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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:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Guideline study. Minor restriction: no paired-fed control (similar food and water consumption than the high dose group); no historical clinical chemistry data presented (see BUN value). Phenol is a major component of the reaction mass so that phenol hazard data are applied in the hazard assessment.

Data source

Referenceopen allclose all

Reference Type:
publication
Title:
Two-generation reproduction study and immunotoxicity screen in rats dosed with phenol via the drinking water
Author:
Ryan BM, Selby R, Gingell R, Waechter JM, Butala JH, Dimond SS, Dun BJ, House R, Morissey R
Year:
2001
Bibliographic source:
Int J Toxicol 20: 121-142
Reference Type:
study report
Title:
Unnamed
Year:
1999
Report date:
1999

Materials and methods

Test guideline
Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 416 (Two-Generation Reproduction Toxicity Study)
Deviations:
no
GLP compliance:
yes
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Purity: 100% phenol
- white solid
- Lot number 112796; batch number 102596
- Source: Harrell Industries, Rock HilI, SC, USA
- received and stored in amber glass bottles blanketed with nitrogen to minimize oxidation/degradation of phenol

Chemical analysis confirmed the stability of the phenol in drinking water for at least 14 days (data not shown).
No further data.

Test animals

Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
Source: Taconic Fauns, Germantown, NY, USA
Acclimatisation: rats were 4 weeks old when received; quarantined for 12 days and then examined for suitability (6 weeks-old at initiation); prior to mating, all rats were housed singly in stainless steel wire mesh cages; during mating, animals were housed in polycarbonate eages and after mating, males were returned to their home cages, whereas females and their litters remained in polycarbonate cages during gestation and lactation; weanlings were moved to stainless steel cages.
Conditions:
- temperature 20° to 25°C
- 30 to 70% relative humidity
- Lights cycled 12hours on and 12 hours off
- animals received Purina Certified Rodent Meal #5002 (PMI Feeds Inc., St. Louis) tap water or phenol formulated in tap water ad libitum.

Use of animals in this study was in accordance with all applicable animal welfare guidelines and regulations (USDA; CFR 91A; NRC, 1996).

