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Administrative data

Description of key information

Oral toxicity:
Subchronic neurotoxicity study, Sprague-Dawley rat, 13 w gavage (5 d/w) at doses of 0, 20, 64 and 200 mg/kg bw/d: NOAEL 20 mg/kg bw/d, LOAEL 64 mg/kg bw/d (observation of tremors as clinical signs in male and female rats) (Topping, 1988, 2007).
Combined carcinogenicity and chronic toxicity study, Fischer 344 rat, males, 103 w gavage (5 d/w) at doses of 0, 25 and 50 mg/kg bw/d: NOAEL 25 mg/kg bw/d, LOAEL 50 mg/kg bw/d (decreased body weight, increased severity of chronic progressive nephropathy, significant increase of renal tubuli adenoma; renal findings as sex- and species-specific effect of no toxicological relevance for human risk assessment) (Kari et al., 1992; NTP, 1989).
Dermal toxicity
14 day range finding dermal toxicity study, F344 rats, 12 open applications on 5 d/w of 240 - 3840 mg/kg bw/application: NOAEL 3840 mg/kg bw (Kari et al., 1992; NTP, 1989). No effects were observed in a 90-day dermal study in rats, but HQ was applied at only 0.5% in a cream formulation (i.e. eq. to 74 mg/kg/day), which limited the use of a NOAEL as point of departure for risk assessment.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
20 mg/kg bw/day
Study duration:
chronic
Species:
rat

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 adverse effect observed
Dose descriptor:
NOAEL
3 840 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
There are limitations in the available studies, with either a duration shorter than standard requirements, or with a formulation containing the substance in concentration lower than the standard requirements that does not allow to fully investigate potential adverse effects.

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed

Additional information

ORAL TOXICITY STUDIES

 

In a 14-day range-finding toxicity study mortalities, clinical signs, and reduced body weight gain indicated toxicity in male and female F344 rats at doses of ≥ 500 mg/kg bw/d and in male and female B6C3F1 mice at ≥ 250 mg/kg bw/d by NOAELs were 250 mg/kg bw/d in rats and 125 mg/kg in mice (Supporting study: Kari et al., 1992; NTP, 1989).

 

In a subchronic range finding toxicity study, HQ was applied on 5 days per week for 13 weeks by gavage (25 - 400 mg/kg bw/d to Fischer 344 rats andB6C3F1 mice.

In Fischer 344 rats, mortalities occurred at 400 and 200 mg/kg bw/d. Often, tremors were observed after dosing, and convulsions preceding death. The most common clinical sign was lethargy in rats from 200 mg/kg up. Final body weights were similar to controls in all dose groups of females, whereas in males final body weights were decreased by 8% and 9% at 100 and 200 mg/kg, respectively (no data for food consumption available). In rats, prominent pathological findings were inflammation and epithelial hyperplasia of the forestomach seen at 200 mg/kg (4/10 males, 1/10 females), and toxic nephropathy, characterized by tubular cell degeneration and regeneration in the renal cortex, seen at 200 mg/kg (7/10 males, 6/10 females), and at 100 mg/kg (1/10 females).

In B6C3F1 mice, mortalities occurred at 400 and 200 mg/kg bw/d. Often, tremors were observed after dosing and convulsions preceding death. The most common clinical sign was lethargy in male mice of all dose groups (from 25 mg/kg up), and female mice from 100 mg/kg up.In mice,ulceration, inflammation, or epithelial hyperplasia in the forestomach were found at 400 mg/kg (3/10 males, 2/10 females), and at 200 mg/kg(1/10 females)..

Based on negligible effects at lower doses, the NOAELs are 50 mg/kg bw/d and the LOAELs are 100 mg/kg bw/d, both in rats and mice. The findings in the forestomach are indicative of a local irritant action in the forestomach due to bolus application via gavage. At 100 mg/kg, body weight reduction and toxic nephropathy is the critical effect in the Fischer 344 strain of rats (for further discussion see below: Assessment of specific target organ toxicity). In B6C3F1 mice, lethargy observed in both sexes at 100 mg/kg is considered as a clinical sign indicating an adverse effect on the central nervous system.The observation of lethargy only in males at the low dose range of 25 and 50 mg/kg bw/d was not reproducible in the chronic study at doses of 50 and 100 mg/kg bw/d and thus is considered to be of no toxicological relevance.At the higher dose of 200 mg/kg effects are much more severe with mortality of 30% of female rats and 20% of male mice(Key study: Kari et al., 1992; NTP, 1989).

