Registration Dossier

Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
two-generation reproductive toxicity
Remarks:
based on test type (migrated information)
Type of information:
experimental study
Adequacy of study:
key study
Study period:
14 February 1994 to 27 July 1994
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Studies were conducted according to generally valid and/or internationally accepted testing guidelines.

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Unnamed
Year:
2002
Reference Type:
study report
Title:
Unnamed
Year:
1996
Report Date:
1996

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
other: 87/302/EEC; OECD Guideline No. 416; EPA/TSCA Guidelines 40 CFR, para.798.4700
GLP compliance:
yes (incl. certificate)
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material: Tetrahydrofuran- Physical state: Liquid, clear, colorless- Analytical purity: >99.9% analyzed- Impurities (identity and concentrations): Not given- Purity test date: Report from Feb. 1995- Test substance no.: 93/144-2- Lot/batch No.: B 568- Expiration date of the lot/batch: Not given- Stability under test conditions: Was determined to be stable over the study period- Storage condition of test material: Room temperature, dark, overlaid with nitrogen

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS- Source: Karl THOMAE an der Riss, FRG- Age at study initiation: (P) 35 +/- 1 days (including acclimatization period); (F1) mated 98 days after weaning- Weight at study initiation: (P) Males: 126 - 150 g; Females: 108 - 132 g; (F1) Males: 91.2 - 102.3 g; Females: 84.4 - 94.4 g- Fasting period before study: None- Housing: During the study period, housed individually in DK III stainless steel wire mesh cages (BECKER & Co., Castrop-Rauxel, FRG) except during mating periods, with males housed in Makrolon (BECKER & Co.) type M III cages for overnight mating. After birth, pregnant animals also housed in Makrolon type M III cages.- Diet (ad libitum): ground Kliba diet rat/mouse/hamster, 343 meal, KLINGENTALMUHLE AG, Kaiseraugst, Switzerland.- Water (ad libitum): tap water with added test article- Acclimation period: 7 daysENVIRONMENTAL CONDITIONS- Temperature (°C): 20 - 24- Humidity (%): 30 - 70- Air changes (per hr): Not stated- Photoperiod (hrs dark / hrs light): 12/12IN-LIFE DATES: From: 21 February 1994 To: 16 December 1994

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:Drinking water solutions were prepared once or twice a week in tap water. The required amount of tetrahydrofuran (THF) was added and the mixture agitated with a magnetic stirrer until test substance dissolution. The nominal concentrations of THF were 0 (control), 1000, 3000 or 9000 ppm).
Details on mating procedure:
- M/F ratio per cage: 1:1- Length of cohabitation: mated overnight for a maximum of 3 weeks- Proof of pregnancy: vaginal plug / sperm in vaginal smear referred to as day 0 of pregnancy- After 3 weeks if a F0 or an F1 parental animal had not produced offspring, it was again mated for 3 weeks with a fertile animal from the control group.- Further matings after two unsuccessful attempts: no- After successful mating each pregnant female was caged: Makrolon type III cages (BECKER & Co.)- Any other deviations from standard protocol: No
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The content of THF in drinking water solutions was verified by capillary-column gas chromatography with internal standard evaluation. Analyses were performed at the beginning of the study and approximately at 3-month intervals until study termination. The column used was a fused silica DB 1701; length, 30 m; internal diameter, 0.25 mm; and film thickness 1 micrometer. The carrier gas was helium (30 ml/min). A 1 microliter injection of each sample was analyzed under the following conditions: oven, 80 to 280 deg C at 8 deg C/min; injector, 250 deg C; detector, 300 deg C.An internal standard solution was prepared in a 100 ml volumetric flask by weighing about 200 mg of 1,4-dioxane and bringing to the mark with N,N-dimethylacetamide.Each sample was analyzed by weighing about 2 g of the sample and adding 25 ml of internal standard solution and 3 ml of N,N-dimethylacetamide. After mixing, the solution was ready for injection.The 7-day stability of tetrahydrofuran drinking water solutions was confirmed in a previous range-finding study (Project No. 16R0144/93020). Analysis of nominal 0.52 or 0.51 g/100 g samples indicated no measured changes after 7 days.All concentration control analyses of drinking water from the study were within acceptable limits of the analytical method. For periodically measured values, analytical results corresponded to 92 to 106% of expected values.
Duration of treatment / exposure:
Test animals were exposed continuously to the test material. The F0 animals received the test article in the drinking water beginning after acclimatization and for at least 70 days prior to mating. Treatment was continued through mating and until pups were weaned (21 days post-parturation), at which time parental animals were sacrificed. The F1 generation parental animals were exposed continuously to the same dose levels as parental animals. At least 98 days after assignment of F1 parental animals, males and females were mated. Females were allowed to litter. The F1 parental animals were sacrificed after weaning of pups (21 days post-parturition).
Frequency of treatment:
Test article was administered continuously in the drinking water.
Details on study schedule:
- F0 parental animals were treated continuously for at least 70 days prior to mating.- F1 parental animals were treated continuously for at least 98 days prior to mating.- Parental animals from the F1 generation were selected randomly before weaning.
Doses / concentrations
Remarks:
Doses / Concentrations:0, 1000, 3000 or 9000 ppmBasis:nominal conc.in drinking water
No. of animals per sex per dose:
25
Control animals:
yes, concurrent no treatment
Details on study design:
- Dose selection rationale: The doses were chosen based on the results of a previous range-finding study (BASF AG, 1994).

