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Description of key information

Several repeated oral dose toxicity studies were available. The benchmark dose method was used to derive a BMDL10. The most critical effect was determined to be the renal hyperplasia in male rats. Combining the subchronic and chronic studies in rats a BMDL10 of 369 mg/kg bw/day has been derived.
In a 90-day repeated-dose dermal toxicity study in white rabbits toxicologically non relevant effects were observed. Therefore the highest dose tested (500 mg/kg bw/day) was designated as the NOAEL for systemic toxicity.
In a 14-day inhalation study with rats pathological examinations revealed no treatment-related changes in either males or females. Morphological changes indicating irritation were found in nasal cavity, larynx and lung of male and female mid- and high-concentration animals. A NOAEC of 48.2mg/m³ was determined.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Endpoint conclusion
Dose descriptor:
BMDL10
369 mg/kg bw/day
Study duration:
chronic
Species:
rat

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEC
48.2 mg/m³
Study duration:
subacute
Species:
rat

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Dose descriptor:
NOAEL
500 mg/kg bw/day
Study duration:
subchronic
Species:
rabbit

Additional information

Oral:

Sub-chronic repeated dose studies:

Two repeated dose drinking water studies (13 weeks) were performed according to OECD 408 and in compliance with GLP. The first drinking water study was conducted with F344/DuCrj rats (JBRC.0459, 2003). 10 rats per sex were exposed to 0, 1250, 2500, 5000, 10000 and 20000 mg/L. Analytical concentrations in drinking water were determined with HPLC. Based on chemical intake data the mean intake of test substance across the duration of the study was estimated to be 96, 185, 369, 687, and 1514 mg/kg/day in males and 163, 313, 652, 1000, and 1702 mg/kg/day in females. Food intake, water intake and body weight were determined weekly. After 13 weeks urinalysis, haematology, blood chemistry, gross pathology, organ weights and histopathology were examined. Effects on the red blood cell parameters and changes in histopathology of the kidney and bladder were observed in rats dosed with 10000 mg/L test substance and above. Based on these results the NOAEL was determined to be 5000 mg/L. This corresponds with an intake of 369 mg/kg/day in males and 652 mg/kg/day in females.

 

A similar study was conducted in Cru:BDF1 mice (OECD 408) (JBRC 0460, 2003). The study design and examination/observations were similar to the study in rats. However the dose levels differed and were 0, 1250, 2500, 5000, 10000 and 20000 mg/L in drinking water. The mean intake of test substance across the duration of the study was estimated to be 182, 390, 765, 1178, and 2135 mg/kg/day in males and 236, 478, 948, 1514, and 2483 mg/kg/day in females. Effects on red blood cell parameters (Females: hemoglobin, MCHC, MCV and males:reticulocytes) were found in mice dosed with 20000 mg/L test substance. In males dosed with ≥5000 mg/L changes in blood chemistry parameters (decreases in cholesterol and phospholipids) were measured and suggest an effect on the liver however no histopathological changes were observed in the liver. Based on these effects the NOAEL was determined to be 2500 mg/L and this corresponds to an intake of 390 mg/kg/day.

 

2-Phenoxyethanol was administered via the diet to Wistar rats in doses of 0, 500, 2500 and 10000 ppm for a period of 13 weeks (Bayer AG, 2002). Additional groups were treated with 0 and 10000 ppm in the same way and observed for a subsequent treatment-free period of 4 weeks for recovery. Satellite groups comprising also recovery groups were treated with doses of 0, 500, 2500 and 10000 ppm for 13-14 weeks or 0 and 10000 ppm, respectively. Animals of all satellite groups were subjected to whole-body-perfusion during necropsy for possible neuropathological investigations. However, since the functional observation battery, motor activity determination and reflex testing did not indicate any treatment related effects, no further neuropathological examinations were performed. Survival was unaffected by 2-phenoxyethanol treatment. Furthermore, there were no treatment-related effects on behaviour, body weight/body weight gains, feed/water consumption, haematological or clinical chemistry parameters, organ weights, or gross or histopathological findings. Some organ weight changes were seen in the treated and/or recovery groups, but there was no consistent pattern of effects and no corresponding histopathology changes; therefore, these organ weight changes were not interpreted to be toxicologically significant. There were no signs of neurotoxicity in the functional observational battery, motor activity test, reflex testing or grip strength. No inflammatory changes in kidneys were identified at any dose levels and the organ weight pattern including the kidney did not indicate an adverse effect at any dose level tested. The NOAEL for this study was 10000 ppm, the highest concentration tested in the diets (corresponding to 700-940 mg/kg bw/day).