 

There was no evidence of subchronic neurotoxicity after oral exposure of groups of 10 male and 10 female Sprague-Dawley rats to doses of 20, 64, and 200 mg HQ/kg bw/d by gavage for 13 weeks on 5 d/was assessed by functional observation battery examinations, quantitative grip strength measurements, brain weights, or neuropathology examinations (Study protocol similar to OECD Guideline 424, Neurotoxicity study in rodents). Effects were restricted to clinical signs indicating responses of the central nervous system asdepression of general motor activity at 200 mg/kg, and appearance of tremorsafter dosing of HQ at 64 and 200 mg/kg bw/d. No renal changes were evident in this rat strain given 200 mg HQ/kg bw/d, a dose level that was nephrotoxic to F344 rats.Under the conditions of this study, in Sprague-Dawley rats the LOAEL was 64 mg/kg bw/d based on clinical signs indicating an adverse effect on the central nervous system and the NOAEL was 20 mg/kg bw/d (Key study: Topping et al., 1988, 1991, 2007).

 

HQ was administered to groups of 65 male and 65 female F344 rats or B6C3F1 mice for 103 weeks on 5 days per week via gavage (vehicle water) at doses of 0, 25, and 50 mg/kg bw/d for rats or 0, 50 and 100 mg/kg bw/d for mice. The study protocol was similar to OECD Guideline 453 with several minor deviations. There were only 2 instead of 3 dose groups, and food consumption and urinalysis were not examined. Hematology and clinical chemistry examinations were performed at a single timepoint after 65 w of dosing in subgroups of 10 animals of each sex and dose. Sacrifice for gross and histopathological examination was at about 66 w (N=10) and 104-105 w (N=55) after start of dosing.Both in rats and mice, no significant differences in survival and no compound-related clinical signs were reported.

In male F344 rats, toxicity was indicated at 50 mg/kg by decreased body weights (5-9% between week 73-93, 10-13% between week 94-104) and relative kidney weights were increased after 65 and 103 w of administration. All male rats of all groups (dosed and vehicle control) showed chronic progressive nephropathy (CPN), which is a common effect in ageing F344 rats. Severity of CPN was increased at the 66-week interim sacrifice in both dose groups and at the terminal sacrifice in the high-dose group (gradings of CPN: 5/55 mild, 15/55 moderate, 32/55 marked compared to respective gradings of 12/55, 26/55, 12/55 in the vehicle control). In male F344 rats, the LOAEL for non-neoplastic chronic toxicity was 50 mg/kg bw/d, based on body weight reduction and increased severity of CPN as an effect specific for this strain of rats (for further discussionsee below: Assessment of specific target organ toxicity), and the NOAEL was 25 mg/kg bw/d.. At 50 mg/kg bw/d, a significant increase of renal tubuli adenoma was observed in male rats (for detailed discussion of neoplastic histopathology see Section 7.7).Female F344 rats were found to be less sensitive as indicated by a NOAEL of 50 mg/kg bw/d for non-neoplastic toxicity. At 25 and 50 mg/kg bw/d, statistically significant increased incidences of mononuclear cell leukaemia were observed in female rats (for detailed discussion see Section 7.7). (Key study: Kari et al., 1992; NTP, 1989).

In B6C3F1 mice, toxicity was indicated at 100 mg/kg by decreased body weights in females (5-8% lower between week 20-44, 10-14% lower between week 45-104). Significant increases of relative liver weights were found at 100 mg/kg in both sexes after 65 and 103 w of administration, and at 50 mg/kg in males after 103 w. Centrilobular fatty change and cytomegaly were observed in male mice at the 65-week interim sacrifice but not at the terminal sacrifice. As necropsies at these timepoints were performed within 24 hrs and 14 days after the last dosing, respectively, fatty change and cytomegaly seem to be reversible after cessation of hydroquinone administration. Additionally, at 100 mg/kg findings in livers of male mice after 105 w were characterized by increased incidences of anisokaryosis (variation in size of hepatocyte nuclei), syncitial alteration (hepatocytes with more than 5 nuclei per cell), and foci of cellular alteration (basophilic foci) compared to incidences in vehicle controls. The LOAEL for chronic toxicity was 50 mg/kg bw/d both in male B6C3F1 mice based on liver weight effects and liver histopathology at the 65-week interim sacrifice, and in female mice based on increased incidences of hepatocellular adenomas and of hepatocellular adenomas or carcinomas combined(detailed evaluation of neoplastic histopathology in Section 7.7) (Key study: Kari et al., 1992; NTP, 1989).

