Hydroquinone

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records

Reference

Reference 1

Endpoint:

two-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

25.02.1988 - 29.11.1988

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EPA OTS 798.4700 (Reproduction and Fertility Effects)

Deviations:

no

GLP compliance:

yes

Species:

rat

Strain:

other: CD Sprague-Dawley

Sex:

male/female

Details on test animals or test system and environmental conditions:

Age at receipt: 28 d
Acclimation period (P0): 14 d
Age at initiation of treatment (P0): 42 d
Age at initiation of mating (P0): 112 d
Temperature (°C): 14 - 27
Humidity (%): 40 - 88
Photoperiod (hrs dark / hrs light): 12 / 12
Sprague-Dawley rats (Charles River CD strain, Charles River Laboratories, Inc., Portage, MI) were assigned randomly to groups (30 rats/sex/group) 1 week prior to initiation of treatment. These animals were designated as FO parents.
All animals were individually housed during the study except during mating (1 male and 1 female/cage) and lactation (dam and litter/cage).
Tap water and Purina certified rodent chow, No. 5002, were provided ad lib.

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

Applied volume dose: 5 mL/kg

Details on mating procedure:

P0 and P1 parents were dosed for at least 70 days prior to mating, throughout the mating and lactation periods, and until scheduled euthanasia. Body weights and feed consumption of parental animals were measured at approximately weekly intervals throughout the study. At mating, one male and one female within the same treatment group were housed together nightly until evidence of mating (presence of copulatory plug or sperm in a vaginal smear) was observed. If after 7 days no evidence of mating was noted, the female was reassigned to another male within the group for a second 7 day period. The day on which evidence of mating was observed was considered to be day 0 of gestation. Females were allowed to litter, and day 0 of lactation was the day on which all pups in a litter were delivered.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Dosing solutions were analyzed by HPLC.
Dosing solutions were prepared daily by weighing an appropriate amount of HQ into amber glass jars and then adding degassed distilled water immediately prior to dosing. Analytical verification, performed periodically during the study, demonstrated that the dosing solutions were stable throughout the dosing period and averaged 99.4, 101, and 100 % of target concentrations for the low, mid, and high doses, respectively.

Duration of treatment / exposure:

P0: 10-week premating period and daily treatment during the ensuing mating period. Males continued to be treated daily until sacrifice, while mated females continued to be treated daily during ensuing gestation and laction periods until sacrificed.
P1: 11-week premating period and throughout the ensuing mating, gestation and lactation period until sacrificed.
Study was terminated at day 278

Frequency of treatment:

Dosing once daily on 7 d per w

Details on study schedule:

F1 and F2 litters were evaluated for number of pups (live and dead) and sex of each pup, pup weights, and gross external abnormalities on Days 0, 4, 7, 14, and 21 of lactation. On Day 4 of lactation, litters were culled to 8 pups/litter, if necessary, with sex distribution equalized as close as possible (4 pups/sex/litter). At weaning of the F1 litters on Day 24 of lactation, at least 1 pup/sex/litter was chosen, if possible, for the F1 parental generation which would be used to produce the F2 generation (30 animals/sex/group). Treatment of the animals selected for F1 parents was initiated at 25 days of age. During mating of the P1 animals, care was taken to avoid brother-sister matings.

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

15 mg/kg bw/day (nominal)

Dose / conc.:

50 mg/kg bw/day (nominal)

Dose / conc.:

150 mg/kg bw/day (nominal)

No. of animals per sex per dose:

30 m / 30 f

Control animals:

yes, concurrent vehicle

Details on study design:

Dose selection rationale:
Doses of 15, 50, and 150 mg/kg/d were selected based upon previous studies which suggested the high dose would produce modest parental toxicity and the low dose would be a NOEL for all effects. The high dose was selected based upon overt toxicity (tremors, convulsions, mortality) observed at 300 mg/kg/d (oral dosing in 5 days per week) in male rats in a dominant lethal study.

In this study the following parameters were examined:
Gonadal function, mating behavior, conception, parturition, lactation, weaning, growth and development of offspring

Postmortem examinations (parental animals):

P0 and P1 parents were exsanguinated under ethyl ether anesthesia. Males were euthanatized approximately 3 to 4 weeks after completion of the mating period, and females were euthanatized after weaning of the last litter. All parental animals were necropsied and the following tissues were preserved in 10 % neutral buffered formalin: for males, seminal vesicles, prostate gland, pituitary gland, and gross lesions; testes and epididymides were fixed initially in Bouin's solution for 24 – 48 hrs; for females, vagina, uterus, ovaries, pituitary gland, and gross lesions. After fixation, tissues for all P0 and P1 control and high-dose animals were embedded in paraffin, cut at 6 µm, mounted on glass slides, stained with hematoxylin and eosin, and examined by light microscopy. All gross lesions from all parental animals were processed and examined as well. Reproductive tissues for any P0 or P1 parents in the low- and mid-dose groups that failed to produce a litter were also processed and examined by light microscopy.

Postmortem examinations (offspring):

All pups culled on day 4 of lactation, F1 pups not selected as parental animals, and F2 pups were euthanatized and given a gross external and internal examination. Intact pups found dead at birth or during lactation were also given a gross external and internal examination.

Statistics:

Quantitative continuous variables were analyzed first using Bartlett's test for equal variances with a p <= 0.01 for statistical significance. Data with homogeneous variances (i.e., parametric data) were then analyzed by a one-way ANOVA using the F distribution for significance followed, when necessary (p <= 0.05), by Dunnett's test for pairwise comparisons. For data with heterogeneous variances, the Kruskal-Wallis test was used and if differences were indicated (p <= 0.05), a summed rank test (Dunn) was employed for pairwise comparisons. Trends in dose levels were also analyzed using standard regression techniques with a test for trend and lack of fit for parametric data and Jonckheere's test for nonparametric data. For pairwise comparisons and trend analyses, the probability value of p <= 0.05 was used as the criterion for statistical significance. Statistical analysis of frequency data was performed using x2 to test for goodness of fit followed by Fisher's exact test for pairwise comparisons with the significance level corrected by the Bonferroni method. Trend analysis was performed by Armitage's test for linear trend. A probability value of p <= 0.05 was used as the criterion for statistical significance.

