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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:
supporting study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP study. Published in peer reviewed literature. Limitations in design and/or reporting but otherwise adequate for assessment.
Cross-reference
Reason / purpose:
reference to same study

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
1999
Report Date:
1999
Reference Type:
other: cited in NTP (1999)
Title:
Unnamed
Year:
1997

Materials and methods

Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Subchronic (14 week) toxicity study as a preliminary to a two tier carcinogenicity study. Endpoints include vaginal cytology and sperm analysis hence relevance for reprotoxicity.

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): furfuyl alcohol
- Physical state: clear yellow liquid
- Analytical purity: greater than 98%
- Supplier: QO Chemicals, Inc.(Memphis, TN, USA)
- Lot/batch No.: 7B19M-2
- Stability under test conditions: stable
- Storage condition of test material: under nitrogen blanket at approx. -20°C

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Simenson Laboratories (Gilroy, CA, USA)
- Age at study initiation: approximately 6 weeks
- Weight at study initiation: group mean body weights: Male 98-102 g; female 91-96 g
- Housing: Individual in stainless steel cages
- Diet: NIH-07 open formula pelleted diet (Zeigler Brothers Inc., Gardners, PA, USA), available ad libitum except during exposure periods
- Water: tap water via an automatic system, ad libitum
- Acclimation period: 12 to 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): mean 23.6-34.1
- Relative humidity (%): mean 55-56
- Air changes (per hr): 15
- Photoperiod: 12hrs dark /12 hrs light

IN-LIFE DATES: From: 19 December 1988 To: 22 March 1989

Administration / exposure

Route of administration:
inhalation: vapour
Type of inhalation exposure (if applicable):
whole body
Vehicle:
air
Details on exposure:
Furfuryl alcohol was pumped into the top of a glass evaporation column containing glass beads. A stream of heated nitrogen entered the column from below, vaporized the furfuryl alcohol and carried it to a heated condenser column. Additional heated nitrogen was used to dilute the furfuryl alcohol vapor leaving the evaporation column. The vapor was drawn through a heated line and injected into the inlet air stream of a mixing chamber and then pumped into the distribution line. The charcoal and HEPA-filtered air was conditioned to room temperature and maintained at minimum relative humidity to prevent the vapor from condensing. Uniform vapor concentrations were maintained throughout the chamber.

Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
A small particle detector (Type CN, Gardner Associates, Schenectady, NY, USA) was used with and without animals in the exposure chambers to ensure that furfuryl alcohol vapor, and not aerosol, was produced. Particle concentrations in the 32 ppm chamber were 200 particles/cm3 without animals present and 245 particles/cm3 with animals; concentrations in all other chambers were below the limit of detection, with and without animals present. The minimum resolvable level of the detector was approx. 200 particles/cm3.
Vapour concentration monitoring was done using an on-line gas chromatograph. No degradation of furfuryl alcohol was detected during the exposure periods.
Duration of treatment / exposure:
6 hours/day
Frequency of treatment:
5 days/week

Duration of test:
14 weeks
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 2, 4, 8, 16 or 32 ppm
Basis:
nominal conc.
Remarks:
Doses / Concentrations:
0, 8, 16, 32, 64 or 128 mg/m3
Basis:
nominal conc.
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle
Details on study design:
14 week study was conducted to evaluate the cumulative toxic effects of repeated exposure to furfuryl alcohol and to determine appropriate exposure concentrations for use in subsequent 2 year study. Full study details are included in section 7.5.

Sperm samples were collected from males in the 0, 2, 8 and 32 ppm groups at the end of the study and evaluated for sperm count and motility.
Vaginal samples were collected from females for up to 12 consecutive days prior to the end of the studies and evaluated for the relative frequency of estrous stages and for estrous cycle length. Only these results are presented in this summary. Full study results are included in section 7.5.
Statistics:
Organ weight data with approximately normal distributions, were analyzed with the parametric multiple comparison procedures of Dunnett and Williams. Spermatid and epididymal spermatozoal data typically with skewed distributions, were analyzed using the nonparametric multiple comparison methods of Shirley and Dunn. Jonckheere’s test was used to assess the significance of the dose-related trends.
Vaginal cytology data are proportions (the proportion of the observation period that an animal was in a given estrous stage) and thus an arcsine transformation was used to bring the data into closer conformance with a normality assumption. Treatment effects were investigated by applying a multivariate analysis of variance (Morrison) to the transformed data to test for simultaneous equality of measurements across exposure concentrations.

