62.3  -18.3  18.9  -30.0
 Females        
 Negative control   86.8  -  18.9  -
 T1  79.5  -8.4  16.0  -15.3
 T2  77.6  -10.6  15.3  -19.0
 T3  87.3  0.6  17.8  -5.8
 T4  66.5  -23.4  12.7  -32.8

Overall study averages for consumption of test material (mg SANTOFLEX 14/kg body weight/day) were approximately 36.7, 51.8

101.2 and 186.9 in males and 39.8, 58.2, 134.3 and 199.6 in females, respectively.

Gross Pathology

There were no gross lesions that were attributed to treatment

Slightly increased (not statistically significant) absolute liver weights occurred in the high level males (+6 %) and females (+10 %) . Increased relative liver weights were seen at the same dietary level and also in the next two lower level male and female groups, but were attributed to decreases in body weights at those levels.

Liver weights absolute (after scheduled sacrifices)

 Group  Liver weight (g) (mean ± S.E.)  % from control
 Males    
 Negative control  12.301 ± 0.528  100 %
 T1  12.545 ± 0.937  102 %
 T2  12.165 ± 0.574  99 %
 T3  11.756 ± 0.343  96 %
 T4  13.044 ± 0.665  106%
 Females    
 Negative control  7.405 ± 0.387  100 %
 T1  7.376 ± 0.395 99.7 %
 T2  7.473 ± 0.517  100.1%
 T3  7.593 ± 0.110  103 %
 T4  8.136 ± 0.170  110 %

Liver weights relative to terminal body weight

 Group  rel liver weight (%) (mean ± S.E.)
 Males  
 Negative control  3.401  ± 0.132
 T1  3.494  ± 0.126
 T2  3.678  ± 0.115
 T3  3.670  ± 0.109
 T4  4.273  ± 0.106*
 Females  
 Negative control  3.412  ± 0.119
 T1 3.766  ± 0.150
 T2 3.899  ± 0.178
 T3  3.924  ± 0.060*
 T4 4.512  ± 0.089*

*significant different from control (p<0.05)

Applicant's summary and conclusion