Examinations

Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes- Time schedule: At least once daily a check was made for dead or moribund animals. If in a moribund state, animals were sacrificed and necropsied.DETAILED CLINICAL OBSERVATIONS: Yes- Time schedule: All parental animals were checked daily for clinical signs of toxicity. The nesting, littering and lactation behavior of the dams was generally evaluated in the mornings in connection with daily clinical inspections.BODY WEIGHT: Yes- Time schedule for examinations: Body weights of male and female parental animals were determined once a week.FOOD CONSUMPTION:Yes- For F0 parental animals, food consumption was determined once weekly for the first 10 weeks (or 14 weeks, F1 parental animals). After week 10 (or week 14, F1 animals), food consumption for the females during the gestation period was determined for days 0 - 7, 7 - 14 and 14 - 20. During lactation (animals with litters), food consumption was determined on days 1 - 4, 4 - 7 and 7 - 14. Food consumption was not determined on days 14 to 21 (as per Test Guideline). Food consumption of F0 males was not determined after week 10 (or week 14, F1 animals) until sacrifice.WATER CONSUMPTION AND COMPOUND INTAKE: Yes- Time schedule for examinations: For F0 parental animals, water consumption was determined once weekly for the first 10 weeks (time periods of 3 days) (or 14 weeks, F1 parental animals). After week 10 (or week 14, F1 animals), water consumption for the females during the gestation period was determined for days 0 - 1, 6 - 7, 13 - 14 and 19 - 20. During lactation (animals with litters), water consumption was determined on days 1 - 2, 4 - 5, 7 - 8 and 14 - 15. Water consumption was not determined on days 20 to 21 (as per Test Guideline). Water consumption of F0 males was not determined after week 10 (or week 14, F1 animals) until sacrifice.OTHER: The number of mating days until vaginal sperm could be detected in the female, and the gestational status of the female, were noted for F0 and F1 pairs.
Oestrous cyclicity (parental animals):
Not measured.
Sperm parameters (parental animals):
Not measured.
Litter observations:
STANDARDISATION OF LITTERS- Performed on day 4 postpartum: Yes- Individual litters were in general standardized such that each litter contained 4 male and 4 female pups. If 4 pups/sex were not possible, then litters were standardized on 8 total pups. Standardization was not performed on litters containing less than 8 pups. All excess pups were sacrificed by means of CO2 asphyxiation.PARAMETERS EXAMINEDThe following parameters were examined in F1 and F2 offspring:- Clinical observations: Pups were examined each day for clinical signs (including gross morphological findings).- Pup number and status at delivery: All pups derived from F0 and F1 parents were examined as soon as possible on the day of birth to determine the total number of live born and stillborn in each litter. Pups which died before the first determination were recorded as stillborn.- Pup viability/mortality: Checks were made for any dead or moribund pups twice daily on workdays (morning and afternoon) and mornings on weekends and holidays. The number and percentage of dead pups on the day of birth (day 0) and of pups dying between days 1 - 4, 8 - 14 and 15 - 21 of the lactation period were determined; however, pups dying accidentally or which had to be sacrificed due to maternal death were not included in these calculations. The number of live pups/litter was calculated on the day of birth and on lactation days 4, 7, 14 and 21.- Sex ratio: On the day of birth, the sex of pups was determined and the sex ratio calculated.- Pup body weight: Pups were weighed on the day after birth (day 1 postpartum) and on days 4 (before standardization), 7, 14 and 21 after birth.- Developmental stages of the pups were monitored: Appropriate physiological development was assumed if: (1) pinna unfolding on day 4 after birth (before standardization); (2) opening of the auditory canal (day 13 after birth); and openings of the eyes (on day 15 after birth).BEHAVIORAL TESTSUp to weaning, several developmental tests were performed on surviving pups:-Grip reflex: On day 13 after birth (+/- 1 day), pups were tested for this reflex by placing the front extremities on a bar about 3 mm in diameter. Animals clinging to the bar and pulling themselves up were rated as showing a positive response.- Hearing test (Acoustic startle): On day 21 (+/- 1 day), animals were placed in a soundproof box (49.5 x 49.5 x 38.5 cm). After a short acclimation, animals were exposed (twice at most) to a startle stimulus (sound, 0.1 seconds, 5000 Hz, about 90 dB). Movement of ears or a jerk was considered a positive response.- Pupillary reflex (Constriction): On day 20 after birth (+/- 1 day), animals pupils were dilated in a low-light environment. Pupillary constriction reflex was assessed by shining a penlight on the eye and observing the reaction of the pupil.
