Isobutyric acid

Toxicity to reproduction: other studies

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 for cross-reference:

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

Test material information

Constituent 1

Reference substance name:

2-methylpropan-1-ol

EC Number:

201-148-0

EC Name:

2-methylpropan-1-ol

Cas Number:

78-83-1

Molecular formula:

C4H10O

IUPAC Name:

2-methylpropan-1-ol

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 or test system 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.