 

A reevaluation of the renal histopathology findings of certain dose groups of the NTP cancer bioassay with Fischer 344 rats (all males with terminal sacrifice, and the control groups and 50 mg/kg groups of males with 66 week interim sacrifice and of females with terminal sacrifice) was performed with emphasis on evaluation of incidences, severity and location of chronic progressive nephropathy (CPN) and renal proliferative lesions (for details see Section 7.7). In this detailed reevaluation of the histological sections there was no indication of alpha-2µ-globulin nephropathy or a direct nephrotoxic effect of HQ in high dosed male rats (50 mg/kg bw) after chronic exposure. However, HQ exacerbated the spontaneously occurring chronic progressive nephropathy (CPN) and additionally exerted a stimulatory effect on the proliferative potential of the advanced stages of CPN at both 25 and 50 mg/kg (for details see Section 7.7). Of the rats surviving into the last 10 w of the study 49% had endstage CPN and 40% had severe CPN. Principally, these renal effects are of little relevance for humans, as CPN is a rodent-specific spontaneous renal disease (Key study:Hard et al., 1997).

 

 

DERMAL TOXICITY STUDIES

 

Subchronic dermal toxicity with emphasis on aspects of nephrotoxicity and renal cell proliferation was investigated in groups of 20 male and 20 female F344 rats with a test protocol similar to OECD Guideline 411. Dermal application of 0, 2.0, 3.5, and 5.0% HQ in an oil-in-water emulsion cream, comparable to cream base of commercial cream preparations with HQ, was performed on 5 d/w, for 6 h/d during 13 w. Resulting dermal doses were 29.5, 51.9, and 73.9 mg/kg bw/d in male rats, and 43.8, 77.0, and 109.6 mg/kg bw/d in female ratsapplied on a skin surface area of 24 cm2(dermal doses of ca. 1 to 4 mg/cm2). Dermal application of 5% HQ produced transient minor irritation of the skin (no indication that the maximal tolerable dose (MTD) was exceeded) but no evidence of exogenous ochronosis. Up to the highest tested dose, there were no clinical signs of intoxication, and no statistically significant or toxicologically relevant changes of body weights, organ weights, of food and water consumption, of haematological and clinical chemical parameters. Treatment-related nephrotoxicity was not indicated from urinalysis data and from kidney histology. There were no changes indicative of sustained renal cell proliferation in different proximal tubule segments (P1, P2, P3 and other cells) investigated via a BrdU incorporation assay. Consequently, NOAELs in this subchronic dermal toxicity study were at least 73.9 mg/kg bw/d in male rats, and 109.6 mg/kg bw/d in female rats (no higher doses tested) (Key study: David et al., 1998).

 

In a 14 day range finding dermal toxicity study with F344 rats (12 open applications on 5 d/w of 240 to 3840 mg/kg bw/d in 95% ethanol as vehicle), no toxicologically significant effects were observed up to the highest dose, so that 3840 mg/kg bw/d is the NOAEL for male and female F344 rats. After equal exposure of male and female B6C3F1 mice to doses of 300 to 4800 mg/kg bw/d, there was no indication of toxicity from survival, clinical signs, body weights and gross necropsy up to 4800 mg/kg bw/d, so the NOEL for B6C3F1 mice is 4800 mg/kg bw/d. A preliminary qualitative dermal absorption study in both species indicated systemic availability of unknown amounts of HQ, excreted as glucuronide and sulfate conjugates in urine (Key studies: NTP, 1989).

INHALATION TOXICITY STUDIES

There are no experimental inhalation studies with test animals available. All the information available was considered to assess the potential concerns for the inhalation route and conduct the risk assessment in humans.

 

 

HUMAN EXPERIENCE

 

From health surveys of workmen, exposed to benzoquinone (BQ) vapors and HQ dust during the manufacture of HQ, there was no indication of systemic effects from annual physical examinations and hematological parameters (Sterner et al., 1947). The absence of effects on erythrocyte numbers, hematocrit and hemoglobin concentrations in workers exposed to higher levels of HQ dust before 1946, with reported air concentrations of up to 35 mg/m3, shows that the blood system is not a possible target of an adverse action of HQ in humans. In contrast, local eye injury was found as the prominent effect in these HQ-exposed workers (Key study: Anderson, 1947; Sterner et al., 1947; Anderson and Oglesby, 1958; for details see IUCLID Section 7.10.1 and 7.3).

