3-nitrotoluene

Toxicity to reproduction

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

Reference

Reference 1

Reference Type:

publication

Title:

Unnamed

Year:

1992

Reference 2

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

Test material information

Constituent 1

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

Molecular formula:

C7H7NO2

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 (10^7/g testis)	11.38 ± 0.58	9.81 ± 0.49	11.07 ± 0.63	3.54 ± 1.50**
Spermatid heads (  10^7/ testis)	15.99 ± 0.74	14.26  ± 0.70	16.18  ± 0.88	3.79 ± 1.71 **
Spermatid count (mean/10^4mL 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 cycle^4
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