FUNDAMENTAL

AND

APPLIED

TOXICOLOGY

(1992)

l&255-265

Evaluation of the Potential for Developmental Toxicity in Rats and Mice following Inhalation Exposure to Tetrahydrofuran TERRYLJ. MAST,RICHARDJ. WEIGEL,R.BRUCEWESTERBERG, BERNARD A. SCHWETZ,* AND RICHARD E. MORRISSEY*,’ Battelle-Pacific

Northwest Laboratory, Research and Testing,

Richland, Washington, 99352; and *Developmental National Institute of Environmental Health Sciences, Received

February

19. 1991; accepted

Evaluation of the Potential for Developmental Toxicity in Rats and Mice following Inhalation Exposure to Tetrahydrofuran. MAST, T. J., WEIGEL, R. J., WESTERBERG, R. B., SCHWETZ, B. A., AND MORRISSEY, R. E. (1992). Fundam. AppL Toxicol. l&255-265. Sprague-Dawley rats and Swiss (CD-l) mice were exposed to 0,600, 1800, or 5000 ppm THF (a four-carbon cyclic ether, widely used as an industrial solvent) vapors, 6 hrlday, 7 days/ week (6-19 days of gestation (DG) for rats; 6-17 DG for mice). Body weights of pregnant rats in the 5000 ppm group were reduced at euthanization. There were no effects on the percentage of live rat fetuses/litter or on the fetal sex ratio. Fetal body weight was significantly reduced for the 5000 ppm group, but the incidence of abnormalities was not increased. Mice in the 1800 and 5000 ppm groups were sedated during exposure; approximately 27% of the mice in the 5000 ppm group died. Mean body and uterine weights of mice were reduced for the 1800 and 5000 ppm groups at euthanization (18 DG), but adjusted maternal weight gain was not affected at 1800 ppm. There was a reduction in the percentage of live fetuses/litter for the mice in 1800 and 5000 ppm groups (95% resorptions in the 5000 ppm group). Fetal weight and sex ratio in mice were not affected. An increase in the incidence of reduced stemebral ossifications was correlated to THF concentration, although differences between groups were not statistically significant. There were no increases in the incidences of other malformations or variations. These results suggest that THF may be embryotoxic in mice, but if the conceptus survives, development as assessed by this experimental design continues in a normal fashion. The no-observable-adverseeffect level (NOAEL) for maternal toxicity was 1800 ppm in both rats and mice. The NOAEL for developmental toxicity was 1800 ppm in rats and 600 ppm in mice. o 1992 Society of Toxicology.

Tetrahydrofuran (THF), widely used as an industrial lution of plastic resins such idene chloride copolymers,

a four-carbon cyclic ether, is solvent, primarily in the dissoas polyvinylchloride and vinyland as a reaction medium. Ap-

’ Present address: Point, PA 19486.

and Dohme

Merck,

Sharp,

Research

Laboratory,

West

and Reproductive Research Triangle

Toxicology Group, Division of Toxicology Park, North Carolina 27709

July 25, 1991

proximately 150 million pounds of THF is produced each year by three major U.S. chemical companies. The National Occupational Hazard Survey estimates that more than 90,000 workers in 3000 plants are exposed to THF; consequently, it is classified in the “high” category of potential human exposure. Because of the high volatility of THF (bp 65°C) there is a significant possibility for industrial exposure to THF vapors via inhalation. Although THF has been used in industrial settings for many years, few long-term toxicity studies have been conducted on this compound. Furthermore, no reports of studies addressing the potential of THF to cause reproductive or developmental toxicity were found. The American Conference of Governmental Industrial Hygienists (ACGIH, 1988) has adopted a time-weighted average threshold limit value (TWA-TLV) of 200 ppm (590 mg/m3) with a short-term exposure limit (STEL) of 250 ppm (735 mg/m3). Although no permanent effects resulting from short-term exposures to high concentrations of THF have been reported (Rosensteel and Thoburn, 1975), subjects have complained of nausea and occipital headaches following exposure (Sittig, 1985). At lower concentrations THF is irritating to the skin, eyes, and mucous membranes. THF, in conjunction with several other solvents, was implicated as a causal agent in an allegedly high prevalence of urinary tract infections among all employees, and in reproductive and menstrual problems among 10 female employees, in a fiberglass fabricating plant in Baton Rouge, Louisiana. However, results of a field investigation conducted by NIOSH in 1979 stated that the incidence of urinary tract infections was not high, that none of the female employees had experienced reproductive problems, and that exposures to THF (and other solvents) were well below maximum recommended levels (Markel and Jannerfeldt, 198 1). Concerns over adverse health effects in Japanese workers exposed to THF were discussed in a review of THF toxicity (Horiguchi et al., 1983). Acute toxicity studies in laboratory animals, employing both inhalation and oral routes of exposure, place THF in the moderately toxic range. Lethal concentrations administered to animals (e.g., 49,000 ppm for 51 min in mice)

255 Copyright

0272-0590/92 $3.00 of Toxicology. in any form reserved.