Results and discussion

Effect levels

Dose descriptor:
NOAEC
Effect level:
128 mg/m³ air (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: no effect on estrous cylicity or sperm parameters

Observed effects

The final mean body weight and body weight gain of females exposed to 32 ppm were significantly less than those of the control group.
Spermatid count and number of spermatid heads per testis were significantly increased at 32 ppm. Spermatid heads per gram of testis were significantly increased at 16 and 32 ppm.
There were no effects of treatment on estrous cyclicity.

Any other information on results incl. tables

Male Reproductive Tissue Evaluations

 

Exposure Concentration of Furfuryl Alcohol (ppm)

 

0

2

8

32

 

 

 

 

 

 

Terminal body weight (g)

Mean

325

322

323

311

 

SE

7

7

5

6

Left testis weight (g)

Mean

1.3579

1.3626

1.3569

1.4049

 

SE

0.0389

0.0262

0.0278

0.0304

Left epididymis weight (g)

Mean

0.4514

0.4406

0.4315

0.4586

 

SE

0.0184

0.0085

0.0098

0.0075

Left cauda epididymis weight (g)

Mean

0.1637

0.1627

0.1578

0.1626

 

SE

0.0079

0.0042

0.0064

0.0064

 

 

 

 

 

 

Spermatid heads (107/g testis)

Mean

10.43

12.20

12.32*

12.96**

 

SE

0.57

0.68

0.61

0.54

Spermatid heads (107/testis)

Mean

14.26

16.65

16.65

18.13**

 

SE

0.96

1.05

0.74

0.61

Spermatid count

Mean

71.30

83.25

83.23

90.63**

(mean /10-4mL suspension)

SE

4.80

5.25

3.69

3.07

 

 

 

 

 

 

Epididymal spermatozoa

Mean

87.48

93.35

88.02

92.53

Motility (%)

SE

7.80

1.16

4.91

0.58

Concentration

Mean

443

511

460

442

(106/g cauda epididymal tissue)

SE

46

21

19

15

Data are presented as mean ± standard error (SE)

*Significantly different (<0.05) from the control group Shirley’s Test

**Significantly different (<0.01) from the control group Shirley’s Test

No significant differences from control by Dunnett’s test (weights)

No significant differences from control by Dunn’s test (epididymal spermatozoa measurements)

 

Female Estrous Cycle Characterisation

 

Exposure Concentration of Furfuryl Alcohol (ppm)

 

0

2

8

32

 

 

 

 

 

 

Terminal body weight (g)

Mean

198

198

189

178**

 

SE

4

3

3

4

Estrous cycle length (days)

Mean

4.80

4.85

4.90

4.80

 

SE

0.11

0.11

0.10

0.11

Estrous stages (% of cycle)

 

 

 

 

 

Diestrus

 

42.5

42.5

39.2

40.0

Proestrus

 

19.2

15.8

15.8

14.2

Estrus

 

21.7

22.5

25.0

28.3

Metestrus

 

16.7

18.3

16.7

15.0

Uncertain diagnoses

 

0.0

0.8

3.3

2.5

Body weight and cycle length are presented as mean ± standard error (SE)

**Significantly different (<0.01) from the control group Williams’ Test

No significant differences from control by Dunn’s test (cycle length)

No significant differences from control by multivariate analysis of variance (relative length of time in estrous stages)

Applicant's summary and conclusion

Conclusions:
Exposure to concentrations of furfuryl alcohol up to 32 ppm for 14 weeks produced few overt signs of toxicity. The mean body weight of female rats exposed to 32 ppm was less than that of the chamber controls, but body weights of other groups of rats were unaffected. The most significant response occurred in the nose, where exposure to furfuryl alcohol vapor produced a spectrum of inflammatory, degenerative, and proliferative lesions of the respiratory, transitional, and olfactory epithelium. There was no effect of furfuryl alcohol on estrous cyclicity or on sperm parameters.
Executive summary:

A 14 week toxicity study was conducted as a preliminary to a two year carcinogenicity study. Rats were exposed by inhalation to furfuryl alcohol vapour at concentrations of up to 32 ppm. The measured endpoints included vaginal cytology and sperm analysis. The mean body weight of the female rats exposed to 32 ppm was less than that of the chamber controls, but body weights of other groups of rats were unaffected. The most significant response occurred in the nose, where exposure to furfuryl alcohol vapor produced a spectrum of inflammatory, degenerative, and proliferative lesions of the respiratory, transitional, and olfactory epithelium. There was no effect of furfuryl alcohol on estrous cyclicity or on sperm parameters.