Postmortem examinations (parental animals):
NECROPSYAnimals were sacrificed by decapitation under CO2 anesthesia and assessed by gross pathology. Animals dying prematurely were necropsied as soon as possible and assessed for gross pathology.ORGAN WEIGHTSThe following were weighed for all animals sacrificed at scheduled dates: anesthetized animals, liver, kidneys, testes, and epididymides.HISTOPATHOLOGYThe following were fixed in 4% formaldehyde solution: all gross lesions, vagina, uterus (with cervix uteri), ovaries, oviducts, testes, epididymides, seminal vesicles, coagulating gland, prostate gland, pituitary gland, liver, kidneys, esophagus, stomach (glandular and non-glandular), and duodenum.
Postmortem examinations (offspring):
GROSS AND MICROSCOPIC EXAMINATION OF PUPS:- All culled pups (sacrificed on day 4 postpartum as a result of standardization) and surplus pups (not reared to adulthood) were examined externally, eviscerated, and their organ assessed macroscopically. If there were notable finding, or if abnormalities were found in daily clinical observations after delivery, affected animals were examined using appropriate methods (e.g., skeletal staining) and/or with further processing of the heads according to Wilson’s method.- All stillborn pups dying up to weaning were examined externally, eviscerated, and their organ assessed macroscopically. If there were notable finding, or if abnormalities were found in daily clinical observations after delivery, affected animals were examined using appropriate methods (e.g., skeletal staining) and/or with further processing of the heads according to Wilson’s method.- Stained skeletons were evaluated under a stereomicroscope or magnifying glass. All pups without notable findings were discarded after examination.
Statistics:
Dunnett’s test (two-sided) was used to evaluate food and water consumption, body weights and weight changes, number of mating days, duration of gestation and number of pups delivered per litter. The mean weight of each litter was used for statistical analysis (statistical unit = litter). Fisher’s exact test (one-sided) was used to evaluate male and female mating indices, male and female fertility indices, gestation index, females with live born, stillborn, pups that died, pups cannibalized, pups sacrificed moribund, viability indices, lactation indices, and number of litters with affected pups at necropsy. The Wilcoxon test (one-sided) was used for analyzing the proportion of affected pups per litter, with necropsy observations, with physical development and reflex data, and for the proportion of pups reaching the special criteria for each litter (statistical unit = litter).Mean and standard deviations were calculated for terminal body weights and absolute and relative organ weights for the animals in each test group and tabulated together with the individual values.
Reproductive indices:
MALE REPRODUCTIVE DATA- A male mating index (%) was calculated for F1 and F2 litters as: the percentage of the number of males with confirmed mating (defined as female with vaginal sperm or that gave birth to a litter or with pups/fetuses in utero) versus numbers of males placed with females.- A male fertility index (%) was calculated for F1 and F2 litters as: the percentage of the number of males proving their fertility (defined as female giving birth to a litter or with pups/fetuses in utero) versus the number of males placed with females.FEMALE REPRODUCTION AND FERILITY- A female mating index (%) was calculated for F1 and F2 litters as: the percentage of females mated (defined as female with vaginal sperm or that gave birth to a litter or with pups/fetuses in utero) versus the number of females placed with males.- A female fertility index (%) was calculated for F1 and F2 litters as: the percentage of pregnant females (defined as females giving birth to a litter or with pups/fetuses in utero) versus the number of females mated (defined as female with vaginal sperm or that gave birth to a litter or with pups/fetuses in utero).-A female gestation index (%) was calculated for F1 and F2 litters as: the percentage of females with live pups on the day of birth versus the number of pregnant females.- A live birth index (%) was calculated for F1 and F2 litters as: the percentage of the number of live born pups at birth versus total number of pups born.
Offspring viability indices:
- A viability index (%) was calculated as: the percentage of live pups on day 4 (before standardization of litters) versus the live pups on the day of birth.- A lactation index (%) was calculated as: the percentage of live pups on day 21 after birth versus the number of live pups on day 4 after birth (after standardization of litters).

