Hydroquinone

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

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

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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.

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.