2-methylhydroquinone

Endpoint summary

Description of key information

The range of NOAEL for congeners of Methylhydroquinone in rodents (rats, mice) after oral administration is in the range of 20 – 402 mg/kg/d repeated oral doses considering the duration of experiments of 28d up to 2 years.

The targeted toxicological endpoints are primarily decreased body weight and liver toxicity. Regarding the effects on the thyroid gland function, it appears that the OH-groups in para-position, like in methylhydroquinone, are inactive. Mild, transient tremors and reduced home-cage activity were also considered.

Since the smallest experimental NOAEL obtained in animals are 20 mg/kg bw./ day, the experts set the NOAEL for the targeted substance Methylhydroquinone on 20 mg/kg bw./day. Nevertheless, it appears that a value of 50 mg/kg/day is also acceptable since the tremors obtained in the study of Topping, D.C. et al. 2007, are reversible and disappear during long term use.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

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.

Qualifier:

equivalent or similar to guideline

Guideline:

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

Deviations:

not specified

GLP compliance:

not specified

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.

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

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

Dose / conc.:

20 mg/kg bw/day (nominal)

Dose / conc.:

64 mg/kg bw/day (nominal)

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

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).

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

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

Key result

Critical effects observed:

no

Lowest effective dose / conc.:

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

System:

nervous system

Organ:

brain

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.

Reference 2

Endpoint:

short-term repeated dose toxicity: oral

Type of information:

experimental study

Adequacy of study:

key study

Study period:

during 1992-1993

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.

Qualifier:

according to guideline

Guideline:

OECD Guideline 407 (Repeated Dose 28-Day Oral Toxicity Study in Rodents)

GLP compliance:

yes

Limit test:

no

Specific details on test material used for the study:

SOURCE OF TEST MATERIAL
- Source and lot/batch No.of test material: The test material was obtained from Aldrich Chemical Co. Ltd., Gillingham, Dorset, U.K.
Identification Trimethylhydroquinone
Batch number 4361662
Purity 99.8%
Date received 19 August 1993
Description yellow powder
Container opaque plastic jar
Storage conditions. room temperature (19/08/93 to 14/09/ 93)
room temperature in the dark, over silica gel, under nitrogen gas (14/09/93 to present)
- Expiration date of the lot/batch: -
- Purity test date: The purity and chemical identification of the test material was determined by Safepharm Analytical laboratory prior to the start of
the study and, following storage under the conditions specified above, at the end of the study (Safepharm Project Number 463/3). A
Certificate of Analysis is given in Appendix XV.
For the purpose of this study the test material was prepared at the appropriate concentrations as a suspension in dried Arachis oil B.P. The
stability and homogeneity of the test material formulations were determined by Safepharm Analytical Laboratory. Results are given in
Appendix X and show the formulations to be stable for at least ten days. Formulations were therefore prepared weekly and stored at 4-C° in the
dark.
Samples were taken of each test material formulation and were analysed for concentration of No. 240 Trimethylhydrochinon at Safepharm Analytical Laboratory. The method used for}analysis of formulations and the results obtained are given in APPendix X. The results indicate that the prepared formulations were within ± 10% of the nominal con centration.

Species:

rat

Strain:

Sprague-Dawley

Details on species / strain selection:

A sufficient number of male and female Sprague-Dawley CD strain rats were obtained from Charles River (U.K.) Limited, Manston, Kent.

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River (U .K .) Limited, Manston, Kent
- Age at study initiation:
- Weight at study initiation: 131-165g (males), 124-158g (females)
- Fasting period before study:
- Housing: groups of five by sex in polypropylene gridfloor cages suspended over trays lined with absorbent paper
- Diet: pelleted diet (Rat andMouse SQC Expanded Diet No . 1, Special Diets Services Limited, Witham, Essex, U .K .) ad libitum
- Water: ad libitum
- Acclimation period: 7d


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-22
- Humidity (%): 44-61
- Air changes (per hr): minimum of 15
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:

oral: gavage

Details on route of administration:

Four groups, each of ten trats (five males and five females) were dosed as follows:
GROUP Dose Level Treatment Concen- Treatment period
Volume tration
Number mg/kg/day ml/kg mg/ml
1 (Control) 2 0 28 days
2 45 2 22.5 28 days
3 125 2 62.5 28 days
4 400 2 200 28 days

The test material was administered daily, for twenty -eight consecutive days, by gavage using a stainless steel cannula attached to a disposable plastic syringe. Control animals were treated in an identical manner with 2 ml/kg/day of dried Arachis oil B. P.

