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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
toxicity to reproduction
Remarks:
other: reproductive system evaluation
Type of information:
experimental study
Adequacy of study:
other information
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Comparable to guideline study with acceptable restrictions (no post exposure period, slight deviations from guideline recommended housing conditions, limited chemical chemistry, not all recommended organs were weighed)
Cross-reference
Reason / purpose for cross-reference:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1992
Reference Type:
publication
Title:
Comparative toxicities of o-, m- and p-nitrotoluene in 13-week feed studies in F344 rats and B6C3F1 mice
Author:
Dunnick JK, Elwell MR, Bucher JR
Year:
1994
Bibliographic source:
Fundam Appl Toxicol 22: 411-421

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
other: 408
Deviations:
yes
Remarks:
NTP study (standard protocol comparable to OECD 408 with acceptable restrictions (no post exposure period, slight deviations from guideline recommended housing conditions, limited chemical chemistry, not all recommended organs were weighed). Study indicat
Principles of method if other than guideline:
NTP standard protocol for determination of subchronic toxicity after 90 days repeated dose application. Groups of rat animals were fed diets containing p-nitrotoluene for 13 weeks.
GLP compliance:
yes

Test material

Constituent 1
Chemical structure
Reference substance name:
3-nitrotoluene
EC Number:
202-728-6
EC Name:
3-nitrotoluene
Cas Number:
99-08-1
Molecular formula:
C7H7NO2
IUPAC Name:
3-nitrotoluene
Constituent 2
Reference substance name:
2-nitrotoluene
EC Number:
201-853-3
EC Name:
2-nitrotoluene
Cas Number:
88-72-2
IUPAC Name:
1-methyl-2-nitrobenzene
Details on test material:
- Name of test material (as cited in study report): m-nitrotoluene
- Analytical purity: >96%

Test animals

Species:
rat
Strain:
other: Fischer 344/N
Sex:
male/female

Administration / exposure

Route of administration:
oral: feed
Vehicle:
other: not applicable
Duration of treatment / exposure:
Exposure period: 13 w
Duration of test: 13 w
Frequency of treatment:
daily
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 625, 1250, 2500, 5000, 1000 ppm
Basis:
nominal in diet
No. of animals per sex per dose:
10
Control animals:
yes, concurrent no treatment

Results and discussion

Results: F1 generation

Details on results (F1)

In male rats at 10000 ppm: degeneration of the testes; reduction in sperm density, motility, and number. In female at 100000 ppm: increased length of the estrous cycle.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

All male rats from the 1000 ppm group displayed mild to moderate degeneration of the testis, characterized by reduction of germ cells and mature spermatids in the seminiferous tubules; cellular debris was present in the ducts of the epididymis. The testicular lesionswas accompanied by a reduction in epididymal sperm count and concentration. Among females there was a dose-related decrease in the length of estrous and an increase in the period of diestrus. The length of the estrous cycle increased while the number of cycling animals diminished. There were no gross or histopathologic effects on the uterus or ovaries in this 13-week study.

Summary of reproductive tissue evaluations in male rats in the 13 week feed study of m-nitrotoluene

 Study parameters  0 ppm  2500 ppm  5000 ppm  10000 ppm
 Weights (g)            
Necropsy body weight  346 ± 8  353 ± 6  338 ± 6 281 ± 5**
 Left testicle  1.41 ± 0.026  1.46 ± 0.028  1.47 ± 0.024  0.79 ± 0.087 **
 Left epididymis  0.46 ± 0.009 0.47 ± 0.010  0.46 ± 0.012   0.29 ±0.017**
 Left epididymis tail  0.16 ± 0.007 0.16 ± 0.008   0.15± 0.007 ²  0.08 ± 0.005**
 Spermatid measurements        
 Spermatid measurements             
 Spermatid heads (107/g testis)  11.38 ± 0.58  9.81 ± 0.49  11.07 ± 0.63  3.54 ± 1.50**
 Spermatid heads (  107/ testis)  15.99 ± 0.74 14.26  ± 0.70   16.18  ± 0.88  3.79 ± 1.71 **
 Spermatid count (mean/104mL suspension)  79.93  ± 3.70  71.30  ± 3.50  80.88  ± 4.40 18.95  ± 8.56 **
  Spermatozoal measurements            
 Motility (%)  70 ± 4  73 ± 3   76 ± 3  20  ± 13³
 Concentration (10 6/g cet) 4  581 ± 31  496 ± 28* 629  ± 41²  143  ± 52**

1 Data presented as mean  ± standard error; n=10, except where noted

²n=9

³n=8

4 gcet= grams of cauldal epididymal tissue

* significantly different (p < = 0.05) from the control group by Dunn´s or Shirley´s test

**significantly different (p < = 0.01) from the control group by Dunn´s or Shirley´s test

Summary of estrous cycle characterization in female rats in the 13 -week feed study of m-nitrotoluene1

 Study parameters  0 ppm  2500 ppm  5000 pmm  10000 ppm
 Necropsy body weight (g)  194 ± 3  195  ± 3  177  ± 2*   166  ± 3**
 Estrous cycle lenght (days)  5.00  ± 0.13  5.00  ± 0.00  6.50  ± 0.38**  6.00  ± 0.58*³
 Estrous stages as% of cycle4        
 diestrus  37.5 40.8  49.2  75.8 
 proestrus  10.0 15.0  15.8  4.2 
 estrus  36.7  29.2  19.2  11.7
 metestrus  15.8 15.0   15.8  7.5
 uncertain diagnosis  0.0  0.0  0.0  0.8

1 Data presented as mean  ± standard error, n=10 except were noted

² n=9;estrous cycle lenght longer than 12 days or unclear in 1 of 10 animals

³ n=3; estrous cycle lenght longer than 12 days or unclear in 7 of 10 animals

4 Evidence by multivariate analysis of variance (MANOVA) suggests that females int hte 10000 ppm groups differ signifcantly (p <0 0.01) from controls in the relative frequency of time spent in the estrous stages. Females in this group spent more time in diestrus and less time in other stages than did controls

* Significantly different (p<=0.05) from the control group by Dunn´s or Shirley´s test

** Significantly different (p<=0.01) from the control group by Dunn´s or Shirley´s test

Applicant's summary and conclusion