Administration / exposure

Route of administration:
oral: drinking water
Vehicle:
other: tap water
Details on exposure:
Rats exposed to phenol formulated in tap water; formulations were prepared weekly at 0, 200, 1000, and 5000 ppm.
During this study, the daily intake of phenol in adult rats was calculated to be 0, 14, 70, and 310 mg/kg bw/day for males and 0, 20, 93, and 350 mg/kg bw/day for females in both generations.
Details on mating procedure:
Parental (P1) rats randomly assigned to 4 groups of 30 rats per sex per group (0, 200, 1000, or 5000 ppm); exposed to phenol via drinking water for 10 weeks prior to mating, during the 2-week mating period, through gestation, lactation, and until sacrifice. Doses were based on a reproductive pilot study (exposure included 4 weeks prior to mating, mating, gestation, lactation, and 3 weeks post weaning) in which decreased drinking water, food consurnption, and body weight gain were observed at 5000 and 7500 ppm (data not shown).
Treatment of the first generation (F1) of P1 rats began at approximately 6 weeks of age. P1 rats from the same dose level were mated one male with one female at approximately 10 weeks of age. Daily vaginal lavage specimens were taken from each female 3 weeks prior to mating to ensure and evaluate cyclicity, and during mating until a sperm-positive smear (gestation day 0) was detected. The target number of rats was 25 sperm-positive dams/group to produce the first generation (F1). Females were allowed a natural parturition. On parturition (postnatal day 0), the pups were counted, sexed, and examined grossly for morphological anomalies.
On postnatal day 4, the first generation (F1) litters were culled to four per sex per litter. Pups were weaned on postnatal day 22, and selected F1 animals (at least one per sex per litter) were single-housed and administered the same concentration of phenol in water (as P1) for 11 weeks prior to mating. F1 adults were then paired one male and one female from the same dose group for mating (sibling matings avoided).
Administration of the appropriate drinking water formulation was continued through mating, gestation, lactation, weaning, and until sacrifice. Second generation (F2) litters were culled to four pups per sex per litter on postnatal day 4. The F2 generation was not intentionally exposed to the test substance in the drinking water.
All F2 pups and F1sires and dams were sacrificed after weaning.
When the P1 males were no longer needed for mating, 10 P1 males/group were randomly assigned to undergo clinical pathology (haematology and clinical chemistry) evaluation and immunotoxicity screening. In addition, five extra male rats, which were not assigned to study groups, were randomly selected as positive controls for the immunotoxicity screening (treatment see method immunotoxicity).
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
formulations prepared weekly at 0, 200, 1000, and 5000 ppm. Confirmation of the concentration of phenol in the drinking water as well as stability analyzed using reverse-phase high performance liquid chromatography (HPLC) with ultraviolet (UV) detection at weeks 1, 3, 5, 7 and every other month thereafter. SampIes
were considered to be within an acceptable range if they were within 3% of the target concentrations.
Results: Analyses of samples (all three dose levels) prepared during weeks 1, 3, 4, 7, 15, 24, and 33 showed that the mean concentrations in the tape water supplied to the animals was within 1.5% of the target levels. No phenol was detected in any control drinking water.
Duration of treatment / exposure:
P1: 10 weeks prior to mating, during the 2-week mating period, through gestation, lactation, and until sacrifice
F1: after weaning, 11 weeks prior to mating; continued through mating, gestation, lactation, weaning, and until sacrifice
F2: no exposure via drinking water
Frequency of treatment:
daily ad libitum (drinking water)
Details on study schedule:
See details on mating procedure.
Doses / concentrationsopen allclose all
Remarks:
Doses / Concentrations:
0, 200, 1000, and 5000 ppm
Basis:
analytical conc.
Remarks:
Doses / Concentrations:
0, 15, 71, and 300 mg/kg bw/day
Basis:
other: calculated for P1 males at exposure week 10
Remarks:
Doses / Concentrations:
0, 20, 93, and 320 mg/kg bw/day
Basis:
other: calculated for P1 females at exposure week 10
Remarks:
Doses / Concentrations:
0, 13, 70, and 320 mg/kg bw/day
Basis:
other: calculated for F1 males at exposure week 10
Remarks:
Doses / Concentrations:
0, 21, 94 and 380 mg/kg bw/day
Basis:
other: calculated for F1 females at exposure week 10
No. of animals per sex per dose:
n = 30 rats/sex/group
Control animals:
yes, concurrent vehicle
Details on study design:
See details on mating procedure
Positive control:
Yes, but only for immunotoxicity.

Examinations

Parental animals: Observations and examinations:
All rats were examined at least once each day for clinical signs and mortality. During gestation, dams were examined twice each day for evidence of parturition. Each rat also received a weekly hand-held clinical observation, which was recorded by electronic data capture using LABCAT.

Body Weight, and Food and Water Consumption
Water and food consumption for all rats was measured weekly prior to mating (not during cohabitation). After mating, water and food consumption of male rats was measured weekly, whereas for females it was measured on gestation days 0, 7, 14, and 20, and on postnatal days 0, 4, 7, 14, and 21.
All animals were weighed weekly prior to mating. After mating, males were weighed weekly until sacrifice. Dams were weighed on gestation days 0, 7, 14, and 20, and dams and pups were weighed on postnatal days 0, 4, 7, 14, and 21. The average pup weight was calculated per litter and per group. Body weight gains were calculated for all animals, except pups during lactation. All P1 and weaned F1 body weights, water and food consumption data were collected, while body weight gains and consumption values were ca1culated using LABCAT. In addition, body weights were recorded on the day of observed vaginal patency and preputial separation in the F1 generation.