Vehicle:

arachis oil

Details on oral exposure:

VEHICLE
- Concentration in vehicle: 0, 22.5; 62.5; 200 mg/ml
- Amount of vehicle (if gavage): 2 ml/kg
The volume of test and control material administered to each animal was based on the most recent bodyweight and was adjusted at weekly intervals.

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

See above.

Duration of treatment / exposure:

28 days

Frequency of treatment:

Single dose daily

Dose / conc.:

45 mg/kg bw/day (nominal)

Dose / conc.:

125 mg/kg bw/day (nominal)

Dose / conc.:

400 mg/kg bw/day (nominal)

No. of animals per sex per dose:

5

Control animals:

yes, concurrent vehicle

Details on study design:

No post exposure period

Positive control:

Not applicable.

Observations and examinations performed and frequency:

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule:
All animals were examined for overt signs of toxicity, ill-health or behavioural change immediately before dosing and one and five hours
after dosing during the working week . Animals were observed immediately before dosing and one hour after dosing at weekends .

BODY WEIGHT: Yes
- Time schedule for examinations:
Individual bodyweights were recorded on Day 0 (the day before the start of treatment) and on Days 7, 14, 21 and 28 . Bodyweights were also recorded at terminal kill .

FOOD CONSUMPTION:
Food consumption was recorded for each cage group at weekly intervals throughout the study .

FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No

WATER CONSUMPTION:
Daily visual inspection of the water bottles during the first half of the treatment period revealed overt intergroup differences.
Water intake was, therefore, measured and recorded for each cage group from Day 15 onwards.

OPHTHALMOSCOPIC EXAMINATION: Yes / No / No data
- Time schedule for examinations:
- Dose groups that were examined:

HAEMATOLOGY: Yes
- Time schedule for collection of blood: day 28
- Anaesthetic used for blood collection: Yes (identity) / No / No data
- Animals fasted: No
- How many animals: all surviving animals
- Parameters:
Haematocrit, Haemoglobin, Erythrocyte count, Total leucocyte count, Differential leucocyte count
Anisocytosis, Polychromatic erythrocyte count, Micronucleated erythrocyte count, Platelet count , mean corpuscular haemoglobin, mean corpuscular volume, mean corpuscular haemoglobin concentration, clotting time

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: day 28
- Animals fasted: No
- How many animals: all surviving animals
- Parameters:
Blood urea, Calcium, Total protein, Inorganic phosphorus, Albumin, Alkaline phosphatase, Albumin/globulin ratio, Alanine aminotransferase, Aspartate aminotransferase, Sodium Glucose, Potassium ,Total bilirubin,Chloride, Creatinine

URINALYSIS: Yes
- Time schedule for collection of urine: during week 4 (collection time 16h)
- Metabolism cages used for collection of urine: Yes
- Animals fasted: No
- Parameters :
Volume, Specific gravity, pH, Protein, Glucose, Ketones, Bilirubin, Urobilinogen, Reducing substances, Blood

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
All animals were subjected to a full external and internal examination, and any macroscopic abnormalities were recorded .
On completion of the dosing period all surviving animals were killed by intravenous administration of sodium pentobarbitone solution
(Sagatal, 60 mg/ml; May and Baker Limited, Dagenham, Essex, U.K.) followed by exsanguination.
ORGAN WEIGHTS:
Adrenals, Brain, Gonads, Heart, Kidneys,
Liver, Pituitary, Spleen, Uterus
HISTOPATHOLOGY:
Adrenals, Jejunum, Sciatic nerve, Aorta (thoracic), Kidneys, Seminal vesicles,
Bone & Bone Marrow (femur, sternum) , Liver, Skin (hind limb)
Lungs, Spleen, Lymph nodes (cervical and mesenteric), Spinal Cord (cervical), Brain, Muscle (skeletal), Stomach,
Caecum, Oesophagus, Testes,Colon, Ovaries, Thymus,
Duodenum, Pancreas, Thyroid/parathyroid, Eyes, Pituitary, Trachea,Gross lesions, Prostate, Urinary bladder,
Heart, Rectum, Uterus, Ileum, Salivary glands

Statistics:

Absolute and relative organ weights, haematological and blood chemical data were analysed by one way analysis of variance incorporating
'F-max' test for homogeneity of variance . Data showing heterogeneous variances were analysed using Kruskal Wallis non-parametric analysis of variance and Mann Whitney U-Test .

