[No public or meaningful name is available]

Carcinogenicity

Description of key information

No standard carcinogenicity studies are available for Hydrocarbons, C6-C10 (even numbered), n-alkanes, isoalkanes, >5% n-hexane. However, data is available for a structural analogue, hexane and presented in the dossier. This data is read across to Hydrocarbons, C6-C10 (even numbered), n-alkanes, isoalkanes, >5% n-hexane based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

Commercial hexane

 

Carcinogenicity Study (OECD TG 451)

Inhalation NOAEC (rat) = 31743 mg/m³

Inhalation NOAEC (mouse) = 10560 mg/m³(females)/ 31380 mg/m³(males)

Key value for chemical safety assessment

Carcinogenicity: via oral route

Endpoint conclusion

Endpoint conclusion:

no study available

Carcinogenicity: via inhalation route

Link to relevant study records

Reference

Reference 1

Endpoint:

carcinogenicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1990-01-23 to 1992-01-20

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: This study is classified as reliable without restrictions because it was conducted in accordance with testing guideline OECD 451 and is GLP compliant.

Justification for type of information:

A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

GLP compliance:

yes (incl. QA statement)

Species:

rat

Strain:

Fischer 344

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Raleigh, NC
- Age at study initiation: 8 weeks
- Weight at study initiation: approx. 167 g males, approx. 119 g females
- Housing: individually in stainless steel wire mesh cages, identified by tail tattoo
- Diet (e.g. ad libitum): Purina Certified Rodent Chow Brand Animal Diet #5002, ad libitum, except during exposure
- Water (e.g. ad libitum): Elizabethtown Water Company, ad libitum, except during exposure
- Acclimation period: 26 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 53 +/- 14
- Air changes (per hr):
- Photoperiod (hrs dark / hrs light): 12 hrs light/12 hrs dark


IN-LIFE DATES: From: Jan. 23, 1990 To: Jan. 29, 1992

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 10,000 l glass and stainless steel exposure chamber
- Method of holding animals in test chamber: individual cages
- Source and rate of air: chamber supplied air, 2000-2130 lpm
- Method of conditioning air: Test substance in a Protectoseal laboratory can passed through a fluid metering pump into teflon tubing to a coiled glass rod in the volatilization generator. Nitrogen was also fed into the volitization generator. A heating element was positioned in the center of the glass coil to aid volatilization. The nitrogen and test substance mixture then entered the exposure chamber.
- Air flow rate: 2000-2130 lpm
- Air change rate: 4.7-5.0 min.
- Method of particle size determination: TSI Aerodynamic Particle Sizer
- Treatment of exhaust air: Air was exhausted through a HEPA filter, charcoal filter, and into a MOCO incinerator. A charcoal drum was used as a back-up in case of incinerator failure.

TEST ATMOSPHERE
- Brief description of analytical method used: GC
- Samples taken from breathing zone: yes, monthly

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Hourly samples were taken from the test chamber and analyzed using a MIRAN 1A Ambient Air Analyzer. In addition, samples were taken monthly and analyzed using GC.

Duration of treatment / exposure:

2 yrs, total of 511 exposures

Frequency of treatment:

6 hrs/day, 5 days/week

Remarks:

Doses / Concentrations:
0, 900, 3000, 9000 ppm
Basis:
other: target concentration

Remarks:

Doses / Concentrations:
0.043, 900, 3000, 9016 ppm
Basis:
analytical conc.

No. of animals per sex per dose:

50 per sex/per group

Control animals:

yes, sham-exposed

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations: mortality, toxicological and pharmacological signs


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to test and weekly thereafter

BODY WEIGHT: Yes
- Time schedule for examinations: 3 times pretest, weekly for first 13 weeks, monthly thereafter


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
2 times pretest, weekly for first 13 weeks, monthly thereafter


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pretest, month 5, termination


HAEMATOLOGY: Yes
- Time schedule for collection of blood: pretest, month 12, month 18, termination
- Anaesthetic used for blood collection: No
- Parameters checked: differential leucocyte counts

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
nasal cavity, cranial cavity, brain, spinal cord, thoracic cavity, abdominal cavity, pelvic cavity, and neck

HISTOPATHOLOGY: Yes
lungs, abdominal aorta, adrenals, bone, bone marrow, brain, esophagus, exorbital lacrimal gland, eyes, gonads, heart, intestine, kidneys, larynx, liver, lymph nodes, nasopharyngeal tissues, nerves, pancreas, pituitary, prostate, salivary gland, seminal vesicles, skin, spinal cord, spleen, stomach, thymic region, thyroid, trachea, urinary bladder, uterus, gross lesions, tissue masses

Statistics:

Body weight, body weight change, and mean food consumption were statistically analyzed.

Clinical signs:

effects observed, treatment-related

Mortality:

mortality observed, treatment-related

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

no effects observed

Details on results:

CLINICAL SIGNS AND MORTALITY
67% of control males and 76% of control females survived. Results for treatment groups were similar. Excess lacrimation was noticed in all groups, including controls, but was increased in 3000 ppm and 9016 ppm males.