After mating, 10 P1 males/group were randomly assigned to undergo clinical chemistry and haematology evaluation and immunotoxicity screening (see below). Blood samples were collected from retro-orbital plexus after 13 weeks of treatment.
Serum chemistry parameters: albumin, globulin, albumin/globulin ratio, total protein, blood urea nitrogen, glucose, alkaline phosphatase, total bilirubin, aspartate aminotransferase, alanine aminotransferase, chloride, calcium, phosphorus, sodium, potassium, creatinine, cholesterol, and triglycerides.
Haematological parameters: hematocrit, hemoglobin, total erythrocyte count, total leukocyte count, differential leukocyte count (percent and absolute), mean corpuscular volume, mean corpuscular hemoglobin concentration, mean corpuscular hemoglobin, red cell morphology and platelet count.
Oestrous cyclicity (parental animals):
Vaginal lavage evaluated from all females (P1 and F1) for 3 weeks prior to mating to evaluate cyclicity. Evaluations of vaginal cytology continued through mating until the presence of sperm or a vaginal plug was observed. In addition, stage of the estrus cycle for each female determined at termination.
Sperm parameters (parental animals):
After the mating phase of the study, the right testis and epididymis of at least 20 males per group in the P1 and F1 generations removed and weighed. Sperm motility determined in two pinhead-sized samples of sperm from the right caudal epididymis.
After the motility evaluation, caudal epididymis weighed and then macerated in phosphate-buffered saline and this preparation was used for sperm count analyses (all groups) and sperm morphology evaluation.
Litter observations:
Litter size, viability and body weight determined; gross external appearance of each pup was evaluated on the day of birth.
Postmortem examinations (parental animals):
At least 20 rats per sex per group in P1 and F1 subjected to necropsy, which included examination.
The following organs were weighed at necropsy: uterus, ovaries with oviducts, testes, epididymides (left, total, and left caudal), prostate, brain, liver, kidneys, adrenals, spleen, thymus, and seminal vesicles.
The following tissues were collected from at least 20 P1 and F1 rats of each dose group at necropsy: vagina, uterus, ovaries with oviducts, cervix, stornach, pituitary, testes, epididymides (left, total, and left caudal), prostate, brain, liver, kidneys, adrenal, spleen, thymus, and seminal vesicles with coagulating glands. In addition, any gross lesions noted at necropsy were collected. All tissues fixed in 10% buffered formalin except testes, which were fixed in Bouin's solution.
Histopathology
The vagina, uterus, ovaries and oviducts, cervix, testes, prostate, and seminal vesicles of 20 randomly selected rats, in the control and high-dose groups from each generation, were examined using light microscopy by a veterinary pathologist as well as spleen, thymus, liver, and kidneys from 10 randomly selected rats/sex in the control and high-dose groups of both generations.
Postmortem examinations (offspring):
F2 rats and culled pups were euthanized and discarded without necropsy.
Statistics:
All data were evaluated by analysis of variance (ANOVA; a = 0.05) followed, where appropriate, by Dunnett's test (cx =0.05), except mating indices (e.g., percent mated) which were analyzed by chi-square or Fisher Exact test.
Reproductive indices:
See results
Offspring viability indices:
See results

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
effects observed, treatment-related
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:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Details on results (P0)

Clinical Observations and Mortality
Three parental male rats (one control and two high-dose rats) died during the study; their deaths were not considered treatment-related. Shortly after weaning, three high-dose pups (F1 generation) died; these deaths appeared to be associated with absence of acclimatization (flavour aversion) to the test substance in the drinking water. Later, three F1 dams (one each in control, low- and high-dose groups) died spontaneously; these deaths were not considered to be treatment-related.
The most prominent clinical signs consisted of discolored or wet inguinal fur and redness around the nose or eyes. These signs were noted in all groups; however, the incidence was higher in the phenol-treated rats (particularly redness around nose fur and discolored or wet inguinal fur in the F1 weanlings). In addition, twitching was observed in one F1 high-dose male rat on one occasion.

Water consumption
Daily water consumption was significantly decreased throughout the study in the high-dose group males and females. This decrease was attributed to an aversion to the flavour of phenol in the drinking water.

Food consumption
Daily food consumption in the high-dose group was significantly decreased in the P1 generation at the onset of treatment and during the lactation phase of the study (P1 females).