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Body weight and weight changes:
effects observed, treatment-related
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
effects observed, treatment-related

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
not examined
Reproductive function: sperm measures:
not examined
Reproductive performance:
no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)There were no significant adverse clinical effects reported in parental animals. There were no deaths attributed to compound administration.BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)Body weight:For F0 parental animals, there were slight but statistically significant reductions in mean body weights (generally prior to week 5) at the 9,000 ppm dose level during the first study weeks (both sexes) and mean body weights of F0 dams on gestation days 7 and 14 and lactation days 1 - 21.For F1 parental animals, statistically significantly reduced body weights at the 9,000 ppm dose level in male were recorded throughout the study (in total about 6% lower than concurrent controls). This was accompanied by statistically significantly reduced weight gains in males and in females, but during gestation only.Food Consumption:For F0 parental females, food consumption was statistically significantly reduced during premating, gestation and lactation periods (approx. 8% lower than concurrent controls).For F1 parental males, food consumption was statistically significantly reduced during several intervals of the premating phase (in total about 6% less than concurrent controls); statistically diminished food consumption was also recorded in F1 females, predominantly during lactation (about 14% less than concurrent controls).TEST SUBSTANCE INTAKE (PARENTAL ANIMALS)For F0 parental animals, statistically significantly reduced water consumption at the 9,000 ppm dose level in male were recorded during premating (males: about 18% less, females: about 27% less) and in dams during gestation (about 25% less) and during lactation (about 20% less).For F1 parental animals, generally statistically significantly reduced water consumption at the 9,000 ppm dose level in male were recorded during premating (males: about 14% less, females: about 17% less) and in dams during gestation (about 14% less) and during lactation (about 24% less).At the 3,000 ppm dose level, slight and only sometimes statistically significant declines in water consumption in F0 males and females was recorded during premating (about 7% less) and in dams during gestation and lactation (about 14% or 12% less). In F1 parental animals at the 3,000 ppm dose level, water consumption in F1 dams was marginally diminished during lactation (about 9%).The amount of test substance consumed by parental animals (mg/kg bwt/day) was calculated for the periods of premating, gestation, and lactation. The results are shown in Tables 1 and 2.REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)The fertility of F0 parental males was not adversely influenced by the administration of tetrahydrofuran in the drinking water. In F0 parental females, reproduction and delivery data were not adversely affected by administration of tetrahydrofuran in the drinking water.The fertility of F1 parental males was not adversely influenced by the administration of tetrahydrofuran in the drinking water. In F1 parental females, reproduction and delivery data were not adversely affected by administration of tetrahydrofuran in the drinking water. Although the mean number of delivered pups/dam was lowest at the 9,000 ppm dose level, the result was without statistical significance but was outside of the range of historical control values. It was considered to be spontaneous in nature both because no such findings appeared in the F0 generation n the current study or in a preceding range-finding study with concentrations employed up to 12,000 ppm.Summary of Parental (F0) Reproductive Indices for control and dosed groups:Male Mating Index (%): 100;100;96;100Male Fertility Index (%): 96;88;92;92Female Mating Index (%): 100;100;96;100Gestation Index (%): 100;100;100;100Pups Delivered (mean): 13.0;12.4;13.3;14.4Liveborn Index (%): 98;98;98;98Summary of Parental (F1) Reproductive Indices for control and dosed groups:Male Mating Index (%): 100;100;100;100Male Fertility Index (%): 96;92;96;92Female Mating Index (%): 100;100;100;100Gestation Index (%): 100;100;100;100Pups Delivered (mean): 12.4;13.0;12.9;10.4Liveborn Index (%): 98;93;94;97ORGAN WEIGHTS (PARENTAL ANIMALS)At the highest dose level, statistically significantly increased absolute and/or relative kidney weights were recorded in both sexes in F0 parental animals. There were no other relevant organ weight effects noted in any other parental animals.GROSS PATHOLOGY (PARENTAL ANIMALS)There were no substance-related gross pathological findings noted in F0 or F1 parental animals.HISTOPATHOLOGY (PARENTAL ANIMALS)There were no substance-related histopathological findings noted in F0 or F1 parental animals.

