2-methylhydroquinone

Repeated dose toxicity: oral

Administrative data

Endpoint:

sub-chronic toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

HYPOTHESIS FOR THE ANALOGUE APPROACH
Common functional group(s) and common mechanism(s) of action.

Data source

Reference

Reference Type:

publication

Title:

Unnamed

Year:

2006

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

EPA OPPTS 870.3100 (90-Day Oral Toxicity in Rodents)

Deviations:

not specified

GLP compliance:

not specified

Test material

Test material information

Constituent 1

Reference substance name:

Hydroquinone

EC Number:

204-617-8

EC Name:

Hydroquinone

Cas Number:

123-31-9

Molecular formula:

C6H6O2

IUPAC Name:

hydroquinone

Test material form:

solid: particulate/powder

Specific details on test material used for the study:

The purity of the sam ples was at least 99, and the mass spectrum was consistent with the structure of HQ.

Test animals

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

For these acute oral toxicity and subehrenie studies, male and female Sprague-Dawley rats were obtained from Charles River Laboratories (Wilmington, MA).

Sex:

male/female

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

test solution was prepared daily

Duration of treatment / exposure:

13 weeks

Frequency of treatment:

5 days per week

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

20 mg/kg bw/day (nominal)

Doses / concentrations 2

Dose / conc.:

64 mg/kg bw/day (nominal)

Doses / concentrations 3

Dose / conc.:

200 mg/kg bw/day (nominal)

No. of animals per sex per dose:

10 male and 10 female rats were randomly assigned to each of three test groups and one control group.

Control animals:

yes

Details on study design:

The purpose of the subchronic study was to evaluate the neurotoxic and nephrotoxie potential of HQ in the Sprague-Dawley rat following subchronic exposure at acutely toxie dose levels using an observational battery to evaluate tbe nervous system for functional deficits and by
using histopathology to detect morphological changes in the CNS, PNS, and kidneys.

Positive control:

not stated

Examinations

Observations and examinations performed and frequency:

According to this newly added data, no adverse effects on the kidney were reported in male and female Sprague-Dawley rats treated in groups of 10 animals by gavage with 0, 20, 64 or 200 mg/kg BW/day hydroquinone in distilled water, 5 days per week for 13 weeks. Neuro-histopathology was conducted on various brain areas. Mild, transient tremors and reduced home-cage activity were observed in the mid- and high-dose groups im-mediately after dosing with the incidence increased in a dose-dependent manner, no more detailed quantitative data were reported). No differences in body weight, feed consumption, and brain or kidney weight were noted. Morphologic lesions associated with the treatment were not observed

Sacrifice and pathology:

The kidneys of the high dose and control male rats were also processed for histopathology.
No treatment related changes at gross necropsy.

Statistics:

For the subchronic study, mean data were evaluated for statistical significance using the following statistical tests: one-way analysis of variance
(ANOVA, p 6 0.05), Bartlett’s test (p 6 0.01), and Duncan’s multiple range test (p 6 0.05). Organ weights from perfused and unperfused animals
were analyzed separately. Prior to analyzing counts of defecations, urinations, and vocalizations, the data were transformed to make the
variances independent of the means (Sokal and Rohlf, 1969; Daniel, 1978).

Results and discussion

Results of examinations

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

In this study, repetitive acute CNS stimulation did not result in evidence of subchronic neurotoxicity as assessed by FOB examinations.
Tremors were routinely observed shortly after dosing both males and females with 64 or 200 mg/kg HQ, and depression of general activity
was also noted at the 200 mg/kg HQ dose level. Tremors were observed as a fine shaking or trembling of the body or in mild cases, just the ears. Tremors appeared in the 200 mg/kg males between 30 min and 1 h after dosing and in the 200 mg/kg females, between 4 and 25 min. Minimal to minor tremors were observed in all 200 mg/kg animals, all 64 mg/kg females, and in 7/10 64 mg/kg males. Recovery from the tremors was rapid.

Mortality:

no mortality observed

Description (incidence):

within the applied doses no mortality was observed.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

For the 200 mg/kg males, a slightly lower mean body weight relative to control was observed from Day 1 until termination of the study; this difference was not significant

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Feed consumption for the 200 mg/kg males was significantly lower than the control between Days 0 and 4. Thereafter, feed consumption for
the 200 mg/kg males increased to a level comparable to controls. Feed consumption and body weights were comparable to controls throughout the study for all other HQ groups.

Food efficiency:

not specified

Water consumption and compound intake (if drinking water study):

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not examined

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

Brown discolored urine stains of minor intensity were observed on the paper under the home cages of all surviving rats between the day of dosing (Day 0) and Day 2.

Behaviour (functional findings):

effects observed, treatment-related

Description (incidence and severity):

Behavioral changes associated with HQ exposure were observed primarily during the 1 and 6 h FOB examinations (Table 2). Changes were observed in both sexes, although not in an identical manner. Among cage-side observation parameters, males showed a significant decrease in home cage activity during the 6 h FOB (6/10 males at 200 mg/ kg vs. none of the controls). The incidence of decreased activity was also greater for the 64 mg/kg males at the 6 h FOB, but this difference was not significant. A significant decrease in activity level while the animals were being
removed from the cage was seen among females: at the 1 h FOB, all ten 200 mg/kg females were affected compared with 6/10 control animals. HQ-related changes observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Description (incidence and severity):

No treatment-related changes were observed at gross necropsy of any of the HQ-treated animals and no HQ-related histologic changes were present in the kidneys from any of the HQ-exposed animals.

Neuropathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

Neuropathology examination revealed that the sciatic nerve of one control female contained a focal area of fibrosis with a minor decrease in the number of axons. A second control female had a single group of myelin ovoids present in the tibial nerve. One 200 mg/kg female had single degenerating axons in the sciatic and tibial nerves. One male control animal had two degenerating axons in the plantar nerve and one 200 mg/kg male had a single group of myelin ovoids in the tibial nerve. None of these changes were considered related to HQ.

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not specified

Effect levels

Key result

Dose descriptor:

LOAEL

Effect level:

64 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

Target system / organ toxicity

Key result

Critical effects observed:

no

Lowest effective dose / conc.:

64 mg/kg bw/day (actual dose received)

System:

nervous system

Organ:

brain

Applicant's summary and conclusion

Conclusions:

For Hydroquinone a LOAEL of 64 mg/kg bw was derived.

Executive summary:

Repetitive doses of HQ resulted in transient tremors and reduced motor activity levels following daily treatment and during the functional observational battery examinations performed shortly after administration of P64 mg/kg HQ, but not 20 mg/kg. The threshold for CNS stimulation appears to be very close to 64 mg/kg because the effects were just barely detectible in this study and were not detectible in F-344 rats given 100 mg/kg for 13 weeks or 50 mg/kg for 2 years. In this study, repetitive acute CNS stimulation did not result in evidence of subchronic neurotoxicity as assessed by FOB examinations, quantitative grip strength measurement, brain weight, or neuropathology examinations. In addition, no nephropathy was evident in Sprague-Dawley rats given 200 mg/kg HQ; a dose level that is nephrotoxic to F-344 rats.