0 1992 by the Society

All rights of reproduction

256

MAST

TABLE

ET

AL.

1

Mean Tetrahydrofuran Exposure Chamber Concentrations during the Exposure Period (ppm + SD) Actual Target exposure concentration (km) 0 600 1800 5000 a Less than minimum

detectable

Rats

Mice

3 resorptions Percent of Pregnant Live fetuses/littef Resorptions/litteP Earlye Late Litters with resorptions Litters with >3 resorptions Percentage male fetuses Fetal weight Male Female

0

600

1800

5000"

33

33 28 26'

33 27 21

33 27 20

31 30b

12.8 St 1.8 11.9 f 1.9 0.9 f 1.1 0.6 f 1.0 0.3 + 0.5 1

12.0 f 11.1 f 0.9 +_ 0.7 k 0.2 f 1

94

93.1 ? 6.9 k 4.1 +_ 2.1 &

1.8 1.8 0.5

12.0 f 9.3 f 2.1 f

8.2 7.6

3.7

+- 15.8

1.4 -t 0.1 1.3 * 0.1

11.9 f

4.0'

0.1 f

0.5

19'

82 11.4 22.6 14.6 8.0

50 3

+ + f f

83 34.8' 34.8/ 3 1.4’ 21.5

63 19

f 15.0

1.4f 1.3 f

12.6 +_ 2.8 0.6 f 2.7' 12.0 k 3.7e

5

91.2 + 19.6 8.4 rt: 19.5 6.1 f 19.4 1.7 -t 4.5

47.0

1.9 4.4' 4.1 3.9 2.2

1.8 f 0.9 f

85

8.2

60 3 46.6

2.2 3.2

0.1 0.1

50.7

f 16.2

1.3 + 0.2 1.2 f 0.2

t 19.2J f 19.2/ + 22.4/ 0.1 f 3.2 1008

4.3 95.1 95.0

958 16.7h

1.Oh l.Oh

a 5000 ppm group exposed 6-l 1 DG only due to high mortality incidence, see text. b One dam removed from study. ’ Two dams removed from study. d Significantly correlated with exposure level, p < 0.05. e Significantly different from control group, p < 0.05. /Significantly different from control group after arcsine transformation, p < 0.05. 8 Significantly different from control group, x2 analysis, p < 0.05. * Only one litter with live fetuses in this group.

of litter means for fetal data) were analyzed using the SAS General Linear Models (GLM) Procedure (SAS, 1985) with an analysis of variance (ANOVA) model for unbalanced data. Response variables, either body weight or the arcsin transformations of proportional incidence data, were analyzed against the class variable, treatment, in a one-way ANOVA model. A Tukey’s t test (two-tailed) was used to assessstatistically significant differences between control and exposed groups. If appropriate, the dose-response relationship was determined by means of an orthogonal trend test (Winer, 197 1). In the case of proportional data this test was performed on transformed variables. The litter was used as the basis for analysis of fetal variables.

RESULTS Chamber Concentrations Actual mean concentrations of THF in the chambers were within 2% of the target exposure concentrations (Table 1). Tetrahydrofuran was found to be stable in the generator reservoir and the exposure chambers. Analyses of chamber vapor samples indicated there were no degradation products present at concentrations greater than 0.1% of the target concentration (with or without animals present). Direct measurements of chamber concentrations of peroxide con-

firmed that chamber concentrations of this less volatile compound were insignificant. Temperature-programmed GC analysis failed to show evidence of any other degradation products. Rat All female rats, pregnant and nonpregnant, survived to scheduled euthanization. The only sign of toxicity in the pregnant females was a significant reduction in cumulative weight gain throughout the exposure period in the 5000 ppm exposure group (Fig. 1). Body weights and cumulative weight gains of virgin females were not altered by exposure to THF for 14 days (data not shown). A few dams in the three THFexposed groups exhibited mild alopecia which was not present in the control group and may have been due to the irritating properties of THF. The reduction in cumulative weight gain in the 5000 ppm pregnant females was primarily due to an initial depression in weight gain which occurred during the first 4 days of exposure (6 to 10 DG; Fig. 1). From 10 to 20 DG the rate of gain for this group was essentially equivalent to that of the

262

MAST

Malformations

ET AL.