Effect levels (P0)

open allclose all
Dose descriptor:
NOAEL
Effect level:
9 000 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No significant adverse effects on reproductive parameters.
Remarks on result:
other: Generation: F0 and F1 parental (migrated information)
Dose descriptor:
NOAEL
Effect level:
3 000 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see 'Remark'
Remarks on result:
other: Generation: F0 and F1 parental and F1 and F2 litters (migrated information)

Results: F1 generation

General toxicity (F1)

Clinical signs:
effects observed, treatment-related
Mortality / viability:
mortality observed, treatment-related
Body weight and weight changes:
effects observed, treatment-related
Sexual maturation:
effects observed, treatment-related
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Histopathological findings:
not examined

Details on results (F1)

VIABILITY (OFFSPRING)There were no deaths attributed to test compound administration in F1 or F2 pups.F1 Litter Viability Indices for control and dosed animals (%): 97;97;94;96F2 LItter Viability Indices for control and dosed animals (%): 96;82**;93;94**The reduced viability for the lowest dosed group (1000 ppm) was due to 2 animals (331 and 337). All pups from these dams died before schedule or were cannibalized. This effect was not considered compound related as the 2 higher dose levels were similar to control values and were well within historical control ranges.CLINICAL SIGNS (OFFSPRING)There were no significant adverse clinical effects reported in F1 or F2 pups. BODY WEIGHT (OFFSPRING)In F1 pups at the 9,000 ppm dose level, statistically significantly lower body weights (about 8% lower than concurrent controls) from day 7 post-partum until 21 were recorded and reduced weight gains from day 4 post-partum up until weaning.In F2 pups at the highest dose level, statistically significantly reduced body weight gains were reported between days 7 - 14 and 4 - 21 post-partum (approx. 7% lower than concurrent controls); this resulted in marginally (about 5%) lower mean pup body weights on day 21 post-partum.LACTATION INDEXThere were no substantial differences in the lactation indices for either F1 or F2 offspring.Summary for Control and dosed F1/F2 Offspring:Lactation Index F1 (%): 100;95;99;99Lactation Index F2 (%): 99;97;98;100SEX RATIOSThere were no substantial differences in the sex ratios of live F1 pups on the day of birth or on day 21 pp.For Control and dosed animals (F1 litter):Day 0, live males (%): 54.8;43.1;53.8;50.5Day 0, live females (%): 45.2;56.9;46.2;49.5Day 21, live males (%): 52.9;46.7;52.0;51.1Day 21, live female (%): 47.1;53.3;48.0;48.9For Control and dosed animals (F2 litter):Day 0, live males (%): 54.1;54.1;51.6;52.6Day 0, live females (%): 45.9;45.9;48.4;47.4Day 21, live males (%): 50.3;50.7;51.4;48.2Day 21, live female (%): 49.7;49.3;48.6;51.8SEXUAL MATURATION (OFFSPRING)In F2 pups there were slight but statistically significantly lower numbers with delayed auditory canal opening and eye openings. The value for auditory canal openings was within historical control ranges but delayed eye openings were considered possibly compound-related. There were no other biologically relevant differences recorded.For Control and dosed groups:F2 Pups reaching criteria, auditory canal opening (%): 96.4;100.0;88.9*;98.9 (per litter - mean)F2 Pups reaching criteria, eye opening (%): 89.9;98.7;94.0;79.2* (per litter - mean)*Wilcoxon test (one-sided), p <= 0.05GROSS PATHOLOGY (OFFSPRING)At necropsy, the minimal findings that were recorded were present in very few animals and were also present in either concurrent controls or had been observed previously in historical control animals.OTHER FINDINGS (OFFSPRING)No remarkable differences were recorded between groups in any of the behavioral tests that were conducted on pups up to weaning.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
other: F1 and F2
Effect level:
3 000 ppm (nominal)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: see remarks
Remarks on result:
other: Generation: F0 and F1 parental and F1 and F2 litters (migrated information)
Remarks:
Signs of general toxicity in parental animals as adverse effects on food and water consumption and on body weight and body weight gains. Progeny of high-dose parents displayed impaired body weight/body weight gains and delays in physiological development of the F2 offspring.