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Mild tremors were observed in several P0 adults (m/f) at 150 mg/kg/d and in a single P0 male at 50 mg/kg/d. Tremors were exhibited infrequently and shortly after dosing. No other clinical signs of toxicity were noted in parental animals.

Mortality:

mortality observed, non-treatment-related

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

no effects observed

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Dose descriptor:

NOAEL

Remarks:

parental toxicity

Effect level:

15 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

Dose descriptor:

NOAEL

Remarks:

reproductive effects

Effect level:

150 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

Mild tremors were observed in several P1 adults (m/f) at 150 mg/kg/d.

Mortality:

mortality observed, non-treatment-related

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Trend analysis revealed a statistically significant (p <= 0.05) dose-related decrease in weight gain suggesting a possible treatment-related effect for the P1 parental males at doses >= 50 mg/kg.

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

no effects observed

Reproductive function: oestrous cycle:

not examined

Reproductive function: sperm measures:

not examined

Reproductive performance:

no effects observed

Dose descriptor:

NOAEL

Effect level:

15 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Dose descriptor:

NOAEL

Effect level:

150 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

reproductive performance

Mortality / viability:

mortality observed, non-treatment-related

Body weight and weight changes:

no effects observed

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

150 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

body weight and weight gain

other: sex ratio

Mortality / viability:

mortality observed, non-treatment-related

Body weight and weight changes:

no effects observed

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

150 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

viability

body weight and weight gain

other: sex ratio

Reproductive effects observed:

no

Evidence of slight parental toxicity (occasional occurrence of transient tremors) was observed for some P0 and P1 animals. Mild tremors were observed in several P0 and P1 adults (m/f) at 150 mg/kg/d and in a single P0 male at 50 mg/kg/d. Tremors were exhibited infrequently and shortly after dosing. No tremors were reported for control or low dose animals. No other clinical signs of toxicity were noted in parental animals. Food consumption and survival at all dose levels were comparable to control values throughout the study. No statistically significant differences in body weights were observed for P0 or P1 parental females throughout the study. Body weights for P0 males were also comparable to those of controls throughout the study. Statistically significant differences in body weights were noted for the P1 parental males at several intervals during the pre-mating, mating, and post-mating periods. P0 male mean body weight gains during pre-mating were 335, 325, 341 and 315 g at 0, 15, 50, and 150 mg/kg/d, respectively. P1 male mean body weight gains at 0, 15, 50, and 150 mg/kg/d were 377, 374, 358 and 354 g, respectively, during pre-mating and 43, 35, 42 and 39 g, respectively, during mating and post-mating periods. Trend analysis revealed a statistically significant (p <= 0.05) dose-related decrease in weight gain suggesting a possible treatment-related effect for the P1 but not the P0 parental males. Reproductive performance was not adversely affected by administration over two generations. Pregnancy rates and male fertility indices were comparable between treated and control groups for both P0 and P1 parents. For the P0 adults, two control, five low-dose, seven mid-dose, and one high-dose female(s) failed to mate with the first male and were reassigned to another male. Of these females, only two low-dose and two mid-dose failed to mate with the second male. For P1 adults, three control, eight low-dose, nine mid-dose, and eight high-dose females failed to mate with the first male and were reassigned to another male. Of these females, only one control, one low-dose, six mid-dose, and two high-dose failed to mate with the second male. In general, gestation length for control and treated females was 20 – 23 days. All females showing evidence of parturition delivered at least 1 live pup. Mean numbers of pups per litter, sex ratio, and pup viability at birth and survival through lactation were similar among all groups for F1 and F2 litters. The total number of dead pups found at birth or during the lactation period were 13, 13, 9 and 10 for F1 litters and 17, 13, 26 and 23 for F2 litters at respective doses of 0, 15, 50, and 150 mg/kg/d. Statistically significant increases in pup weights were noted for F2 pups at 15 and 50 mg/kg on postnatal day 0 (weights for these pups were comparable to those of control at subsequent time points).

Gross postmortem examination gave no treatment-related lesions in either P0 and P1 parental animals or F1 and F2 pups. Further, no microscopic lesions attributable to the treatment were found in tissues from F0 or F1 parental animals subjected to histopathologic examination.

Conclusions:

The results of this two-generation study with rats gave no indication for reproductive toxicity.

Executive summary:

In this study performed according to EPA OTS 798.4700, the effects of hydroquinone on reproductive performance and fertility in a two-generation study with CD Sprague-Dawley rats (one litter per generation) were studied. HQ was administered in an aqueous solution by gavage at doses of 0, 15, 50 and 150 mg/kg bw/d (30 m / 30 f per group). P0 and P1 parental animals were dosed daily for at least 10 weeks prior to cohabitation, during cohabitation, and until scheduled termination. At all dose levels tested, no adverse effects were observed on feed consumption, survival, or reproductive parameters for the P0 or P1 parental animals. Mild, transient tremors were observed shortly after dosing at 150 mg/kg/d in several P0 and P1 parental animals and in a single P0 male at 50 mg/kg/d. These tremors occurred infrequently and were considered to be due to an acute stimulatory effect of HQ on the nervous system. Body weights for F0 and F1 parental females were similar between all dose groups throughout the study. Body weights for P0 parental males were also comparable to those of control throughout the study. Statistically significant differences in body weights were noted for the P1 parental males in the 50 and 150 mg/kg/d dose groups at several intervals during the pre-mating, mating, and post-mating periods. No treatment-related effects on pup weight, sex distribution, or survival were noted for pups of either generation. Upon postmortem examination, no treatment-related gross lesions were observed in either the P0 or P1 parental animals or their weanlings. Histopathological examination of reproductive tissues and pituitary glands from high-dose P0 and P1 parental animals did not reveal any changes related to treatment. Thus, no adverse effects on reproduction or fertility were observed in either generation at any dose level, and the results are indicating that HQ is not a selective reproductive toxicant. The NOEL values for general and reproductive toxicity are 15 and 150 mg/kg/d, respectively.