 

In another experiment, 2 -phenoxyethanol was administered via gavage for 13 weeks to CD rats at doses of 0, 80, 400, and 2000 mg/kg bw/day (Nipa Laboratories, 1977). At 2000 mg/kg bw/day, clinical signs included occasional episodes of prostration and lethargy were observed shortly following 2-phenoxyethanol dosing. Females were more affected than males. These episodes occurred as isolated or low incidence events when dosing was initiated and resolved with continued dosing. Four high-dose females died during the treatment period and their deaths were considered treatment related, although no gross or histopathological changes were identified (one died of bronchopneumonia). The bodyweights of high-dose male and female rats were decreased. Clinical chemistry data showed toxicity to red blood cells and other effects that are associated with this phenomenon (decreased erythrocyte number, decreased packed cell volume and decreased haemoglobin concentration, and kidney inflammation with epithelial cells and polymorphonuclear leukocytes in the urinary sediment) at 2000 mg/kg bw/day. Liver, kidney and thyroid weights were increased at 2000 mg/kg bw/day. Inflammation of the kidneys also was seen in males at 400 mg/kg bw/day. Minor testicular changes were noted in a few high-dose male rats, but these changes were considered to be of equivocal toxicological significance. Furthermore, testicular changes have not been noted in any other studies with 2-phenoxyethanol. The NOAEL in this study was 80 mg/kg bw/day. The NIPA study, 90-day oral (gavage) study in rats is a pre-GLP study from 1977 in which dose levels of 80, 400 and 2000 mg/kg bw were used. The highest dose level in this study by far exceeds the limit dose requested for repeated dose toxicity studies according to actual OECD guidelines for (1000 mg/kg body weight). Moreover, the purity of the phenoxyethanol used in this study is unknown: it may have contained a high level of phenol. Due to the bolus dosing characteristic oral gavage is not the most relevant route of exposure in the view of the use of 2-phenoxyethanol.

 

Chronic repeated dose studies:

Two repeated dose (104 weeks) OECD 451 and GLP compliant studies are available in rats and mice (JBRC.0498 and JBRC.0.497, 2007) (see also robust study summaries in chapter 7.7). A drinking water study was conducted with F344/DuCrlCrlj rats. 50 rats per sex were exposed to nominal concentrations of 0, 2500, 5000, and 10000 mg/L. Analytical concentrations in drinking water were determined with HPLC. Based on chemical intake data the mean intake of test substance across the duration of the study was estimated to be 124, 249, and 510 mg/kg/day in males and 191, 380, and 795 mg/kg/day in females. Mortality and clinical signs were investigated. Food intake, water intake and body weight were determined weekly during the first 13 weeks followed by measurements once every 4 weeks until study termination. After 104 weeks urinalysis, haematology, blood chemistry, gross pathology at necropsy, organ weights and histopathology (both non-neoplastic and neoplastic lesions) were examined. No treatment related neoplastic lesions were found in either sex.

 

Another chronic drinking water study in B6 D2F1/Crlj mice was conducted. The study design and examination/observations were similar to the chronic study in rats. However, the dose levels differed and were 0, 5000, 10000 and 20000 mg/L. Based on chemical intake data the mean intake of test substance across the duration of the study was estimated to be 468, 898, and 1701 mg/kg/day for males and 586, 1072, and 2058 mg/kg/day for females. After 104 weeks repeated dosing, no treatment related neoplastic lesions were found in either sex.

 

Both chronic studies showed that there is no evidence of carcinogenic activity of 2-phenoxyethanol in male or female rat and mice. Although no carcinogenic effects were identified, effects on the blood chemistry parameters and histopathological changes were found that are in line with the above mentioned sub-chronic drinking water studies (JBRC 459 and 460, 2003). In the chronic drinking water study in mice cholesterol, phospholipids, and triglycerides were decreased in male mice and body weight was decreased in both sexes. Based on these results the NOAEL for mice was determined to be 468 mg/kg/day. In the chronic drinking water study in rats increased incidences and severity of renal pelvis urothelial hyperplasia were observed in male rats. Additionally, increased incidences of renal papillary mineralization and necrosis were observed in male rat. These non-neoplastic histopathological changes were minimal (grade 1 or 2) and were not observed in females. It was concluded that the kidney was the target organ in male but not female rats. Based on these results the NOAEL in the chronic drinking water study in rats was determined to be 249 mg/kg/day.

 

NOAEL/BMDL10 determination:

Several repeated dose studies are available were 2-phenoxyethanol was administered via the oral route. Among these studies a subchronic study involving dosing via diet (Bayer, 2002) and an additional study involving dosing by oral gavage are available, but the latter one was concluded of limited relevance/validity (Nipa Labs, 1977). In the Bayer study no adverse effects were detected up to the highest administered dose, approximately 700 mg/kg bw/d via diet.

In contrast several drinking water studies are available were effects were identified which could be used for derivation of a BMDL10. Histopathological findings from the available chronic as well as the sub-chronic drinking water studies indicate that the kidneys are the relevant target organs. Although treatment-related haemolytic effects were found in the sub-chronic drinking water studies in mice and rats, these effects occurred at higher dose levels compared to the effects on the kidneys. Therefore, the pathological findings in the kidneys were used to determine the NOAEL in the repeated dose drinking water studies. The urothelial hyperplasia of the renal pelvis in male rats was the most sensitive endpoint (JBRC.0459, 2003; JBRC 0497, 2007). Based on this effect the NOAELs were determined to be 248 and 369 mg/kg bw/d for male rats in the chronic and sub-chronic studies, respectively. The LOAELs were 510 and 687 mg/kg bw/d for male rats in the chronic and sub-chronic studies, respectively. Studies in mice showed higher NOAELs, thus, the studies with rats were considered as appropriately conservative for risk assessment.