Body weight
Decreases in body weight were detected in high-dose rats throughout the study. These decreases reached statistical significance as compared to control body weights beginning on week 4 of the study for males and as early as week 1 for females. Body weight gain was significantly decreased at 5000 ppm following the fIrst week of treatment. After week 1, body weight gains approached control values, and remained similar to controls from week 2 until the end of the premating phase. But the initial impact resulted in a significant decrease in total body weight gain at the end of the 10-week premating period as weIl as a significant reduction in
absolute body weight throughout the study.
During gestation, maternal body weight gain was similar across all groups on gestation days 7 and 14. But by gestation day 20, a significant decrease in body weight gain was observed in the high-dose dams. Throughout both gestation and lactation the mean maternal body weight was significantly lower in the animals receiving 5000 ppm.

Reproductive performance (see Table below)
There were no significant differences among groups in reproductive performance in P1 and F1 generation:
- The average length of gestation across all groups was approximately 22 to 22.5 days.
- The number and percent of animals, which mated, and the percent undergoing successful parturition were similar across all groups.

Immunotoxicity Screening,
No significant effects were detected in spleen weight, cellularity (cells/spleen), or antibody-forming cells (AFC) (per spleen or per 10E6 cells) for any phenol-treated group. As expected, there was a significant reduction of AFC activity, spleen cellularity, and spleen weight in the positive control rats compared to the vehicle controls.

Haematology and Clinical Chemistry
Parameters were unaffected by phenol treatment, except for a minimal, but statistically significant, increase in blood urea nitrogen (BUN) in the high-dose group following 13 weeks of treatment (mean BUN values were 14 +- 2.3 for the control group and 18 +- 2.4 for the high-dose group).

Gross Pathology
No effects were reported in the result section.

Organ Weights
Significant decreases in absolute seminal vesicle weights were detected in the P1 high-dose males, and decreases in absolute adrenal, brain, spleen and ovary weights were noted in the P1 high-dose females. Organ-to-body weight ratios (relative organ weights) for the brain, kidneys, liver, testes, epididymides, and right testis parenchyma were significantly increased in the high-dose group males; these were ascribed to significantly lower final body weights. Relative weights of the brain and liver were significantly increased in the high-dose group P1 females, again a result of the significantlY lower final body weights.
Various absolute organ weights were reduced in the high-dose group of the F1 generation (males: adrenals, brain, liver, seminal vesicles, spleen, testes, epididymides, right testis parenchyma, and prostate; females: spleen and uterus). In addition, the absolute adrenal, spleen, and prostate weights of the mid-dose F1 males were slightly decreased, whereas mid-dose females absolute liver weights were increased. Relative organ weights were increased in the high dose group (F1 males: brain, kidneys, epididymides, testes, right cauda, and right testes parenchyma; F1 females: brain, kidneys, and liver). Again, the increased organ-to-body weight ratios were ascribed to the reduced final body weight.
Significant decreases in absolute prostate weight (reduced by approximately 15%) were noted in all three phenol-treated groups in the F1 generation, but not the P1 generation. However, relative prostate weights were significantly reduced in only at 1000 ppm. Significant reductions in both absolute and relative uterine weights were noted in all three phenol-treated groups in the F1 generation, but not the P1 generation.

Histopathology
Microscopic examination of the reproductive organs (including accessory sex organs) failed to show any adverse treatment-related lesions in P1 & F1. Histological examination of the uterus (control and high-dose groups in the F1 generation) did reveal an increased incidence of uterine dilatation in the control group (7/20) compared to the high-dose group (2/20). The decreased incidence of uterine dilatation in the high-dose group may partially explain the significant reductions in absolute and relative uterine weights seen in the phenol treated groups; vaginal cytology of rats with uterine dilatation indicated that the stage of the estrus cycle prior to necropsy was either proestrus or estrus. Based on vaginal cytology data collected just prior to necropsy, the number of F1 rats in proestrus/estrus was similar in three of the groups (16/24 controls, 15/24 low, 13/25 mid), but was lowest in the high-dose group (9/22). No treatment-related lesions were detected in any ofthe other organs examined (kidneys, spleen, liver, and thymus) in the P1 or F1 generations.