Reference 2

Endpoint:

fertility, other

Type of information:

experimental study

Adequacy of study:

key study

Study period:

05.12.1983 - 10.02.1984

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Remarks:

Comparable to guideline study with acceptable deviation of extended exposure period. Study report with detailed documentation of test conditions and test results. No detailed information concerning GLP status.

Qualifier:

equivalent or similar to guideline

Guideline:

other: OECD Guideline 478 (Genetic Toxicology: Rodent Dominant Lethal Test) dated 1984

Deviations:

yes

Remarks:

extended exposure period of 10 w

GLP compliance:

yes

Species:

rat

Strain:

other: CRL:COBS®CD®(SD)BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
Source: Charles River Labs., Wilmington
Age at study initiation: 63 d
Weight at study initiation: 296 - 299 g
Assigned to test groups randomly: Following the acclimation period, 125 male rats were randomly assigned on the basis of body weight to three dose groups and two control groups (positive and negative) of 25 animals each
Fasting period before study: no data
Housing: 5 per cage by sex
Diet: Purina Rodent Lab Chow 5001 ad lib.
Water: tap water ad lib.
Acclimation period: 12 d

ENVIRONMENTAL CONDITIONS
Temperature (°C): 22.2 +/- 1
Humidity (%): 55 +/- 15
Air changes (per hr): no data
Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

oral: gavage

Vehicle:

water

Details on exposure:

Hydroquinone was applied as a 5 % solution in distilled water. The volume administered was adjusted weekly to compensate for body weight change. The negative control group was handled similar to the treated groups, but received a volume of distilled water by gavage equivalent to the largest volume given a treated animal. The positive control group was treated similar to the negative control group except on the last five days of treatment (days 63 - 67) they received daily i.p. injections of 1.5 mg/kg apholate (CAS 52-46-0).

Details on mating procedure:

At the evening on day 69 following the final treatment (day 67) the males were randomly assigned to individual breeding cages and paired (1:1) with an untreated virgin female (randomly assigned) for five days per week for the following two weeks. The males were rested over the weekend following the first week's mating and a new female was randomly assigned to each male for the second week's mating. Insemination was verified by daily vaginal smears and the day sperm was seen in the smear was considered day 0 of gestation. When inseminated, the female was removed from the breeding cage and housed individually until the time of caesarean section on day 14 of gestation.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

67 d

Frequency of treatment:

5 d/w

Dose / conc.:

0 mg/kg bw/day (nominal)

Dose / conc.:

30 mg/kg bw/day (nominal)

Dose / conc.:

100 mg/kg bw/day (nominal)

Dose / conc.:

300 mg/kg bw/day (nominal)

No. of animals per sex per dose:

125 male rats were randomly assigned on the basis of body weight to three dose groups and two control groups (positive and negative) of 25 animals each.

Control animals:

yes, concurrent vehicle

Details on study design:

Dose selection rationale: Based on an oral LD50 (800 mg/kg) determined prior to beginning of the study

Positive control:

The positive control group was treated similar to the negative control group except on the last five days of treatment (days 63 - 67) they received daily i.p. injections of 1.5 mg/kg apholate (CAS 52-46-0)

Parental animals: Observations and examinations:

Males:
Individual body weights of males were recorded on day 0, 4 and 7 and at least once a week thereafter. Feed consumption was measured twice per week. Each male was closely examined for clinical signs of toxicity each treatment day when handled for dosing and cage-side observations were done post-dose and at the end of the work day. Mortality checks only were done on weekends.

Females:
Caesarean section on day 14 of gestation: thoracic and abdominal viscera were exposed by a midline incision through the ventral body wall. The ovaries were removed and the corpora lutea of pregnancy were counted. The uterine horns were opened and the implantation sites were counted and categorized as early deaths (no sign of placenta or embryonic tissue), late deaths (placental tissue and/or a resorbing embryo present) or viable embryos. The thoracic and abdominal organs of the dams were examined in situ for gross pathologic changes.

Statistics:

The hydroquinone groups were compared to the negative control group. Continuous data (body weights, feed consumption, corpora lutea, implantations, etc.) were analyzed using a one-way analysis of variance (ANOVA) followed by Duncan's multiple range test when the “F” value was significant. Discrete data (early/late deaths, pre- and post-implantation loss) were subjected to Freeman-Tukey double arcsin transformations and analyzed using ANOVA. The level of significance was <= 0.05.

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:

not specified

Histopathological findings: non-neoplastic:

not specified

Other effects:

effects observed, treatment-related

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Males:
300 mg/kg: mean body weights were consistently significantly lower than the controls from the 4th week to the end of the treatment period. These animals had a mean body weight gain of < 12.2 % than the controls over the ten week period. The feed intake at this dose level was slightly less than the controls, with reduction reaching statistical significance during the first two weeks and the last four weeks of the treatment period.
<= 100 mg/kg: mean body weight response and feed consumption (also for positive controls) were comparable to the controls, except that during the last week of treatment, when the positive controls were being treated with apholate, the positive control males had a reduced feed intake and a significant body weight loss.
Clinical signs of toxicity included brown coloured urine seen on the dropping trays of all treated groups and swollen eyelids, porphyrin-like tears, sialorrhea, spastic gait, tremors, convulsions and spontaneous deaths in the 300 mg/kg group. The brown coloured urine appeared during the 1st, 2nd and 3rd week of treatment in the 300, 100 and 30 mg/kg groups, respectively and was seen in all groups during subsequent weeks of the treatment period. The intensity of the colour was dose-dependent and the discoloured urine was not seen on Monday morning (following two days of non-treatment). Swollen eyelids were noted in three high dose males; five males in the high dose group and two controls had porphyrin-like tears. Beginning during the 4th week of treatment, the majority of the 300 mg/kg males had sialorrhea which persisted throughout the rest of the study. One high dose male had a spastic gait and tremors at this time. During the fifth week of treatment, tremors varying in intensity from being perceptible only by touch to seizures with myoclonic jerks, recumbent running and a chewing reflex were seen in most of the 300 mg/kg animals. Two high dose males died. One was found dead during the middle of the ninth week and the following day another male was observed with seizures following dosing and died within 15 minutes. Two males in the 100 mg/kg group died because of accidental instillations of the test solution into the lungs during dosing. Except for the brown colour urine, no compound related clinical signs were noted in the males given 30 or 100 mg/kg.

