N-(1,4-dimethylpentyl)-N'-phenylbenzene-1,4-diamine

Repeated dose toxicity: oral

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

Test material information

Constituent 1

Reference substance name:

N-(1,4-dimethylpentyl)-N'-phenylbenzene-1,4-diamine

EC Number:

221-374-3

EC Name:

N-(1,4-dimethylpentyl)-N'-phenylbenzene-1,4-diamine

Cas Number:

3081-01-4

Molecular formula:

C19H26N2

IUPAC Name:

N1-(5-methylhexan-2-yl)-N4-phenylbenzene-1,4-diamine

Constituent 2

Reference substance name:

7PPD

IUPAC Name:

7PPD

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

Doses / concentrations 1

Dose / conc.:

0 ppm

Remarks:

(ca. 0 for males and females); 5 per sex and dose group

Doses / concentrations 2

Dose / conc.:

500 ppm

Remarks:

(ca. 36.7 for males and 39.8 for females); 5 per sex and dose group

Doses / concentrations 3

Dose / conc.:

750 ppm

Remarks:

(ca. 51.8 for males and 58.2 for females); 5 per sex and dose group

Doses / concentrations 4

Dose / conc.:

1 500 ppm

Remarks:

(ca 101.2 for males and 134.3 for females), 5 per sex and dose group

Doses / concentrations 5

Dose / conc.:

3 000 ppm

Remarks:

(ca. 186.9 for males and 199.6 for females), 5 per sex and dose group

No. of animals per sex per dose:

5 per sex and group

Control animals:

yes, plain diet

Results and discussion

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

1 500 ppm

Sex:

male/female

Basis for effect level:

other: slight effects on body weights

2

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)