TABLE 8 Observed in Mouse Fetuses following Gestational Exposure to Tetrahydrofuran Vapor Fetuses’

Tetrahydrofuran (ppm):

0

600

358 181 177 177

288 143 145 146

0

0

Edema

0

Exencephaly

1 (0.3) 1 (0.3) 0

Total examinedb Heads examined’ Skulls examined Viscera examined’ Malformations Cleft palate

Forelimb flexure Open eye Folded retina Ectopic ovaries Undescended testes Fused ribs Total affected

1800

5000

600

1800

252 128 124 127

12 6 6 6

30 30 30 30

25 25 25 25

23 23 23 23

I 1 1 1

(i.0)

0

0

0

0

(A.4)

0

0

0

(i.4)

0

0

(i.3)

0

0

0

(i.3)

1 (4.0) 0

1 (4.4) 1 (4.4) 0

0

0

0

(A.4)

0

0

0

(i.0)

0

0

0

0

0

0

(i.0) 0

(1.4,

0 0

1 0

(i.7) 0

0

0

(0.6)

Litter?

0

0

2 (0.3)

1 (0.3)

0

(A.8)

0

J.3) 0

2

0

0

0

(i.3)

0

0

1 (4.4) 0

(LO,

1 (4.4)

(1.6) 0

(Z.0)

1

(8.3

2 (6.7)

5000

0 0

1 ( 100.0) 1 (100.0)

Note. Actual number affected is on the Iine and the percentage affected is one line below. u A single fetus or litter may be represented more than once in this table. b All fetuses examined for external and skeletal defects. One-half had heads removed prior to skeletal staining. ‘Heads fixed in Bouin’s solution for soft-tissue craniofacial evaluations. d Heads remained on the fetuses for skeletal examinations, see (b). e Visceral evaluations were performed on approximately 50% of fetuseswithin 2 hr of death and on all fetuseswith external defects.

other exposure groups, including the controls, although the initial deficit was never regained. The mean gravid uterine weight and the adjusted maternal weight gain’ were also reduced at the time of euthanization for the 5000 ppm group as compared to the control group; however, the differences were not statistically significant (Table 2). Exposure of pregnant rats to THF vapors on 6 through 19 DG had no effect on the number of implantations, the mean percentage of live pups per litter, or the mean percentage of resorptions per litter with respect to the control group (Table 3). The ratio of males to females in the litters was not affected. Fetal weights (calculated as means of litter means) were significantly reduced for the 5000 ppm exposure group when compared to controls (Table 3). Mean body weights for both male and female fetuses in this group were ~82% of the mean weights for the control fetuses. The incidence of fetal malformations was not significantly affected following gestational exposure to THF (Table 4). * Adjusted maternal weight gain = maternal body weight (20 DG) - maternal body weight (0 DC?) - uterine weight (20 DG).

However, several malformations were observed in the single litter from the 5000 ppm group which were not found in either the control group or in the control groups from other studies recently conducted in our laboratory: anal atresia, cleft palate, vestigial tail, and vertebral agenesis. The incidence of fetal variations and reduced ossifications was not significantly altered by exposure to THF although there was a slight increase with respect to the control group (Table 5).3 Mice There were no maternal deaths in either the 600 or 1800 ppm exposure groups; however, female mice exposed to 5000 ppm THF exhibited an unexpectedly high mortality rate27% of the positively mated females died between 6 and 11 3 In the caseof the pelvis, the skull, and the phalanges, reduced ossifications are shown in Tables 6 and 7 as bone group totals, although each bone is individually evaluated. For example, of fetuseswith reduced ossification in the skull, 69% had reduced ossification of the interparietal bone, 25% of the supraoccipital, 12.5% of the parietal, 6% of the mandible, 6% of the zygomatic arch, 6% of the nasal, and 6% of the frontal bone.

INHALATION

DEVELOPMENTAL

TOXICITY

263

OF THF

TABLE 9 Variations Observed in Live Mouse Fetuses following Gestational Exposure to Tetrahydrofuran Fetuses” Tetrahydrofuran (pprn): Total examinedb Heads examined’ Skulls examinedd Viscera examined’ Variations Misaligned sternebrae Supernumerary rib Reduced ossifications Pelvis Phalanges Ribs’ Skull Stemebrae Vertebral centra Total affected

Litters?

