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Toxicological information

Toxicity to reproduction: other studies

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Administrative data

Endpoint:
toxicity to reproduction: other studies
Type of information:
experimental study
Adequacy of study:
other information
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Relevant methodological deficiencies
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1996
Report Date:
1996

Materials and methods

Test guideline
Qualifier:
no guideline available
Principles of method if other than guideline:
Type: other: andrological measures (testicular homogenization resistent (late step) spermatid head count, testicular staging, epididymal spermatozoan count)
GLP compliance:
yes
Type of method:
in vivo

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): isobutanol, 2-methyl propanol (obtained from Union Carbide Chemicals and Plastics Company, Houston, TX, USA
- Physical state: colorless, volatile organic liquid
- Analytical purity: 99%
- Impurities (identity and concentrations): no data
- Purity test date: no data
- Lot/batch No.: no data
- Stability under test conditions: no data
- Storage condition of test material: no data

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male
Details on test animals and environmental conditions:
TEST ANIMALS- Source: Charles River Laboratories Inc., NC, USA
- Age at study initiation: approx. 8 weeks
- Weight at study initiation: males 285 - 365 g, females 179 - 242 g
- Fasting period before study: no data- Housing: individually in stainless steel wire-mesh cages
- Diet (e.g. ad libitum): Purina Mills rodent Lab Chow #5002
- Water (e.g. ad libitum): yes- Acclimation period: no data

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 18 -26-
Humidity (%): 30 - 70
- Air changes (per hr): nodata
- Photoperiod (hrs dark / hrs light): 12 /12

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
unchanged (no vehicle)
Details on exposure:
GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 2000 L stainless steel and glass Hazelton H-2000 chambers
- Method of holding animals in test chamber: individually caged
- Source and rate of air: 500 L/minute
- Method of conditioning air: no data
- System of generating particulates/aerosols: adjustable-flow valveless metering pump (Fluid Metering Inc., Oster Bay, NY, USA) and a Laskin-typ nebulizer mounted in the supply air inlet at the top of the exposure chamber
- Temperature, humidity, pressure in air chamber: 23 to 24°C, 48 to 53%, no data
- Air flow rate: appr. 500 L/minute
- Air change rate: 15 changes/hour
- Method of particle size determination: no data
- Treatment of exhaust air: no data

TEST ATMOSPHERE
- Brief description of analytical method used: Fourier Transform infrared analyzer (FVB / Analect, Irvine, CA, USA) calibrated for isobutanol
- Samples taken from breathing zone: yes; 18 samples per exposure
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analytical determinations of the exposure chamber concentration yielded nominal-to-analytical ratios of means between 0.95 and 0.97
Duration of treatment / exposure:
14 weeks
Frequency of treatment:
6 hours/day, 5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 250, 1000, and 2500 ppm
Basis:
nominal conc.
No. of animals per sex per dose:
control and 2500 ppm groups: 20
250 ppm and 1000 ppm groups: 10
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: preliminary study (5 rats/sex, 0, 750, 1500, and 3000 ppm)
- Rationale for animal assignment (if not random): random
- Rationale for selecting satellite groups: no satelite groups
Statistics:
For parametric data Bartlett's test for homogenmeity of variances, analysis of variance (ANOVA) for overall significance, Dunnett's test for comparison of dosed groups to the controls.
For nonparametric and percentage based data Kruskal-Wallis test for the overall analysis, Mann Whitney U test for pairwise comparisons to the controls.
for normality of distribution

Results and discussion

Observed effects

negative

Any other information on results incl. tables

(1) No changes in epididymal sperm count were detected in any exposure group. 
(2) Total spermatid counts (on a per mg testis basis) were significantly higher in the mid-dose group (p<0.05).



Control 250 ppm 1000 ppm 2500 ppm
------------------------------------------
n= 15 5 5 15
------------------------------------------
Testes
weight (g) 1.90 1.75 1.95 1.85
no. spermatids
(x10E06) 101 117 167* 115
Spermatids (x10E03)
/mg tissue 53 67 86* 63
------------------------------------------
Epididymis
weight (g) 709 716 747 694
spermatozoa 48 69 68 57
(x10E06)
spermatozoa (x10E03)
/mg tissue 67 100 92 83

------------------------------------------
Stage XIII
(%) 8.1 8.6 7.6 10.6*
------------------------------------------
*=p<0.05; ANOVA, Dunnett's, 2-tailed


(3) Statistically significant (although minimal) increases in
the frequency of stage XIII in the 2500 exposure group were
observed.

There were no major changes to the seminiferous epithelium (histopathology; Monsanto 1995) or reduction in the number of spermatozoa available for fertilization of the ova.

Applicant's summary and conclusion

Conclusions:
Due to methodological deficiencies, the study results are not conclusive. Combined evidence (no dose-dependent effect on spermatid head count and spermatozoa count) indicates that testicular functions are not affecte by isobutanol treatment of test animals. This finding is supported by the results from a 2-generation reproductive toxicity inhalation study.