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

CLINICAL SIGNS AND MORTALITY
400 mg/kg/day:
Several females dosed at 400 mg/kg/day showed clinically observable signs of toxicity during the first three days of treatment . One animal appeared pale towards the end of Day 1 whilst another was hunched and lethargic during Days 2 and 3 . These two animals quickly recovered and appeared normal in comparison with controls from Days 2 and 4 respectively . A further female from this dose group was pale and lethargic approximately one hour after dosing on Day 1 and showed respiratory abnormalities . This animal was found dead approximately ten minutes after the observations had been performed . There were no further deaths during the study . Animals of either sex dosed at 400 mg/kg/day also showed increased salivation immediately after dosing from Day 9 onwards .
125 or 45 mg/kg/day: no clinical signs of toxicity

BODY WEIGHT AND WEIGHT GAIN
Animals treated with the test material showed similar bodyweight gains to controls over the treatment period .

FOOD CONSUMPTION
There was no adverse effect on food consumption during the study .

WATER CONSUMPTION
400 mg/kg/day; slightly greater water intake than controls during the study . No appreciable differences in water intake were evident at the remaining
dose levels.

HAEMATOLOGY
400 mg/kg bw/d: Animals of either sex had a slightly lower haemoglobin concentration, erythrocyte count, haematocrit and mean corpuscular haemoglobin concentration than controls together with a slightly elevated mean corpuscular volume . In addition, these animals showed a significantly higher number of polychromatic erythrocytes than controls together with a marginally higher incidence of micronucleated cells. Total leucocyte counts were also slightly higher in males than in controls.
125 or 45 mg/kg/day: no treatment-related changes

CLINICAL CHEMISTRY
400 mg/kg/day: Animals of either sex dosed had a higher total plasma protein concentration than controls . Female plasma albumin concentration was also raised at this dose level whilst male albumin/globulin ratio was reduced.
125 or 45 mg/kg/day: no treatment-related changes

URINALYSIS
no treatment-related changes

ORGAN WEIGHTS
400 mg/kg/day : Males showed a statistically significant increase in spleen weight (absolute and relative) and females showed increased relative spleen weights.
Animals of either sex showed a statistically significant increase in relative liver weight c whilst an increase in absolute liver weight was confined to females.
125 mg/kg/day : males showed increased relative spleen weights.
No other test substance related changes were observed.

GROSS PATHOLOGY
No toxicologically significant macroscopic abnormalities

HISTOPATHOLOGY
400 mg/kg/day:
spleen: increased severities of extramedullary haemopoiesis, characterised as essentially erythropoiesis , and haemosiderin pigment deposition were observed in relation to treatment , for rats of either sex. No treatment-related microscopic changes were identified in the sections of bone marrow examined
and an increased severity of haemosiderin pigment deposition was not evident in either the liver or the kidneys at this dose level .

45, 125 mg/kg/day:
Increased severity of splenic extramedullary haemopoiesis in male rats.

No morphological abnormalities were detected for female rats dosed at 125 or 45 mg/kg/day.

Mortality:

not specified

Description (incidence):

One female dosed at 400 mg/kg/day was found dead approximately seventy minutes after dosing on the first day of treatment.
Theere were no further deaths during the study.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Animals treated with the test material showed similar bodyweight gains to controls over the treatment period

Food consumption and compound intake (if feeding study):

no effects observed

Description (incidence and severity):

There was no adverse effect on either food consumption or weekly food efficiency during the study.

Food efficiency:

not specified

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

effects observed, treatment-related

Description (incidence and severity):

400 mg/kg/day; slightly greater water intake than controls during the study. No appreciable differences in water intake were evident at the remaining dose levels.

