Registration Dossier

Administrative data

Description of key information

Acute toxicity, oral: rat female LD50 = 367 mg/kg bw; rat male LD50 > 375 mg/kg bw (Sheppard, 2002; Topping et al., 2007)
Acute inhalation: based on LD50 on surrogate substance, resorcinol (8hrs LC50 > 7800 mg/m3, 1 µm size), particle size distribution, metabolisation kinetics, low acute toxicity is expected by inhalation.
Acute toxicity, dermal: rabbit male or female LD50 > 2000 mg/kg bw (Sheppard, 2002; Topping et al., 2007)

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
November 13 - December 18, 2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Wilmington, MA, USA
- Age at study initiation: range finding study 10-13 w, main study 9 w for males, 14-15 w for females
- Weight at study initiation: males 258-298 g, females 228-292 g
- Fasting period before study: 17 h
- Housing: single
- Diet: PMI #5002, pelleted ad libitum
- Water: tap water ad libitum
- Acclimation period: 5 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.3-23.6
- Humidity (%): 39.2-61.1
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
other: degassed water
Details on oral exposure:
VEHICLE
- Concentration in vehicle: 2.85%, 3.15%, 3.45%, 3.75% in the main study; dosing solutions freshly prepared
- Amount of vehicle (if gavage): 10 mL/kg bw

MAXIMUM DOSE VOLUME APPLIED: 1 mL
Doses:
285, 315, 345, 375 mg/kg bw
No. of animals per sex per dose:
7 males, 5 females
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: clinical signs three times on day of dosing and once daily thereafter, body weights on day 0, 7, and 14
- Necropsy of survivors performed: yes, also for animals found dead
- Other examinations performed: clinical signs, body weight, gross findings; clinical observations included, but were not limited to, examination of the hair, skin, eyes, mucous membranes, motor activity, feces, urine, respiratory system, circulatory system, autonomic nervous system, central nervous system, and behaviour patterns.
Statistics:
LD 50 values and confidence intervals determined by using the Trimmed Spearman-Karber (TSK) Computer Program, US Environmental Protection Agency
Preliminary study:
400 and 500 mg/kg bw: convulsions followed by death
100 to 375 mg/kg-dose groups: tremor immediately after dosing; brown discoloration of urine between day 0 and 3 after dosing indicating excretion of hydroquinone
Sex:
male
Dose descriptor:
LD50
Effect level:
> 375 mg/kg bw
Remarks on result:
other: mortality 1/5 at 375 mg/kg bw
Sex:
female
Dose descriptor:
LD50
Effect level:
367.3 mg/kg bw
95% CL:
> 342.1 - < 394.3
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 375 mg/kg bw
Remarks on result:
other: mortality: 1/5 male and 3/5 females at 375 mg/kg bw
Mortality:
males: 1/5 at 375 mg/kg
females: 1/5 at 285 mg/kg, 0/5 at 315 mg/kg, 1/5 at 345 mg/kg, 3/5 at 375 mg/kg
all deaths within 1 h after administration
Clinical signs:
- Immediately after dosing:
minor to moderate tremors observed in all dose groups;
minor convulsions characterized by spasmodic jumping immediately after dosing noted for 2/5 f at 285 mg/kg, for 1/5 m and 1/5 f at 345 mg/kg, and for 1/5 m and 3/5 f at 375 mg/kg; convulsions mostly in animals found dead within 1 h

- 1h p.a.: minor tremors in 1/5 f at 315 mg/kg, and 1/5 m and 1/4 f at 345 mg/kg

- 4 h p.a.: no signs of tremors or convulsions

- Day 0 - 2: brown discoloration of urine indicating excretion of hydroquinone
Body weight:
No effect
Gross pathology:
Minor to moderate thymus hemorrhage for some of the animals that died on the day of dosing;
Minor hydronephrosis in a single male surviving rat at 345 mg/kg not considered to be treatment-related
Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Based on LD50 values of 367 mg/kg bw in female rats and >375 mg/kg bw in male rats hydroquinone was classified as harmful according to the criteria of EC Directive 67/548/CEE. Central nervous system stimulation was indicated immediately after dosing by the observation of tremors in all animals as well as by the induction of convulsions in single animals over the whole dose range.
Executive summary:

In an acute oral toxicity study according to OECD Guideline 401, hydroquinone was administered to groups of 5 male and 5 female Sprague-Dawley rats at doses of 285, 315, 345 and 375 mg/kg bw (2.85% to 3.75% solutions in degassed water) by gavage. Selection of dose groups was based on a range-finding toxicity study. During a 14 day post-observation period abnormal clinical signs, mortalities, and body weight gain was recorded. Gross necropsy was performed on all dead and surving rats.