 

A retrospective study was performed in a well-characterized 1942-1990 cohort of 879 workers (858 men and 21 women) employed principally in the manufacture and use of HQ at a large chemical plant comprising 22,895 person-years of exposure during the 50-year observation period. Mean duration of tenure in a HQ environment was 13.7 years, mean follow-up from first exposure was 26.8 yrs; 2205 person-years (10%) were represented by subjects with ages of 65 and older. Average exposure concentrations, 1949-1990, ranged from 0.1 to 6.0 mg/m3for HQ dust and less than 0.1 to 0.3 mg/m3for benzoquinone vapour. 20% of cohort members had presumably experienced higher exposures to HQ dust, e.g. up to 35 mg/m3in the packaging area, at the period up to 1949, before measures to reduce exposure had been installed. Causes of mortality were followed up to 1991 and were compared with vital statistics from the general population of the State of Tennessee, and to an occupational reference group of 30,000 hourly wage personnel employed at Kodak's Rochester facilities from 1964 to 1992, few of whom had potential HQ exposure.

There was no evidence of excess mortality in the investigated cohort. In contrast, the number of deaths from all causes of death, and from all forms of malignant cancer was statistically significantly below expectation compared with both the general population and the occupational controls. There was also a lower than expected death rate from circulatory diseases. Additionally, there were fewer than expected deaths from respiratory cancer, non-malignant pulmonary diseases, and genitourinary system illness, including nephrotoxicity(Key study: Pifer et al., 1995; for details see IUCLID Section 7.10.2). Consequently, from this study there are no indications that HQ affects the kidneys, the livers, or the blood system of humans with occupational exposures to HQ, even at the elevated exposure levels of the early years of HQ production before 1950.

 

 

ASSESSMENT OF SPECIFIC TARGET ORGAN TOXICITY AND OF SPECIES-SPECIFITY OF EFFECTS

 

Specific investigations of the mechanisms of the nephrotoxic action of HQ (for details see IUCLID Section 7.9.3) show a strain- and species-specific susceptibility of male F344 rats compared to other strains of rats, to mice and other species. Nephrotoxic effects of HQ were found after acute and subchronic oral exposure of F344 rats with LOAELs of 200 and 25 mg/kg bw/d, respectively. Renal lesions are characterized by tubular cell necrosis followed by cell regeneration. HQ-induced renal cell proliferation, presumably is an attempt to compensate for proximal tubular cell lossrather than representing a direct mitogenic effect of HQ.The nephrotoxic action of HQ is dependent on the formation of metabolites that require processing by GGT, that are glutathionyl conjugates of HQ. 2,3,5-(tris-glutathion-S-yl)HQ displayed the highest nephrotoxic potency (about 600-fold that of HQ).Bioactivation steps predominate in rat liver cells leading to higher body burdens of higher substituted GSH HQ conjugates, which are considered to be the key nephrotoxic metabolites, whereas deactivation steps predominate in human liver cells. F344 rats were shown to be especially prone to the formation of these metabolites compared to other strains or animal species. In contrast, humans have an increased capacity for hepatic detoxification, especially for the formation of HQ-glucuronide and the mercapturic acid conjugate (N-AcCysS-HQ), limiting exposure of the human kidney to nephrotoxic metabolites.

Consequently, renal toxic and renal neoplastic effects observed in Fischer 344 rats (Kari et al., 1992; NTP, 1989) but not in Sprague-Dawley rats (Hydroquinone Program Panel, 1998; Topping et al., 1991, 2007) or B6C3F1 mice (Kari et al., 1992; NTP, 1989)are considered not be biologically significant for human exposure (see also discussion in Section 7.7).

A possible hepatotoxic action, indicated by histopathological changes only in male mice after chronic exposure but not in female mice or in rats of either sex (Kari et al., 1992; NTP, 1989), is considered to be of questionable biological significance for human exposure. This is supported by data from a retrospective study with workers exposed to HQ by inhalation (see above: Sterner et al., 1947; Pifer et al., 1995) which gave no indication for specific target organs (especially of the kidneys, livers, or the blood system) even at elevated exposure levels in the early years of HQ production before 1950 with maximum air concentrations of up to 35 mg/m3. At these workplaces, a 8-hour exposure under a condition of light physical activity with an estimated respiratory volume of 10 m3, would account to a maximal dose of 350 mg per person and day or ca. 5 mg/kg bw/d (assumption of 100% absorption from the respiratory tract).