Females (observations at caesarean section):
Doses of 30, 100 or 300 mg/kg did not affect the reproductive capacity of male rats and did not produce dominant lethality in the male. No compound related effects were seen on insemination rate, pregnancy rate, mean number of corpora lutea, implantation sites, viable implants, early and late deaths and pre- and post-implantation loss at any dose levels in both mating periods compared to the negative controls. Mean number of corpora lutea and implantations per dam were statistically greater in the 300 mg/kg group compared to the negative controls in the first mating period. However, all other parameters were normal and these changes were not seen in the second mating period and are not considered to be toxicologically significant.
Females mated to males treated with the positive control compound had a significantly reduced number of viable implantations, an increased number of early deaths and a very high post implantation loss after the first mating. When mated during the second week after treatment, pregnancy rate, number of corpora lutea, implantation sites and viable implants per female were decreased and the number of early deaths per female and the pre- and post-implantation loss were significantly increased. Thus the positive control compound produced a dominant lethal effect in the males.

Dose descriptor:

NOEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

other: all toxic effects

Dose descriptor:

NOEL

Effect level:

300 mg/kg bw/day

Based on:

other: reproductive capacity / dominant lethality

Sex:

male/female

Basis for effect level:

reproductive performance

other: dominant lethality

Remarks on result:

not measured/tested

Reproductive effects observed:

not specified

Conclusions:

Hydroquinone did not produce dominant lethality as evidenced by examination of the reproductive indices following mating to untreated virgin females during the two weeks immediately following the final treatment.

Executive summary:

In a study performed equivalent to OECD Guideline 478, groups of 25 male CRL:COBS®CD®(SD)BR rats were dosed via gavage with 0, 30, 100, or 300 mg/kg on five days per week over ten weeks. During the two weeks following the last dose, each male was mated with an untreated virgin female. Females were killed on the 14th day of gestation and the implantation sites were categorized as viable implant, early or late death. No treatment related effects were seen on insemination and pregnancy rates, pre- and post-implantation loss or the number of corpora lutea, implantation sites, viable foetuses and early or late deaths per female at either mating period.

From this study NOEL values of 100 mg/kg for all toxic effects and 300 mg/kg for reproductive capacity / dominant lethality were derived.

Effect on fertility: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

150 mg/kg bw/day

Species:

rat

Quality of whole database:

reliable studies available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Additional information

Dominant lethal assay (Krasavage, 1984):

In a study performed equivalent to OECD Guideline 478, male CRL:COBS®CD®(SD)BR rats were dosed via gavage with 0, 30, 100, or 300 mg/kg on five days per week over ten weeks. During the two weeks following the last dose, each male was mated with an untreated virgin female. Females were killed on the 14th day of gestation and the implantation sites were categorized as viable implant, early or late death. No treatment related effects were seen on insemination and pregnancy rates, pre- and post-implantation loss or the number of corpora lutea, implantation sites, viable foetuses and early or late deaths per female at either mating period.

The effect levels are as follows:

NOEL (parentals; m): 100 mg/kg bw/d based on all toxic effects such as significantly decreased mean body weights, tremors, convulsions and spontaneous deaths

NOEL (parentals; m/f): 300 mg/kg bw/d based on reproductive capacity / dominant lethality

-------------------------------------------

Two-generation study (Schroeder, 1989; Blacker et al., 1993):

In a study performed according to EPA OTS 798.4700, CD Sprague-Dawley (one litter per generation) were dosed via gavage with 0, 15, 50 and 150 mg/kg bw/d. F0 and F1 parental animals were dosed daily for at least 10 weeks prior to cohabitation, during cohabitation, and until scheduled termination. At all dose levels tested, no adverse effects were observed on feed consumption, survival, or reproductive parameters for the F0 or F1 parental animals. Mild, transient tremors were observed shortly after dosing at 150 mg/kg/d in several F0 and F1 parental animals and in a single F0 male at 50 mg/kg/d. These tremors occurred infrequently and were considered to be due to an acute stimulatory effect of hydroquinone on the nervous system. Body weights for F0 and F1 parental females were similar between all dose groups throughout the study. Body weights for F0 parental males were also comparable to those of control throughout the study. Statistically significant differences in body weights were noted for the F1 parental males in the 50 and 150 mg/kg/d dose groups at several intervals during the pre-mating, mating, and post-mating periods. No treatment-related effects on pup weight, sex distribution, or survival were noted for pups of either generation. Upon post-mortem examination, no treatment-related gross lesions were observed in either the F0 or F1 parental animals or their weanlings. Histopathological examination of reproductive tissues and pituitary glands from high-dose F0 and F1 parental animals did not reveal any changes related to treatment. Thus, no adverse effects on reproduction or fertility were observed in either generation at any dose level.

The effect levels are as follows:

NOAEL (parental toxicity; m/f): 15 mg/kg bw/d

NOAEL (reproductive effects; F1/F2; m/f): 150 mg/kg bw/d (highest dose tested)

Short description of key information:
Possible effects of hydroquinone on fertility after oral dosing were tested in two valid guideline studies with rats:
1.) Dominant lethal assay (Krasavage, 1984)
2.) Two-generation study (Schroeder, 1989; Blacker et al., 1993)

Both studies gave no indication for reproductive toxicity. For dermal or inhalation exposure there are no data available.

Justification for selection of Effect on fertility via oral route:
Information from 2 valid key studies including a 2-generation study in rats showed no evidence of effects on fertility.

Effects on developmental toxicity

Description of key information

Possible effects of hydroquinone on developmental toxicity / teratogenicity after oral dosing were tested in two valid guideline studies with rabbits and rats, respectively:
1.) Prenatal Developmental Toxicity Study with rabbits (Schroeder, 1988, 1989; Murphy et al., 1992)
2.) Prenatal Developmental Toxicity Study with rats (Krasavage, 1985, 1992).
Both studies gave no indication for a potential developmental or reproductive hazard. For dermal or inhalation exposure there are no data available.