Mortality was observed in males at 375 mg/kg (1/5), and in females at 285 mg/kg, at 345 mg/kg, at 375 mg/kg (1/5, 1/5, 3/5). All deaths occurred within 1 h after administration and were mostly preceeded by convulsions. Central nervous system stimulation was indicated immediately after dosing by the observation of tremors in all animals as well as by the induction of convulsions in single animals over the whole dose range. The LD50 values were 367 mg/kg bw in female rats and >375 mg/kg bw in male rats.

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
Value:
367 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
Weight of evidence

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
June 26 - August 10, 2001
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
yes
Remarks:
(occlusive wrapping)
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Covance Reseaerch Products, Denver, PA, USA
- Age at study initiation: at least 3 mo
- Body weight at study initiation: males 2.329-2.492 kg, females 2.040-2.592 kg
- Fasting period before study: no
- Housing: single
- Diet: PMI #5325 ad libitum
- Water: ad libitum
- Acclimation period: 5 d


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19.8-22.9
- Humidity (%): 47.8-70
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12/12
Type of coverage:
occlusive
Vehicle:
other: moistened with water
Details on dermal exposure:
TEST SITE
- Area of exposure: dorsal skin
- % coverage: 10% of total body surface
- Type of wrap if used: not specified


REMOVAL OF TEST SUBSTANCE
- Washing (if done): yes
- Time after start of exposure: 24 h


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 2000 mg/kg bw
Duration of exposure:
24 h
Doses:
2000 mg/kg bw
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: clinical observations at least once during exposure period on day 0 and once daily on days 1-14, weighing on day 0, 7, and 14
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight, gross findings; clinical observations included, but were not limited to, examination of the hair, skin, eyes, mucous membranes, motor activity, feces, urine, respiratory system, circulatory system, autonomic nervous system, central nervous system, and behaviour patterns.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Sex:
male/female
Dose descriptor:
LDLo
Effect level:
> 2 000 mL/kg bw
Based on:
test mat.
Mortality:
None
Clinical signs:
No adverse neurobehavioral effects
Brown discoloration of urine on day 2 after dosing indicating dermal absorption and excretion of hydroquinone
Body weight:
No effect
Gross pathology:
No changes
Other findings:
Application sites appeared normal from termination of exposure up to the end of the observation period
Interpretation of results:
not classified
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
With a dermal LD50 value of more than 2000 mg/kg bw in rabbits no classification for acute dermal toxicity according to criteria of the GHS and EC Directive 1272/2008 is warranted.
Executive summary:

Hydroquinone was administered to groups of 5 male and 5 female New Zealand White rabbits at a dose of 2000 mg/kg bw under an occlusive wrapping (limit test according to OECD Guideline 402). During a 14 day post-observation period no abnormal clinical signs, mortalities or necropsy findings occurred, and body weight gain was not affected. Dermal absorption of hydroquinone was indicated by brown discoloration of urine due to excretion of hydroquinone and its metabolites. The dermal LD50 value in rabbits is more than 2000 mg/kg bw.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

Acute oral toxicity

In an acute oral toxicity study according to OECD Guideline 401, hydroquinone (HQ) was administered to male and female Sprague-Dawley rats at doses ranging from 285 to 375 mg/kg bw by gavage (vehicle water). The LD50 value was 367 mg/kg bw in females and > 375 mg/kg bw in males (mortality rate: 1/5 males at 375 mg/kg bw) (Key studies: Sheppard, 2002; Topping et al., 2007).

In a study with male Wistar rats, no mortalities were observed at 300 mg/kg bw, whereas all rats died at 600 mg/kg bw, supporting the findings in the key study (Supporting study: Saito and Takeichi, 1995).

Signs of intoxication are characterized by central nervous system stimulation as indicated by tremors observed immediately after dosing in all animals and by convulsions observed in single animals within 5-15 minutes at doses from >= 285 mg/kg bw (lowest tested dose) (Saito and Takeichi, 1995; Sheppard, 2002; Topping et al., 2007).