0

600

1800

5000

0

600

1800

358 181 171 177

288 143 145 146

252 128 124 127

12 6 6 6

30 30 30 30

25 25 25 25

23 23 23 23

(i.3) (::.8)

(i.7) 49 (17.0)

49 (19.4)

(li.6) I (58.3)

(i.3) 23 (76.7)

CEO)

0

0

(y.6)

0

0

0

0

0

(Z.0)

0

0

(i.3)

0

0

0

0

5000 1 1 1 1

0 (1.0)

(lo:.o) 14 (60.9)

(1OkO)

0

1 (4.4) (i.4)

0 0

0

0

0

0

2 (8.7)

0

0

0

(:.2)

0

(i.3) 0

2 (16.7) 0

(2:.3) 0

II (44.0) 0

(3i.4) (i.4)

(1OA.O) 0

8 (66.7)

25 (80.7)

(Z.0,

(kG.6)

,1;.0,

9

19

(2.5)

(6.6)

0

0

22 (8.7) (i.0)

85 (23.8)

68 (23.5)

(2667.6)

Note. Actual number affected on the line and the percentage is one line below. a A single fetus or litter may be represented more than once in this table. b All fetusesexamined for external and skeletal defects. One-half had heads removed prior to skeletal staining. ‘Heads fixed in Bouin’s solution for soft-tissue craniofacial evaluations. d Heads remained on the fetuses for skeletal examinations, see (b) above. ’ Visceral evaluations performed on approximately 50% of fetuses within 2 hr of death and on all fetuses with external defects. fIncludes rudimentary ribs.

DG, and 30% of the virgins died during Exposure Days 1 through 5. Severe depression of the central nervous system may have caused or contributed to the deaths of these animals since all females in the 5000 ppm group as well as some in the 1800 ppm group were sedated for up to 1 hr following the daily shutdown of the THF generation system. To prevent further deaths in the 5000 ppm group, females that survived the first 6 exposure days were placed in an exposure chamber supplied with fresh, filtered air and remained there until the scheduled euthanization. The surviving females did not show any further signs of overt toxicity other than a reduced weight gain. The mean body weight of the virgin females in the 5000 ppm group was significantly less than the control group by Exposure Day 5; however, this group had recovered most of its weight by the time of euthanization (Fig. 2). The mean body weight of pregnant females in the 5000 ppm group was also significantly less than controls by the third day of exposure, but in contrast to the virgins, their weight remained low throughout the study (Fig. 3). A significant reduction in

mean body weight became apparent for the 1800 ppm group by 15 DG. For the 5000 ppm group, the body weight depression (which continued up to euthanization) can be attributed in part to the high intrauterine mortality in this group (discussed below). The predominant contribution to the reduced mean body weight for the 1800 ppm group was a deficit in uterine weight (Table 6). Exposure of mice to THF vapors on 6 through 17 DG had no effect on the number of implantations per dam. However, there was a significant decrease in the mean number and percentage of live fetuses per litter for both the 1800 and 5000 ppm groups when compared to the control group (Table 7). These decreases corresponded to a significant increase in the number and percentage of resorptions per litter for both groups. Pregnant females in the 5000 ppm exposure group that survived to the scheduled euthanization had litters with a 95% incidence of early resorption. Neither fetal weights nor the fetal sex ratio was affected by gestational exposure of dams to 600 or 1800 ppm THF vapors (Table 7).