Link to relevant study records

Reference

Reference 1

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

25.02.1985 - 09.03.1985

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

comparable to guideline study

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 414 (Prenatal Developmental Toxicity Study)

Deviations:

not applicable

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

other: COBS-CD-(SD)BR

Details on test animals or test system and environmental conditions:

TEST ANIMALS:
Source: Charles River Labs., Inc., Lakeview
Age at study initiation: 10 - 11 w
Weight at study initiation: 215 - 216 g
Diet: ad lib
Water: ad lib
Acclimation period: 4 w

ENVIRONMENTAL CONDITIONS:
Temperature (°C): 20 - 24.4
Humidity (%): 45 - 50
Photoperiod (hrs dark / hrs light): 12 / 12

Route of administration:

oral: gavage

Vehicle:

water

Details on analytical verification of doses or concentrations:

Hydroquinone was administered to the animals as a 5 % solution in distilled water, prepared daily. Test solutions prepared on the first 2 days of dosing were analyzed (GC) for HQ concentration prior to use. For the remainder of the study, only the solutions prepared on Monday, Wednesday, and Friday were analyzed. On some days of analysis, the test solutions were analyzed both prior to and after dosing and were found to be stable over this period. The mean concentrations for the test solutions of HQ used during the study were within +/- 6 % of the desired concentration.

Details on mating procedure:

The rats were mated 1:1 over a 4-day period to obtain 120 inseminated females. Copulation was confirmed by the presence of a vaginal plug, and the day a plug was found was considered day 0 of gestation. Inseminated females were assigned to the treatment and control groups on the basis of the day 0 body weight using a computer-generated randomization program.

Duration of treatment / exposure:

gestation days 6 - 15

Frequency of treatment:

once daily

Duration of test:

sacrifice on gestation day 20

Dose / conc.:

0 mg/kg bw/day

Dose / conc.:

30 mg/kg bw/day

Dose / conc.:

100 mg/kg bw/day

Dose / conc.:

300 mg/kg bw/day

No. of animals per sex per dose:

30 f

Control animals:

yes, concurrent vehicle

Maternal examinations:

Maternal body weights were recorded on gestation days 0, 6, 9, 12, 16, and 19.
Individual feed consumption was measured from days 0-6, 6-9, 9-12, 12-16, and 16-19 of gestation.
Cage-side observations for clinical signs of maternal toxicity were conducted twice each workday on non-treatment days. On treatment days, clinical observations were made prior to and after treatment and at the end of the workday.
A detailed examination, including but not limited to examination of the hair, skin, eyes, general activity, faeces, and urine, was conducted on each female on the days body weights were recorded.
On day 20 of gestation, the females were anesthetized and the abdominal and thoracic viscera were exposed. Terminal body weights were recorded and gravid uteri, with ovaries attached, were removed and weighed.
A necropsy examination of the thoracic and abdominal viscera was conducted in situ on each female. The liver and kidneys were removed, trimmed of extraneous tissue, and weighed for organ/body weight comparisons. Samples of these organs were preserved in 10 % neutral buffered formalin.

Ovaries and uterine content:

After the gravid uterus was weighed, the uterine horns were opened, and the implantation sites were counted and categorized as viable/dead foetus and late/early resorption.
The ovaries were dissected free and trimmed of extraneous tissue, and the corpora lutea of pregnancy were counted. The uteri of apparently non-pregnant females were stained with a 10 % solution of sodium sulfide and examined for the presence of micro-implantation sites.

Fetal examinations:

Viable foetuses were removed from the uterus, blotted dry on absorbent material, sexed, weighed individually, and examined for external abnormalities. Approximately one-half of the foetuses from each litter were preserved in Bouin's solution and examined for internal soft tissue changes using Wilson's free-hand razor blade technique. The other half of the foetuses were fixed in 95 % ethanol, macerated in 2 % potassium hydroxide, stained with alizarin red S, and examined for skeletal malformations and variations.

Statistics:

Statistical analyses compared the HQ groups with the control group using the SAS software package. Incidence data (pregnancy rate, percentage pre- and post-implantation loss, incidence of foetuses with malformation/variation, incidence of litters with foetuses with malformation/variation, etc.) were analyzed using X2 contingency tables and Fisher's exact test when X2 was significant. Continuous data (maternal body weight, feed consumption, organ weights, foetal body weights, foetuses/litter, etc.) were analyzed using a one-way analysis of variance and Duncan's multiple-range test when the F value was significant. Bartlett's test was used to test the equality of variances (p <= 0.01). Schematic analyses were performed on the litter data to determine normality of distribution, and arcsine transformations were performed to normalize the distribution prior to analysis using the ANOVA. All analyses, except Bartlett's test, were conducted at p <= 0.05 and a two-tailed risk level.

Indices:

number of females inseminated, number of females pregnant (%), number of litters with resorptions (%), litters completely resorbed, corpora lutea/dam, implantations/dam, pre-implantation loss (%), viable foetuses/litter, resorption/litter, dead foetuses/litter, post-implantation loss (%), mean foetal body weight, gravide uterine weight, corrected body weight, sex ratio

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: 300 mg/kg: reduction in body weight gain and feed consumption

Details on maternal toxic effects:
Mean maternal body weights of the high-dose animals (300 mg/kg) were slightly lower than the control mean body weights from the 3rd day of treatment to the end of the study. These differences were due to a significantly reduced body weight gain during the first 3 days of treatment. The mean body weight gain for the high-dose dams was significantly reduced during the treatment period (gestation days 6-16). The mean corrected body weight (day 20 body weight minus the gravid uterine weight) of the 300 mg/kg group was also slightly less than the control (difference was not statistically significant).
Feed consumption for the 300 mg/kg dams was significantly reduced during the treatment period.
Body weight and feed consumption of the dams in the low and intermediate treated groups were not different from controls. The only treatment-related clinical sign was the brownish coloration of the urine noted during treatment (all treated animals).
Mean absolute and relative weights of the liver and kidneys were comparable between treated and control dams.
Histological examinations of the livers and kidneys of the high-dose and control dams revealed no treatment-related lesions, therefore tissues from the intermediate-and low-dose dams were not examined.