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Table 1:

Mean Test Substance Intake F0 Parental Animals (mg/kg bwt/day)

1,000 ppm

3,000 ppm

9,000 ppm

F0 males

91.3

268.1

714.4

F0 females - premating

104.1

301.2

742.2

- gestation

103.5

288.1

790.0

- lactation

165.6

477.6

1365.4

Table 2:

Mean Test Substance Intake F1 Parental Animals (mg/kg bwt/day)

1,000 ppm

3,00 ppm

9,000 ppm

F1 males

97.7

293.2

787.7

F1 females - premating

124.8

350.4

882.4

- gestation

106.5

317.7

792.3

- lactation

151.7

454.8

1164.8

Applicant's summary and conclusion

Conclusions:
Clear signs of general toxicity were noted at the highest dose level (9,000 ppm). Statistically significantly reduced water intake (27% less in comparison with concurrent controls) occurred in F0 and F1 parents throughout the different study phases. Reductions in water consumption may account, in part, for reduced food consumption and body weight/body weight gains. Slight but sometimes statistically significant reductions in water consumption were also seen in the 3,000 ppm F0 parental animals and F1 dams during lactation. Since there were no other significant effects noted at the 3,000 ppm dose level, the minimal water intake reductions are most likely due to an aversion to the test chemical (lack of palatability). Statistically significant reductions in food consumption occurred in high dose F0 female and F1 males and females during premating, gestation and/or lactation periods. Body weights of the high dose F0 parental rats were statistically significantly reduced during the first premating weeks, in the F0 females during gestation and lactation of F1 litters and in F1 males throughout the study period.There was no indication that administration of tetrahydrofuran caused adverse effects on the reproductive parameters of the parental animals from any groups. The only developmental toxicity noted consisted of statistically significantly reduced body weight/body weight gains in the F1 and F2 male and female pups at the 9,000 ppm dose level. In the F2 pups, this was associated with an increased number of pups with developmental delays including, most significantly, eye openings.The lower mean number of high dose F2 pups delivered by F1 parental females was due primarily to 3 dams and although outside of the historical control range, this effect was considered spontaneous in nature due to a lack of such effect in the F0 generation and the lack of reduced litter sizes in a preceding range finding study at concentrations as high as 12,000 ppm.Mean absolute and/or relative kidney weights of the males and females of the highest dose group of the F0 parental animals were significantly increased. Although treatment-related, these increases in kidney weights did not correlate with any morphological abnormalities. As a result of gross and histopathological examinations, there were no indications that treatment with tetrahydrofuran caused any adverse effects on the reproductive organs of parental animals.
Executive summary:

Tetrahydrofuran was administered to Wistar rats over two generations at concentrations in the drinking water of 1000, 3000 and 9000 ppm. This resulted in mean doses of the test chemical of 104, 305 and 782 mg/kg bwt/day, respectively. Clear clinical signs of general toxicity occurred at the highest dose with significantly reduced water intake (27% less compared to controls) and impaired food consumption that may have been related at least partially to reduced water intake. Slight but sometimes statistically significant reductions in water intake were also seen in the 3000 ppm dosed animals (both sexes). Body weights of the F0 parental rats were statistically significantly reduced during the first premating weeks, in F0 females during gestation and lactation, and in F1 males throughout the study period. Slight impairments in body weight gain were only observed in high dose F1 males.

There were no indications from clinical examinations that tetrahydrofuran administration caused any adverse effects on reproductive parameters of the parental animals. The reduced mean number of F2 pups delivered by F1 dams at the highest dose, although lower than control or the historical control range, was considered spontaneous in nature and not compound related. Statistically significant impairments in body weight/body weight gains were observed in F1 and F2 pups. The only signs of developmental toxicity were noted in F2 pups and consisted of delayed auditory canal opening and eye opening.

Mean absolute and/or relative kidney weights of the males and females in the high dose group were significantly increased. These increases were considered treatment related although no morphological correlates were detected to account for the increases. No gross or microscopic lesions were noted in either male or female rats of the F0 or F1 generation parental animals.

There were no indications from organ weight determinations and gross and histopathological examinations that tetrahydrofuran induced any adverse effects on the reproductive organs of the parental animals.