Due to the fact that dose selections were different in the chronic and sub-chronic studies and that these dose selections influenced the NOAELs identified in these studies, a benchmark dose approach was used to determine a study-independent, “true” NOAEL, i.e. a BMDL10. The BMDL10 derived from the single studies were 356 and 350 mg/kg bw/d for the chronic and subchronic study, respectively. In addition, to get a more robust analysis, data from the chronic and sub-chronic studies in male rats were combined and the combined BMDL10 was determined to be 369 mg/kg bw/d. Combining both studies was justified, because progression of the renal effects was not observed with increased exposure duration. The BMDL10 of 369 mg/kg bw/d corresponds to the NOAEL from the subchronic drinking water study and lies between the LOAEL of 510 mg/kg bw/d and the NOAEL of 248 mg/kg bw/d of the chronic study. In conclusion, a BMDL10 of 369 mg/kg bw/d was considered as an appropriately conservative point of departure for DNEL-derivaton (DNEL(oral, long-term)).

 

Additional repeated dose oral toxicity studies:

Two 14 -days dose range finding studies were conducted in rats and mice (JBRC.0453 and JBRC.0454, 2003). In a drinking water study F344/DuCrj rats and DBF1 mice were exposed to 0, 1600, 4000, 7000, 10000, 17500, and 25000 mg/L (nominal) test substance. Clinical signs, mortality, food consumption, water consumption and body weight were observed or measured on the 3rd and 7th study day. After 14 days of exposure haematology, clinical chemistry and urinalysis were measured. Finally the rats were sacrificed and gross and histopathology were conducted. In rats, no mortality was observed in both sexes. Body weight growth, food intake and water intake were suppressed in both sexes in the higher dose groups. Significant changes in haematology were observed in all dose groups but predominantly in the higher dose groups (≥ 17500 mg/L). Significant effects on clinical chemistry were observed in rats dosed with ≥ 17500 mg/L test substance. Relative organ weights (liver and kidneys) were increased in the higher dose groups (≥10000 mg/L).In mice, no mortality was observed in both sexes. In the 25000 mg/L dose group body weight growth was suppressed in both sexes. Food intake was suppressed in the higher dose groups as well as water intake (≥10000 mg/L). No significant changes in haematology were observed. In female mice increased urea nitrogen concentration were measured after administration of 25000 mg/L test substance. No changes in clinical chemistry were observed in male mice. Increase in kidney weights were observed in the higher dose groups (≥7000 mg/L). These results were used to determine the dosage of a 13-week drinking water study in rat and mice described above.

 

Dermal:

In a 90-day repeated-dose dermal toxicity study, white rabbits were administered 0, 50, 150, and 500 mg/kg bw/d 2-phenoxyethanol for 6 h/d for 5 d/week during 13 weeks (The Dow Chemical Company, 1986; Breslin et al. 1991). There were no signs of systemic toxicity. Dermal findings included transient observations of erythema and slight scaling in rabbits exposed to 500 mg/kg bw/d. There were no associated gross or histopathological findings, thus, these dermal observations were not interpreted to be toxicologically significant. Therefore, 500 mg/kg bw/d was considered to be the NOAEL for systemic toxicity.

 

Inhalation:

The inhalation study was performed to characterize the toxicity profile of 2-phenoxyethanol including target organs and determination of a NOAEL upon exposure to a liquid aerosol (BASF AG, 2007). Special emphasis was paid on potential irritation in the respiratory tract. No mortality occurred and no signs of systemic toxicity were observed. There were no treatment-related changes in the clinical-chemical and haematological parameters. Body weight was reduced in the high dose group. The upper respiratory tract showed mild signs of reaction (degeneration, metaplasia, inflammatory cell infiltration); most sensitive seemed to be the respiratory epithelium of the nose, especially in the anterior septum area. The epithelial lining other sites, e.g. respiratory epithelium of lungs, transitional epithelium larynx was also affected but appeared to be less sensitive. The base of the epiglottis was covered by metaplastic squamous epithelium in high concentration males and females and one femaleof the mid-dose group.Pathological examinations revealed no treatment-related changes in either males or females. Morphological changes indicating irritation were found in nasal cavity, larynx and lung of male and female mid- and high-concentration animals.A NOAEC of48.2mg/m³ was determined.


Repeated dose toxicity: via oral route - systemic effects (target organ) urogenital: kidneys

Repeated dose toxicity: inhalation - systemic effects (target organ) respiratory: larynx; respiratory: lung; respiratory: nose

Justification for classification or non-classification

The available data are conclusive but not sufficient for classification.

Oral: no classification (effects above the cut-off values)

Dermal: no classification (effects above the cut-off values)

Inhalation: no classification (no relevant effects in the lung; irritation potential in the upper respiratory tract)