Dose descriptor:

NOEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Basis for effect level:

body weight and weight gain

food consumption and compound intake

Fetal body weight changes:

effects observed, treatment-related

External malformations:

no effects observed

Skeletal malformations:

no effects observed

Visceral malformations:

no effects observed

Details on embryotoxic / teratogenic effects:

Embryotoxic / teratogenic effects:no effects

Dose descriptor:

NOEL

Effect level:

100 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

fetal/pup body weight changes

Developmental effects observed:

no

Observations at Caesarean Section:

No significant changes in reproductive indices. A lower mean foetal body weight seen at the 300 mg/kg dose level was associated with the slightly reduced body weights seen for the dams at this dose level.

Foetal observations:

The anatomic changes were classified as malformations or aberrations (variations, retardations, and deviations). External, internal soft tissue and skeletal examinations of the foetuses revealed no subtance related malformations. Major malformations (considered to have occurred spontaneously) included micrognathia and incomplete closure of the palatine bone in one control foetus, a diaphragmatic hernia in one foetus from a 300 mg/kg litter, and a mal-positioned right subclavian artery in one foetus from a 30 mg/kg litter. The numbers of foetuses with fewer than four ossification sites in the sternum (considered as malformation) were 3, 1, 2, and 3, respectively, for the 0, 30, 100 and 300 mg/kg groups. External variations consisted of small hematomas on single foetuses in the control and 30/100 mg/kg groups and on three foetuses from the 300 mg/kg group.

Internal soft tissue aberrations included dilated renal pelves (due to shortened renal papillae), hydronephrosis (absent renal papillae), and hydroureter. Although these changes were seen more frequently in the treated groups vs. controls, the incidences were not dose related. When analyzed individually and as total soft tissue alterations, the incidence of foetuses with an alteration and the percentage of litters with at least one foetus with an alteration were not statistically different from controls.

Skeletal variations included partial ossification or non-ossification of some intra-membranous bones of the skull and the hyoid bone and variations in vertebral development, such as partial ossification or non-ossification of the first and second thoracic centra, bilobed or split thoracic centra (particularly the 10th, 11th, and 12th), and partially ossified 3rd and 4th sacral arches, which were seen in many of the foetuses from all dose levels including controls. A few foetuses had rib variations. The total number of foetuses with a vertebral variation was statistically significantly greater in the 300 mg/kg group compared with controls, but analyses of individual skeletal variations, including individual vertebral variations, and statistical analysis of total number of foetuses with a skeletal alteration indicated no significant effects on skeletal development in the treated groups compared with controls.

Conclusions:

This study gave no indication for a potential developmental or reproductive hazard of hydroquinone.

Executive summary:

In this study comparable to OECD Guideline 414, pregnant COBS-CD-BR rats were dosed with 0, 30, 100 or 300 mg/kg bw by gavage on days 6 – 15 of gestation. Maternal effects included a slight but significant reduction in body weight gain and feed consumption at 300 mg/kg bw. Reproductive indices (i.e. pregnancy rate, numbers of corpora lutea, implantation sites, viable foetuses, and early and late resorptions, foetal sex ratio, pre- and post-implantation losses, and gravid uterine weights) were not affected by treatment. A slightly reduced mean foetal body weight at 300 mg/kg bw was associated with a slightly reduced body weight gain for the dams at this dose level. Gross external, internal soft tissue, and skeletal examinations of the foetuses revealed no treatment telated malformations. The incidences of gross external variations (small hematomas) and internal soft tissue variations (dilated renal pelvis, hydronephrosis, and hydroureter) in treated litters were not statistically different from the control incidences. Skeletal variations (delayed ossification of membranous skull bones, hyoid bone, thoracic centra 1-3, sacral arches 3 and 4, and bilobed thoracic centra 9-13) occurred with similar frequency in controls and treated groups. The incidences of total skeletal variations were not statistically different between the control and the treated groups.

The NOEL for both maternal and developmental toxicity was 100 mg/kg bw (NOAEL of 300 mg/kg bw).

Reference 2

Endpoint:

developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

01.03.1988 - 18.04.1988

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Qualifier:

according to guideline

Guideline:

EPA OTS 798.4900 (Prenatal Developmental Toxicity Study)

Deviations:

no

GLP compliance:

yes

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

4 – 5 month-old nulliparous female NZW rabbits were obtained from Hazleton Research Products, Inc. (Denver) and allowed to acclimate to laboratory conditions for approximately 6 weeks. They were maintained in animal rooms controlled for lighting (12 hr light/day), temperature (18.4 degrees C) and relative humidity (50 +/- 20 %) and were supplied Purina High-Fiber Rabbit Chow 5325 and water ad lib.
The body weight range of animals at the time of initial dosing for the range-finding study was 3244 - 4561 g.
For the definitive study, initial body weights ranged from 3385 - 4949 g.
Animals were housed individually in stainless-steel wire-mesh hanging cages except during breeding.

Route of administration:

oral: gavage

Vehicle:

water

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Dosing solutions were prepared fresh daily and solution concentrations were verified once a week using liquid chromatography. Representative dosing solutions were found to be stable at room temperature for at least 6 hr.
In the definitive study, mean nominal values were 100 +/- 2.01, 103 +/- 2.69 and 105 +/- 3.39 % of targeted concentrations for the low-, mid-, and high-dose groups, respectively.

Details on mating procedure:

The day on which evidence of mating with two proven breeder males was observed was defined as day 0 of gestation. Females that mated with males from a pool of proven breeders were assigned to groups in a way that equalized Day 0 mean group body wts.