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

400 mg/kg bw/d: Animals of either sex had a slightly lower haemoglobin concentration, erythrocyte count, haematocrit and mean corpuscular haemoglobin concentration than controls together with a slightly elevated mean corpuscular volume . In addition, these animals showed a significantly higher number of polychromatic erythrocytes than controls together with a marginally higher incidence of micronucleated cells. Total leucocyte counts were also slightly higher in males than in controls. 125 or 45 mg/kg/day: no treatment-related changes

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

400 mg/kg/day: Animals of either sex dosed had a higher total plasma protein concentration than controls . Female plasma albumin concentration was also raised at this dose level whilst male albumin/globulin ratio was reduced.
125 or 45 mg/kg/day: no treatment-related changes

Urinalysis findings:

no effects observed

Behaviour (functional findings):

not specified

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

400 mg/kg/day : Males showed a statistically significant increase in spleen weight (absolute and relative) and females showed increased relative spleen weights. Animals of either sex showed a statistically significant increase in relative liver weight c whilst an increase in absolute liver weight was confined to females. 125 mg/kg/day : males showed increased relative spleen weights.
No other test substance related changes were observed.

Gross pathological findings:

effects observed, non-treatment-related

Description (incidence and severity):

The female decedent had a darkened liver and a reddened glandular gastric region at necropsy on Day 1. Both these findings represent commonly observed post-mortem changes and neither was considered to be directly related to test material toxicity.

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

400 mg/kg/day:
spleen: increased severities of extramedullary haemopoiesis, characterised as essentially erythropoiesis ,and haemosiderin pigment deposition were observed in relation to treatment , for rats of either sex. No treatment-related microscopic changes were identified in the sections of bone marrow examined
and an increased severity of haemosiderin pigment deposition was not evident in either the liver or the kidneys at this dose level .
45, 125 mg/kg/day:
Increased severity of splenic extramedullary haemopoiesis in male rats.
No morphological abnormalities were detected for female rats dosed at 125 or 45 mg/kg/day.

Histopathological findings: neoplastic:

not specified

Key result

Dose descriptor:

NOAEL

Effect level:

125 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

clinical signs

Key result

Critical effects observed:

yes

Lowest effective dose / conc.:

400 mg/kg bw/day (nominal)

System:

other: several organs

Organ:

blood

spleen

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

not specified

Discussion in the study report pertaining to the NOAEL:

At the remaining dose level of 125 and 45 mg/kg/day, treatment-related changes were confined to males and involved an increased severity of extramedullary erythropoiesis in the spleen. There was no difference in the amount of haemosidin pigment present in the spleen at these dose compared with that found in the spleen of control maschon in der Tabellele rats but the increased severity of extramedullary erythropoiesis could indicate that an underlying anaemia was present in these animals, or at least had developed at some time during the dosing period. The absence of any haematological evidence of an anaemia indicates however that the normally expected physiological response of increased erythrogenesis was able to fully compensate for any increase in the rate of erythrocyte destruction at these two dose levels. The increased erythrogenesis in these animals was not accompanied by a measurable increase in the number of polychromatic erythrocytes.

Females dosed at 125 or 45 mg/kg/ day were unaffected by repeated administration of No. 240 Trimethylhydrochinon.

Conclusions:

Applicants conclusion in accordance with the conclusions of the authors of the study report:
Oral administration of the test material , No. 240 trimethylhydroquinone to rats by gavage, at dose levels of 45, 125 and 400 mg/ kg/ day for up to twenty-eight consecutive days resulted in treatment-related changes at 400 mg/kg/ day amongst the females and at all dose levels examined amongst the males. No treatment-related changes were detected amongst females dosed at 125 or 45 mg/kg/day and the "No Observed Effect Level" (NOEL) for females was considered to be 125 mg/kg/day.
A NOEL was not established for male rats in this study but the sol e treatment-related change identified amongst maes dosed at 125 or 45 mg/kg/day involved an increased severity of ex-tramedullary haemopoiesis in the spleen. This finding, in isolation, was considered not to in-dicate an adverse effect on the health of the animals and 125 mg/ kg/ day can be regarded as a “No Observed Adverse Effect Level” (NOAEL ) for male rats.

Executive summary:

The reference substance trimethylhydoquinone has the same functional groups as the target substane 2 -methylhydroquinone and is therefore a structural analogue of the targeted substance methylhydroquinone

Both substances are analogues since they have similar structural and functinal properties and similar toxicological preperties are expected.

The subchronic (sub-acute) 28-day oral totxicity study in the rat may therefore serve as reference substance for forcast of the toxicological properties of the targeted 2 -methylhydroquinone after oral use, i.e.the NOAEL value in particular.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

subchronic

Species:

rat

System:

central nervous system

Organ:

brain

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion

Endpoint conclusion:

no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

The substance is not classified for specific target organ toxicity (RE) since no data from a 90 day repeated dose study are available.