 

 

OVERALL EVALUATION

 

Oral exposure

Table: Overview on NOAELS and LOAELsbased on non-neoplastic and neoplastic findings derived from the key studies with repeated oral application of HQ, including critical acute CNS effects.

 

Species

Strain

Sex

Dose (mg/kg bw/d)

Application

Duration

NOAEL

(mg/kg bw/d)

LOAEL

(mg/kg bw/d)

Basis for LOAEL

Acute CNS effects

(effects observed rapidly after dosing)

Reference


F344

rat

m

0, 25 or 50

gavage

103 w, 5 d/w

25

50

body weights ↓; severity of chronic progressive nephropathy ↑; renal tubuli adenomas ↑

No indications for CNS effects.

No neurobehavioral examination

Kari et al. (1992); NTP (1989)

F344

Rat

f

0, 25 or 50

Gavage

103 w, 5 d/w

-

25

mononuclear leukaemia ↑

No indications for CNS effects.

No neurobehavioral examination

Kari et al. (1992); NTP (1989)

B6C3F1

mouse

m / f

0, 50 or 100

gavage

103 w, 5 d/w

-

50

m: relative liver weight ↑; non-neoplastic liver changes only at 65 week interim sacrifice

f: combined liver adenomas / carcinomas ↑

No indications for CNS effects.

No neurobehavioral examination

Kari et al. (1992); NTP (1989)

Sprague-Dawley

rat

m / f

0, 20, 64 or 200

gavage

13 w, 5 d/w

20

64

Tremors

>= 64 mg: tremors, depression

200 mg: behavioural changes

Neurobehavioral examination ()

Topping (1988); Topping et al. (1991, 2007)[1]

F344

rat

m / f

0, 25, 50, 100, 200 or 400

gavage

13 w, 5 d/w

50

100

m: body weights ↓;
f: nephrotoxicity ↑

>= 200 mg: lethargy, tremors and/or convulsions.

No neurobehavioral examination

Kari et al. (1992); NTP (1989)

B6C3F1

mouse

m / f

0, 25, 50, 100, 200 or 400

gavage

13 w, 5 d/w

50

100

Lethargy

≤ 100 mg: lethargy in all dosed males and in females only at 100 mg[2]

>= 200 mg: lethargy, tremors and/or convulsions.

No neurobehavioral examination

Kari et al. (1992); NTP (1989)

F344

rat

m / f

0, 63, 125, 250, 500or 1000

gavage

14 d, 5 d/w

250

500

mortality ↑

>= 500 mg: tremors

No neurobehavioral examination

Kari et al. (1992); NTP (1989)

B6C3F1

mouse

m / f

0, 31, 63, 125, 250or 500

gavage

14 d, 5 d/w

125

250

mortality ↑

>= 250 mg: tremors and/or convulsions

No neurobehavioral examination

Kari et al. (1992); NTP (1989)

[1]Study similar to OECD Guideline 424 (Neurotoxicity study in rodents). With regard to the requests of OECD Guideline 408 investigations focussed on neurotoxicity and nephrotoxicity

[2]The observation of lethargy only in males at the low dose range of 25 and 50 mg was not reproducible in the chronic study at doses of 50 and 100 mg and thus is considered to be of no toxicological relevance

As the overview in the Table shows, both the NOAELs and LOAELs that can be derived from subchronic and chronic toxicity studies including both non-neoplastic and neoplastic findings (for details see Section 7.7) are at similar ranges each, with values ranging generally from 20 to 50 mg/kg bw/d for the NOAEL and 50 to 100 mg/kg bw/d for the LOAEL. The observation of a significant increase of mononuclear leukaemia in female F344 rats at 25 mg/kg bw/d (Kari et al., 1992; NTP, 1989) is a questionable effect based on the high spontaneous incidence of these lesion (for detailed discussion see Section 7.7) and is disregarded for deriving a NOAEL relevant for human exposure as no other adverse effects were observed in dosed female rats up to 50 mg/kg bw/d.

