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Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
fertility, other
Remarks:
based on test type (migrated information)
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:
other: 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.

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1984
Report Date:
1984

Materials and methods

Test guideline
Qualifier:
equivalent or similar to
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

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Name of test material (as cited in study report): hydroquinone
Lot/batch No.: #356, Lot A-13
Analytical purity: 99.5 %
Physical state: white crystalline solid

Batch was analyzed for purity prior to beginning the study and at various times during the study.
Analyses were done prior to beginning treatment to determine the stability of the test solution and based on these results fresh test solutions were prepared every two or three days except during week five of the study when the solution prepared was used over a four day period. Aliquots of all solutions prepared were analyzed immediately after preparation and those solutions used over a three or four day period were analyzed at the end of the use period to check stability.

Test animals

Species:
rat
Strain:
other: CRL:COBS®CD®(SD)BR
Sex:
male/female
Details on test animals 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

Administration / exposure

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
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 30, 100 or 300 mg/kg
Basis:
nominal conc.
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)

Examinations

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.

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:
not specified
Histopathological findings: non-neoplastic:
not specified
Other effects:
effects observed, treatment-related

Reproductive function / performance (P0)

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

Details on results (P0)

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.

Effect levels (P0)

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Dose descriptor:
NOEL
Effect level:
100 mg/kg bw/day
Based on:
other: all toxic effects
Sex:
male
Dose descriptor:
NOEL
Effect level:
300 mg/kg bw/day
Based on:
other: reproductive capacity / dominant lethality
Sex:
male/female

Overall reproductive toxicity

Reproductive effects observed:
not specified

Applicant's summary and conclusion

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.