After single gavage application (vehicle water), HQ was shown to induce a strain-specific nephrotoxic effect in F344 rats but not in Sprague-Dawley rats. Female F344 rats were significantly more sensitive to the acute nephrotoxic effects of HQ (LOAEL: 200 mg/kg bw) than male F344 rats (LOAEL: 400 mg/kg bw). B6C3F1 mice were distinctly less susceptible than F344 rats as only minor nephrotoxic effects occurred following a high dose of 350 mg/kg bw, just below a lethal dose (Key studies: Boatman et al 1993, 1996; for further data on acute nephrotoxicity see IUCLID Section 7.9.3).

Acute inhalation toxicity

No experimental studies are available in animals with exposure to inhalable HQ particles by inhalation.

Based on the available information by other routes (intratracheal administration showing rapid absorption and metabolism), low toxicity observed with a relevant surrogate substance (exposure to inhalable aerosols of the isomer resorcinol), physico-chemical propertes (including mean particle size) and observations from human exposure in the workplace, there is a low concern to humans for acute toxicity and local effects under realistic exposure conditions in the workplace environment. An experimental study by inhalation in rats is not considered necessary.

Acute dermal toxicity

In a limit test according to OECD Guideline 402, HQ was administered to male and female New Zealand White rabbits at a dose of 2000 mg/kg bw under an occlusive wrapping. During a 14 day post-observation period no abnormal clinical signs, mortalities or necropsy findings occurred, and body weight gain was not affected. Dermal absorption of HQ was indicated by brown discoloration of urine due to excretion of HQ and its metabolites (Key study: Sheppard, 2002; Topping et al., 2007). Based on a study with open dermal application to male and female CD rats, the dermal LD50 in rats was estimated to be > 900 mg/kg bw based on the highest tested dose of 875 mg/kg bw (Supporting study: Julou et al., 1973).

Acute toxicity: other routes

After intraperitoneal application of two different grades of HQ (food grade and photographic grade in water) LD50values were reported to be in the range of 160 to 175 mg/kg bw in rats, mice, rabbits, and guinea pigs. Clinical signs of intoxication were characterized by clonic convulsive movements proceeding into running movements pointing to central nervous system effects (Key study: Hodge and Maynard, 1948). After subcutaneous application of HQ as aqueous solution similar LD50values of 190 and 182 mg/kg bw were found in ICL-ICR mice (Supporting study: Nomiyama et al., 1967) and white mice (Supporting study: Marquardt et al., 1947), respectively.

Comparison oral versus parenteral LD50values

LD50 values were about 50% lower after parenteral application compared to oral bolus application via gavage (see above). As HQ absorption from the gastrointestinal tract is complete (see IUCLID Section 7.1.1), these LD50 values confirm data from metabolism studies that showed that a considerable biotransformation to less toxic metabolites takes place during first pass metabolism in the liver following absorption from the gastrointestinal tract.


Justification for selection of acute toxicity – oral endpoint
Reliable study, males and females tested.

Justification for selection of acute toxicity – inhalation endpoint
Experimental data of an intratracheal administration of Hydroquinone at up to 10 mg/kg showed a rapid elimination of HQ from the blood via the formation of glucuronide conjugates with a kinetics similar to the oral route experiments and no adverse effects.
Acute inhalation study with a surrogate substance, Resorcinol, showed no acute toxicity.
The long-term DNEL for systemic effects is considered protective from potential acute effects by inhalation.

Justification for selection of acute toxicity – dermal endpoint
Reliable study

Justification for classification or non-classification

Acute oral toxicity

Based on the key study (Sheppard, 2002; Topping et al., 2007) with a LD50 value of 367 mg/kg in the rat as relevant species for classification, there results a classification in Acute Toxicity Category 4; H302: Harmful if swallowed, according to the criteria of EC Directive 1272/2008 and of the GHS.

Acute toxicity inhalation

Data on a surrogate substance (isomer of HQ, structural analog) indicate an 8hr LC50 > 7.8 mg/L with no clinical signs. Based on the available information on particle size of HQ material, solubility, rapid systemic metabolisation after lung absorption following intratracheal administration, experimental inhalation data on a structurally similar substance, and weight of evidence including observations in the workplace, there is a low concern to humans for acute systemic toxicity and local effects under realistic exposure conditions in the workplace environment.

Acute dermal toxicity

Based on a dermal LD50 value of > 2000 mg/kg bw in rabbits (Key study: Sheppard, 2002; Topping et al., 2007), there results no classification according to the criteria of EC directive 1272/2008 and GHS.