264

MAST

There were no statistically significant increases in the incidence of fetal malformations in mice following gestational exposure to THF (Tables 8). However, as was the case for rats, several malformations appeared in the 1800 ppm group which had not been observed either in the control groups for this study or in control groups from other recently completed studies in this laboratory: cleft palate, edema, ectopic ovaries, and undescended testes. These malformations were all found in a single litter of low-weight fetuses which also had a 54% incidence of late resorptions. There was an increase in the incidence of reduced ossifications of the sternebrae in the 1800 ppm group with respect to the control group (Table 9). The elevated incidence of reduced sternebral ossification sites was significantly correlated to increasing exposure concentration. Values for the 5000 ppm group were not included in statistical analyses since only one litter with live fetuses was present in this group. DISCUSSION Results of this study indicate that exposure of SpragueDawley rats to 0,600, 1800, or 5000 ppm THF, concentrations well above the current TLV of 200 ppm, does not result in selective toxicity to the offspring. The only overt sign of maternal toxicity observed was a significant reduction in body weight for the 5000 ppm group on 20 DG which was due to a depressed rate of gain from 6-l 1 DG. The added stress of pregnancy appeared to exacerbate THF toxicity in rats since no treatment-correlated reduction in body weight was observed in virgin females. The only observed fetal effect, a significant reduction in fetal body weight for the 5000 ppm group, was also accompanied by a corresponding reduction in adjusted maternal weight gain. The presence of malformations in the THF-exposed groups which were not found in this or other Sprague-Dawley rat control groups in this laboratory indicate that 5000 ppm THF is approaching a developmentally toxic concentration in the rat. The 1800 ppm exposure concentration was considered a NOAEL for both maternal and developmental toxicity in the SpragueDawley rat. Swiss (CD- 1) mice appeared to be much more susceptible to the toxic effects of THF than did rats. The highest exposure concentration, 5000 ppm, was lethal to a significant number of mated and virgin females, and narcosis was observed in the 1800 ppm exposure group. This high incidence of lethality of CD- 1 mice in the 5000 ppm group was unexpected in light of the results of a 90&y subchronic study on B6C3Fl mice conducted under identical exposure and environmental conditions (Chhabra et al., 1990). In the 90-day study there were no deaths in either male or female mice in the 5000 ppm group, nor was there a reduction in female body weight in either the 1800 or the 5000 ppm group. The only clinical sign reported in either exposure group was narcosis and histopathological evaluations were negative for the 1800 ppm group; however, liver cytomegaly, uterine atrophy, and de-

ET AL.

generation of the adrenal cortex “X” zone was reported in all females in the 5000 ppm group. The basis for this significant difference in sensitivity between the two strains of mice is unknown, but may be due to the difference in age of the animals at the beginning of the exposure period. Mice in the 90-day study were only 6 to 7 weeks old at the start the study while those in this study were 10 to 11 weeks old. Exposure of pregnant CD- 1 mice to THF was clearly embryotoxic at both the 1800 and 5000 ppm exposure concentrations. This appears to be selective developmental toxicity since it occurred in the absence of a reduction in adjusted maternal weight gain in the 1800 ppm exposure group. The absence of an increase in the incidence of malformations or of a reduction in fetal body weight at 1800 ppm THF suggests that, in the event the conceptus survives, development as assessed by this experimental design continues in a normal fashion in the mouse. The 600 ppm concentration appeared to be a NOAEL for the developmental toxicity in the CD-1 mouse, while 1800 ppm appears to be a maternal NOAEL. The basis for the observed difference in sensitivity to the toxic effects of THF between mice and rats in this study is not readily apparent. It may be due to inherent differences in metabolic or physiologic function between the two species or to differences in the relative body burdens of THF. The minute volume for an adult female Sprague-Dawley rat is approximately 168 ml/min (extrapolation from data in Dorato ( 1985)) and approximately 40 ml/min for an adult CD1 female mouse (Depledge, 1985). Normalizing the minute volume to body weight for rats and mice results in about 0.42 and 0.78 ml/min/g, respectively. Thus, the inhalation rate on a body weight basis for mice is nearly double that of rats, which could result in a greater body burden of THF. Pharmacokinetic analyses of THF and its major metabolites in the blood and tissues of the test animals would provide further insight into the differences in species sensitivity. ACKNOWLEDGMENTS This work was supported at the Pacific Northwest Laboratory by an Interagency Agreement with the National Institute of Environmental Health Sciences National Toxicology Program (Contract No. NIH-YOI-ES-70153) by funds from the Comprehensive Environmental Response, Compensation, and Liability Act trust fund by interagency agreement with the Agency for Toxic Substances and Disease Registry, U.S. Public Health Service. The expert technical assistance of Ramona L. Rommereim, Judith J. Evanoff, Beverly J. Willemsen, Pamela J. Boyd, and Howard W. Hill is gratefully acknowledged in performing fetal evaluations. Tetrahydrofuran vapor generation and concentration monitoring were performed by the Bioengineering and Analytical Chemistry Groups of the Applied Toxicology Section, BattellePacific Northwest Laboratory (Richland, WA).

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Chhabra, R. S., Elwell, M. R., Chou, B., Miller, R. A., and Renne, R. A. (1990). Subchronic toxicity of tetrahydrofuran vapors in rats and mice. Fundarn.

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in Experimental

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pp, t 70-

Evaluation of the potential for developmental toxicity in rats and mice following inhalation exposure to tetrahydrofuran.

Sprague-Dawley rats and Swiss (CD-1) mice were exposed to 0, 600, 1800, or 5000 ppm THF (a four-carbon cyclic ether, widely used as an industrial solv...
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