Vaginal Cytology and Sperm Evaluations
The average frequency of the estrus cycle during the 21-day collection period ranged from 3.8 to 4.7 days and was similar in all groups for both generations.
Epididymal sperm count, motility (percent motile and percent progressively motile) and sperm morphology across both generations were also unaffected. Testicular sperm count and production rate were unaffected in the P1 generation; however, statistically significant increases in testicular sperm count and production rate (both parameters were adjusted for organ weight) were noted at 5000 ppm in F1. These increases were presumed to be associated with the reduced absolute testis weight, which was secondary to reduced body weight and therefore artifactual. The testicular count was extended to the mid-dose group and no difference in testicular count was noted in the mid-dose group; therefore, the observed change in the high-dose group was ascribed to lower testis weight rather than to a true alteration in sperm count or sperm production.

Effect levels (P0)

Dose descriptor:
NOAEL
Effect level:
1 000 mg/L drinking water
Sex:
male/female
Basis for effect level:
other: corresponding to 71 mg/kg bw/day in P1 males and 93 mg/kg bw/day in P1 females at exposure week 10

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:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings:
no effects observed

Details on results (F1)

Offspring viability in F1 and F2
No effects were found in low and mid dose group. The average number of live births per litter and percent of offspring alive on postnatal day 0 was similar for all groups and across both generations (F1 & F2) including the high dose group.
5000 ppm: following postnatal day 0 the survival of the offspring was adversely affected in both generations. The percent of F1 high-dose group surviving was significantly reduced on postnatal day 4 . After culling, the percent survival was similar across all groups. The percent survival was similarly affected in the F2 generation; however, survival in the high-dose group remained affected after culling and was reduced on postnatal days 7 to 21. The decreased survival of offspring was likely linked to the overt maternal toxicity that occurred at 5000 ppm, as indicated by the decreased maternal body weight and water consumption.

EFFECTS IN F1
Clinical observations see above as well as other parameters in F1 adult rats.

Phenol intake
was higher in weanlings (F1: 0, 32, 171, 860 mg/kg bw/day in males and 0, 35, 172, 824 mg/kg bw/day in females at week 1 of exposure) compared to the average intake of adult animals (see above).

Preweaning Body Weight, Water and Food Consumption
F1 offspring body weight was slightly reduced (5%) in the 5000-ppm group as compared to controls beginning on day 0; the difference in body weight between these groups became later more pronounced (up to 15%-20% on postnatal days 4-14 and 30% on postnatal day 21). The decrease in F1 body weights at 5000 ppm occurred concomittantly with overt maternal toxicity (substantially decreased maternal body weight). This lower maternal body weight in the high dose group contributed to the lower F1 birth weights.
The deerease in maternal/litter food and water consumption during lactation at 5000 ppm was likely due (in part) to a decrease in consumption by the offspring. Flavor aversion to phenol was a factor in the larger decrease observed in F1 body weight at the high-dose group between days 7 and 21, because the offspring begin drinking water between days 7 and 14 (generally around day 10).
No differences in postnatal F1 body weights were detected in the low- and mid-dose groups.

Postweaning Food Consumption, Body Weight, and Body Weight Gain
Similar to the parental generation (P1), the daily water consumption of the F1 generation was decreased throughout the study at 5000 ppm.
Daily food consumption in the high-dose group was also reduced during the study, particularly at the onset of treatment; however, food consumption was unaffected during gestation and lactation for the F1 females.
Concomittant with the decreases in water and food consumption decreases in body weights were observed in the high dose F1 throughout the study (F1 body weights decreased prior to weaning and throughout postweaning, including gestation and lactation). Body weight gain was significantly decreased at 5000 ppm following the first week of treatment; however, it approached control values after week 3 in males and week 1 in females. Although body weight gain approached controls
values, total gain in males was significantly decreased at the end of the premating phase, whereas in females it was only reduced during gestation.