Duration of treatment / exposure:

gestation days 6 - 18

Frequency of treatment:

once daily

Duration of test:

caesarean section on gestation day 30

Dose / conc.:

0 mg/kg bw/day

Dose / conc.:

25 mg/kg bw/day

Dose / conc.:

75 mg/kg bw/day

Dose / conc.:

125 mg/kg bw/day

No. of animals per sex per dose:

18 mated females

Control animals:

yes, concurrent vehicle

Details on study design:

The dose selection was based on a range finding study.

Range-finding study:
In the range-finding study, groups of five mated females were administered degassed, distilled water (vehicle control) or HQ in degassed, distilled water at doses of 50, 100. 200, 300, or 400 mg/kg/d (dose volume of 10 ml/kg body wt) by gavage on days 6 - 18 of gestation. A group treated with 500 mg HQ/kg was terminated on gestation day 6 because two animals died immediately after being given the first dose.

Definite study:
Groups of 18 mated females were administered 0, 25, 75, or 150 mg/kg/d in degassed, distilled water (in a dose volume of 8 ml/kg bw) by gavage on days 6-18 of gestation.

Maternal examinations:

Range-finding study:
During gestation, animals were observed twice daily for obvious toxicological effects and/or mortality.
Body weights were recorded on GD 0, 6, 12, 18, 24, and 30.
Feed consumption was recorded on GD 3. 6, 7, 8, 9. 10, 12, 15, 18, 24, and 29.
Test animals were given a detailed physical evaluation on GD 0, 6, 9, 12, 15, 18, 24, and 30. Animals that delivered prematurely were euthanized that same day and given a gross post-mortem examination. Surviving females were euthanized on GD 30 and were given a gross post-mortem evaluation.

Definitive study:
During the treatment period, animals were observed twice daily for signs of pharmacologic or toxicological effects and mortality.
Body weights were recorded on GD 0. 6, 9, 12, 16, 18, 24, and 30.
Feed consumption was recorded daily (GDs 1- 29).
Test animals were given a detailed physical evaluation on GDs 0, 6-19, 24, and 30. On GD 30, each female was euthanized, given a gross post-mortem evaluation and liver and kidney weights were recorded.

Ovaries and uterine content:

Range-finding study:
The intact gravid uterus was removed and weighed, corpora lutea were counted on each ovary, and uterine implantations were identified as live, dead, or resorbed foetuses. When no implants were grossly apparent, the uterus was stained with ammonium sulphide. If no foci were visualized post-staining, the female was considered to be not pregnant.

Definite study:
Examination of corpora lutea/uterine implantation data. Animals that delivered prematurely were euthanized on the day such evidence was observed. Uteri of seemingly non-pregnant females were stained as described above.

Fetal examinations:

Range-finding study:
All live and dead foetuses were removed from the uterus, weighed and given a gross external examination.

Definite study:
Foetuses recovered on GD 30 were weighed and evaluated for external and visceral malformations/variations. Subsequently all foetuses were processed for staining of the skeletal structures with alizarin red S and evaluated for skeletal malformation/variations.

Statistics:

Data from the range-finding study were not analyzed statistically because group sizes were small. Data from the definitive study were analyzed as follows. The equality of means was evaluated using a one-way analysis of variance (ANOVA) technique, followed by a multiple-comparison procedure, when appropriate. Bartlett's test was performed to determine if groups had equal variances. If the variances were equal, parametric procedures were used; if not, nonparametric procedures were used. A one-way ANOVA, using the F distribution to assess the significance level, was followed by Dunnett's test if significant differences (p <= 0.05) among the means were indicated. If nonparametric methods were required, the Kruskal-Wallis test was used; if significant differences were indicated, Dunn's summed rank test was performed to determine which treatment groups differed from the control group. Methods for analyzing trends were also utilized, i.e., standard regression analysis was used for parametric evaluations and Jonckheere's test for monotonic trend was used for nonparametric evaluations. Incidence data from treatment versus control groups (pregnancy rates, the percentage of foetuses with malformations, the percentage of litters containing malformed foetuses, and ossification variations) were analyzed using standard X2 analysis. This analysis was followed by a 2 X 2 Fisher exact test, using the Bonferroni inequality correction to ensure the stated significance level was corrected for multiple comparisons. Armitage's test was performed to determine if there was a linear dose-response.

Indices:

females mated, pregnant (%), pregnancies aborted, premature births, litters with viable foetuses, corpora lutea/dam, implantations/dam, pre-implantation loss, live foetuses/litter, resorptions/litter, resorptions/implants, foetal body weights, sex ratio

Details on maternal toxic effects:

Maternal toxic effects:yes. Remark: >= 75 mg/kg/d: decreased feed consumption and/or body weights

Dose descriptor:

NOEL

Effect level:

25 mg/kg bw/day

Basis for effect level:

other: maternal toxicity

Details on embryotoxic / teratogenic effects:

150 mg/kg caused minimal developmental alterations (e.g. increased incidences of micropthalmia and minor skeletal malformations)

Dose descriptor:

NOEL

Effect level:

75 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

skeletal malformations

Developmental effects observed:

no

Maternal observations:

Survival of control and treated females was comparable and no animals died. There were no adverse effects evident from physical observation data. Mean body weight of dams dosed with 150 mg/kg/d was significantly reduced on GD 18, these animals also exhibited a significantly greater weight loss over GDs 6 - 18 when compared with controls. Feed consumption was significantly reduced on GDs 7 - 15 and on GD 18. Body weight data for mid-dose dams were comparable with controls, but feed consumption was significantly reduced on GDs 12 and 13 . At 25 mg/kg/d no treatment-related changes in body weights or feed consumption were observed. Data for reproductive parameters including percentage pregnant and number of dams delivering prematurely were comparable in all groups. At necropsy, no adverse treatment-related effect was evident on inspection of liver or kidney weight data or gross post-mortem examination data.

Foetal observations:

Mean foetal body weights (by sex and as a composite of both sexes) were comparable between control and treated groups. The ratios of viable male/female foetuses per group were also comparable. Statistically significant differences between groups were not found for the incidences of external malformations both on a per foetus and a per litter basis. Limb flexure defects were seen in one foetus each from the low- and mid-dose groups. In the high-dose group, two foetuses from a single litter did not have eye bulges and at necropsy were found to have small eyes (micropthalmia). The incidences of foetuses/litters with visceral malformations were comparable in all groups. The most frequently seen visceral malformation was absence of the gallbladder (there was no dose-response relationship and the mean historical control incidence was 0.5 % (range: 0.0 - 9.5 %)). In the low-dose group, one foetus had a defect in the lobulation of the left lung. In the high-dose group, a total of three foetuses from two litters exhibited micropthalmia.