Based on the overview of 5 repeated dose toxicity studies by gavage covering 2-week subacute, 13-week subchronic to 103-week chronic studies, effects on the CNS are consistent in rats and mice and occur rapidly after administration and are transient (table 1). In rats, the range of concentrations tested in all studies showed CNS effects at 64 mg/kg/day (13-weeks, rats) and higher, in male and female Sprague-Dawley rats (Topping et al., 1988, 2007, RSS in section 7.9.1), while no CNS effects were observed at 50 mg/kg/day and below, even in chronic studies combined with carcinogenicity (F344 rats, B6C3F1 mice) (Kari et al., 1992; NTP, 1989). The only exception is the report of mild transient tremors in only one Sprague-Dawley male at 50 mg/kg/day in a 2-generation reproductive toxicity study (Blacker et al., section 7.8.1), indicating that this rat strain may display a slightly higher susceptibility. The data of the subchronic and chronic toxicity studies (Kari et al., 1992; NTP, 1989) do not indicate a higher sensitivity of mice compared to rats with regard to toxicologically relevant adverse effects. Based on a weight of evidence considering all the available studies, it can be inferred that there are no CNS effects at 25 mg/kg/day or below. As there was no specific influence of treatment duration, the lowest NOAEL of 20 mg/kg/day from a 13-week study, focused on neurotoxicity in rats, was considered relevant also for long-term exposure and was used as a NOAEL for CNS effects and a possible point of departure for the risk assessment. Benchmark dose modelling from this dataset (see section 7 - DNEL) determined a BMDL10 of 61.2 mg/kg/day.

Inhalation toxicity

There is no repeated dose toxicity study available by the inhalation route. Based on the physico-chemical properties of HQ (vapour pressure, particle size, water solubility), there is a low likelihood that the solid particles reach the deep lung in a significant amount. As a conservative approach, and assuming the absorption is similar by the inhalation route as compared to the oral route, it is usually acceptable to conduct a risk assessment using the oral data and identified adverse effects and route-to route extrapolation to derive a NOAEC for the inhalation route. Based on the discussion above for the oral route, the relevant adverse effect identified in repeated dose toxicity studies considered for the risk assessment is the CNS effects.

 

Dermal toxicity

 

Based on the overall evidence, the NOAEL is 3840 mg/kg bw/d in the Fischer 344 rat for a 14-day dermal exposure. Consequently, the dermal NOAEL is about 15-fold the oral NOAEL of 250 mg/kg after 14-day gavage exposure F344 rats (see Oral toxicity studies; both studies performed as range-finding toxicity studies: NTP, 1989). The difference in dermal and oral repeated dose toxicity is supported by the known low dermal absorption of HQ which amounts to about 10% in comparison to about 100% bioavailability by the oral route. The high dermal NOAEL observed in rats is confirmed by an even higher dermal NOEL of 4800 mg/kg bw/d in the mouse as second species in the 14-day range finding study (NTP, 1989).


Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Because of the dust explosiveness properties shown with the product as manufactured (particle size > 100µm) as well as under standardised conditions (particle size > 63 µm), producing a micronised sample with the particle size distribution required by the test guidelines for a repeated dose inhalation study was not considered feasible under safe conditions. (Communication with ECHA and MSCA).

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Because of the dust explosiveness properties shown with the product as manufactured (particle size > 100µm) as well as under standardised conditions (particle size > 63 µm), producing a micronised sample with the particle size distribution as required by the test guidelines for a repeated dose inhalation study was not considered feasible under safe conditions (Communication with ECHA and MSCA). There are no specific inhalation data or report of local effects on the respiratory tract under the current workplace conditions. Instead, there is a history of eye effects (brown staining of the conjunctiva or cornea, and/or corneal opacities and alterations) reported in workers who had been repeatedly exposed over the years (usually more than 5 years) to very high airborne concentrations of HQ dusts and benzoquinone vapours (section 7.10.1 – Exposure related observations in humans/Health surveillance data, and endpoint summary section 7.5). There are no specific documentation regarding concurrent local respiratory effects but early publications indicated the presence of respiratory tract irritation at the very high airborne concentrations (as high as 20-35 mg/m3) experienced prior to industrial hygiene improvements (Oglesby et al., 1947). These airborne concentrations are no longer relevant to the current workplace conditions since the implementation of pragmatic TWA in many European countries, originating from the ACGIH value set up in the USA to protect against the adverse ocular damage (Oglesby et al., 1947, Pifer et al. 1995) with values all below 2 mg/m3 and most frequently 1 mg/m3 and below. Despite the absence of a clear dose-response and mode of action for the ocular effects, control of workplace airborne concentrations to low levels has also been preventing any potential effects on the respiratory tract.

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
No specific findings in a 14-day repeated dose toxicity studies in rats and mice (NTP studies). In addition, no systemic effects were observed in a 90-day dermal studies in rats exposed to a cream formulation containing 0.5% HQ (i.e. approx. 74 mg/kg/day daily dose for males).

Repeated dose toxicity: via oral route - systemic effects (target organ) neurologic: central nervous system; urogenital: kidneys

Justification for classification or non-classification