Developmental Landmarks
The average time to preputial separation for F1 males was significantly longer in the high-dose group (47.8 days) than control group (44 days). Vaginal patency in the F1 high-dose female rats occurred significantly later than in the control females (38.3 and 34.6 days, respectively).

EFFECTS IN F2

Preweaning Body Weight
The preweaning growth pattern of the F2 generation was similar to the F1 generation. F2 offspring body weight was slightly reduced at 5000 ppm on postnatal day 0 (7%); this decrease persisted through postnatal day 21 and increased over time (up to 20%-28% on postnatal days 4-21). Again, decreased maternal body weight in F1 dams and flavour aversion to phenol in the drinking water were likely significant factors.

Effect levels (F1)

Dose descriptor:
NOAEL
Generation:
F1
Effect level:
1 000 mg/L drinking water
Sex:
male/female
Basis for effect level:
other: corresponding to 70 mg/kg bw/day in F1 males and 94 mg/kg bw/day in F1 females at exposure week 10

Results: F2 generation

Effect levels (F2)

Dose descriptor:
NOAEL
Generation:
F2
Effect level:
1 000 mg/L drinking water
Sex:
male/female

Overall reproductive toxicity

Reproductive effects observed:
not specified

Any other information on results incl. tables

Table on reproductive performance and litter survival

Parameter

Control

200 ppm

1000 ppm

5000 ppm

-

P1 generation

Number of breeding pairs

30

30

30

30

Number of sperm positive

29

30

29

29

Number of successful

parturitions

27

28

27

27

Number of litters

27

28

27

27

Total offspring born

11.2+-2.3

11.5+-3.0

12.3+-2.5

11.0+-2.6

Total born alive, day 0

11.0+-2.2

11.3+-3.1

12.1+-2.4

10.6+-2.5

Percent live, day 0

98

96

99

97

Percent live, day 4

99

97

99

90*

Percent live, days 7-21

100

100

100

96

-

F1 generation

Number of breeding pairs

25

25

25

23

Number of sperm positive

25

24

25

23

Number of successful

parturitions

21

22

23

20

Number of litters

21

22

23

20

Total offspring born

10.8 +-2.3

12.0 +-3.1

11.7 +-3.4

11.3 +-1.6

Total born alive, day 0

10.7 +-2.5

11.6 +-3.0

11.3 +-3.3

11.2 +-1.8

Percent live, day 0

98

98

97

98

Percent live, day 4

93

93

93

67*

Percent live, days 7-21

98

94

96

74*

*: significant (p=0.05)

Applicant's summary and conclusion

Conclusions:
Reported effects in this 2 generation reproduction toxicity study were considered secondary to water avoidance due to an flavour aversion to phenol. The NOAEL of phenol in drinking water is 1000 mg/l (70 mg/kg bw/day for males and 93 mg/kg bw/day for females).
Executive summary:

This is a guideline study with minor restrictions.

Phenol was investigated for effects on reproductive performance and fertility in a valid two generation reproductive toxicity study in Sprague-Dawley rats. P1 and F1 rats were exposed via the drinking water to 0, 200, 1000, 5000 mg/l (calculated to be 0, 14, 70, and 310 mg/kg bw/day for males and 0, 20, 93, and 350 mg/kg bw/day for females in both generations). At the high dose level

decreased body weight/body weight gain, decreased water and food consumption, reduced litter survival, decreased offspring body weight/growth delay, increased organ to body weight ratios, and delayed sexual maturation was detected. These effects were considered secondary to water avoidance due to an flavour aversion to phenol. However, no impairment of reproductive capability and fertility was revealed for both sexes. No effects were found on immunological parameters, in haematology and in clinical chemistry studied in male P1 rats after 13 weeks of exposure.

Conclusion: Reported effects in this 2 generation reproduction toxicity study were considered secondary to water avoidance due to an flavour aversion to phenol. The NOAEL of phenol in drinking water is 1000 mg/l (70 mg/kg bw/day for males and 93 mg/kg bw/day for females).