The incidences of foetuses with visceral variations were comparable in the control and mid-dose groups, but were higher than the controls in the low- and high-dose groups. The difference for the low-dose group was statistically significant. The most prominent visceral variation was an absence of the postcaval lobe of the lung (in the absence of a dose-response relationship and because other types of variations appeared with similar frequency in all groups, the occurrence of this variation was not considered to be indicative of a treatment-related response).

The incidence of skeletal malformations did not differ statistically between control or treated groups on either a per foetus or per litter basis. The most frequently seen skeletal malformation was angulated arch of the hyoid (incidence: 2.7, 0.7, 0 and 7.2 % at 0, 25, 75 or 150 mg/kg bw; mean historical control incidence was 1.7 % (0.0 to 3.7 %)). The incidence of fused sternebrae was higher in the control group than in any of the treated groups. In the control and high-dose groups, the incidence of foetuses with skeletal malformations exclusive of angulated hyoid arch and fused sternebrae was 0.9 and 4.8 %, respectively, the predominant malformation involved rib defects. No adverse effect of treatment was evident from ossification variation data.

Conclusions:

This study gave no indication for a potential developmental or reproductive hazard of hydroquinone.

Executive summary:

In a guideline study performed according to EPA OTS 798.4900, hydroquinone was administered to pregnant NZW rabbits (18 mated per dose group) in an aqueous solution at doses of 0, 25, 75, or 150 mg/kg/d by gavage on gestation days 6 to 18. Caesarean sections were performed on gestation day 30. Doses of >= 75 mg/kg/d adversely affected feed consumption and/or body weights of dams during the treatment period. However, at these doses no treatment-related clinical effects and no changes in liver and kidney weights, premature delivery incidence, and caesarean sectioning data were noted. For the dams the NOEL was 25 mg/kg/d. In offspring the dosing with 150 mg/kg/d caused no significant changes in total incidences of external, visceral, and skeletal findings, but there were some slightly increases (statistically not significant when compared with controls) in the incidences of ocular and minor skeletal malformations (micropthalmia, vertebral/rib defects, angulated hyoid arch) on both a per foetus and a per litter basis. These findings were only seen in the presence of maternal toxicity. The NOEL for developmental toxicity was 75 mg/kg/day.

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no adverse effect observed

Dose descriptor:

NOAEL

75 mg/kg bw/day

Quality of whole database:

reliable studies available in 2 species

Effect on developmental toxicity: via inhalation route

Endpoint conclusion:

no study available

Effect on developmental toxicity: via dermal route

Endpoint conclusion:

no study available

Additional information

Prenatal Developmental Toxicity Study with rabbits (Schroeder, 1988, 1989; Murphy et al., 1992):

In this study performed according to EPA OTS 798.4900, hydroquinone was administered to pregnant NZW rabbits (18 mated per dose group) via gavage at doses of 0, 25, 75, or 150 mg/kg bw/d on gestation days 6 to 18. Caesarean sections were performed on gestation day 30. Doses of >= 75 mg/kg bw/d adversely affected feed consumption and/or body weights of dams during the treatment period. However, there were no treatment-related clinical effects and no changes in liver and kidney weights, premature delivery incidence, and caesarean sectioning data. In offspring the dosing with 150 mg/kg bw/d caused no significant changes in total incidences of external, visceral, and skeletal findings, but there were some slightly increases (statistically not significant when compared with controls) in the incidences of ocular and minor skeletal malformations (micropthalmia, vertebral/rib defects, angulated hyoid arch) on both a per foetus and a per litter basis.

The effect levels are as follows:

NOAEL(maternal toxicity): 25 mg/kg bw/d

NOAEL(developmental toxicity): 75 mg/kg bw/d

Prenatal Developmental Toxicity Study with rats (Krasavage, 1985, 1992):

In this study comparable to OECD Guideline 414, pregnant COBS-CD-BR rats were via gavage at doses of 0, 30, 100 or 300 mg/kg bw/d on days 6 – 15 of gestation. Maternal effects included a slight but significant reduction in body weight gain and feed consumption at 300 mg/kg bw/d. Reproductive indices (i.e. pregnancy rate, numbers of corpora lutea, implantation sites, viable foetuses, and early and late resorptions, foetal sex ratio, pre- and post-implantation losses, and gravid uterine weights) were not affected. A slightly reduced mean foetal body weight at 300 mg/kg bw/d was associated with a slightly reduced body weight gain for the dams at this dose level. Gross external, internal soft tissue, and skeletal examinations of the foetuses revealed no treatment related malformations. The incidences of gross external variations (small haematomas) and internal soft tissue variations (dilated renal pelvis, hydronephrosis, and hydroureter) in treated litters were not statistically different from the control incidences. Skeletal variations (delayed ossification of membranous skull bones, hyoid bone, thoracic centra 1-3, sacral arches 3 and 4, and bilobed thoracic centra 9-13) occurred with similar frequency in controls and treated groups. The incidences of total skeletal variations were not statistically different between the control and the treated groups.

The effect levels are as follows:

NOAEL(maternal toxicity): 100 mg/kg bw/d

NOAEL(developmental toxicity): 100 mg/kg bw/d

Justification for selection of Effect on developmental toxicity: via oral route:
Data from 2 reliable studies in rats and rabbits showed no evidence of effects on the development.

Toxicity to reproduction: other studies

Additional information

Possible effects of hydroquinone on fertility and developmental toxicity / teratogenicity after oral dosing were tested in valid guideline studies with rats and rabbits. All of these studies gave no indications of reproductive toxicity or a potential developmental / reproductive hazard.

Justification for classification or non-classification

There is no need for a classification as reproductive effects are only observed at maternally toxic doses.