BODY WEIGHT AND WEIGHT GAIN
There was a small dose related decrease (0.8-11.2%) in body weight gain in both sexes. This may have been due to reduced food consumption.

FOOD CONSUMPTION
There was decreased food consumption in treatment groups, however, there was no clear dose related response.

OPHTHALMOSCOPIC EXAMINATION
Some corneal dystrophy was seen, however, this is common in Fischer 344 rats and is not considered treatment related.

HAEMATOLOGY
No treatment related effects were noted.

GROSS PATHOLOGY
No macroscopic abnormalities related to treatment were observed.

HISTOPATHOLOGY:
Hyperplasia of the respiratory epithelium was seen most frequently in males and females exposed to 9000 ppm. The 3000 ppm and 9016 ppm groups had the most frequent hypertrophy/hyperplasia of goblet cells. This effect was more severe in exposure groups, and quite severe in the 9016 ppm group. These effects were likely due to mucosal irritation. Intracytoplasmic eosinophilic material in the respiratory epithelial cells, and sustentacular cells of the olfactory epithelium was seen in almost all animals in the exposure groups. This effect was most severe in the 3000 and 9016 ppm groups, but was also seen in the 900 ppm group. Inflammatory cells debris in the nasal lumen was also observed in most treatment groups, along with subacute /chronic inflammation of the nasal mucosa.

Squamous/squamoid metaplasia/hyperplasia of the pseudostratified columnar epithelium was seen in animals from both the control and exposure groups. Highest incidence was in the 9016 ppm group, followed by the 3000 ppm group.

Key result

Dose descriptor:

NOAEC

Effect level:

9 016 ppm

Sex:

male/female

Basis for effect level:

other: 31743 mg/m3;

Remarks on result:

other: Effect type: carcinogenicity

Dose descriptor:

NOAEC

Effect level:

9 016 ppm

Sex:

male/female

Remarks on result:

other:

Remarks:

Effect type: other: systemic toxicity

Dose descriptor:

LOAEC

Effect level:

900 ppm

Sex:

male/female

Basis for effect level:

other: Irritation leading to inflammation effects in the nasoturbinal tissue.

Remarks on result:

other:

Remarks:

Effect type: other: local toxicity (nasalturbinal tissue)

Results of Rat Oncogenicity Study - Body Weights (g)     

Dose	Males - 13 Weeks	Females - 13 Weeks	Males - 105 Weeks	Females - 105 Weeks
0	290.2	179.4	345.8	250.6
900 ppm	283.4 (-2.3%)	174.4 (-2.8%)	342.8 (-0.8%)	250.7 (0%)
3000 ppm	281.3 (-3.1%)	174.9 (-2.5%)	327.3 (-5.3%)	243.3 (-2.9%)
9000 ppm	279.3 (-3.8%)	174.3 (-2.8%)	321.3 (-7.1%)	222.5 (-11.2%)

Dose	Kidney Inflammation	Liver Hemorrhage	Liver Inflammation
Male
0 ppm	2	0	0
900 ppm	0	0	0
3000 ppm	4	0	0
9000 ppm	9	3	2
Female
0 ppm	1	0	0
900 ppm	Not examined	Not examined	Not examined
3000 ppm	Not examined	Not examined	Not examined
9000 ppm	1	0	0

Conclusions:

There were no oncogenic effects in rats exposed to the test substance via inhalation at the maximum concentration tested, 9016 ppm (31736 mg/m3).

Executive summary:

The purpose of this study was to determine the oncogenic effect of inhalation exposure of commercial hexane. Groups of 50 male and 50 female rats were exposed to 0, 900, 3000, or 9016 ppm of test substance for 6 hrs/day, 5 days/week, for 2 yrs. During the study, the animals were examined for clinical signs, mortality, body weight, opthomological, and food consumption effects. At study termination, animals were sacrificed and gross pathology and histopathology performed. Mortalities of exposure groups were consistant with control groups. Body weight gain was significantly reduced in exposure groups. Histopathology revealed dose-related effects in the nasoturbinal tissue in all exposure groups. Therefore, there was no NOAEC level for local irritation effects. The LOAEC level for both sexes was 900 ppm. No oncogenic effects were seen in the exposure groups. The NOAEC for systemic effects was 9016 ppm in rats of both sexes.

Reference 2

Endpoint:

carcinogenicity: inhalation

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

1990-01-23 to 1992-01-20

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: This study is classified as reliable without restrictions because it was conducted in accordance with testing guideline OECD 451 and is GLP compliant.

Justification for type of information:

A discussion and report on the read across strategy is given as an attachment in IUCLID Section 13.

Reason / purpose for cross-reference:

read-across: supporting information

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 451 (Carcinogenicity Studies)

GLP compliance:

yes (incl. QA statement)

Species:

mouse

Strain:

B6C3F1

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River Breeding Laboratories, Inc., Portage, MI
- Age at study initiation: 8 weeks
- Weight at study initiation: approx. 24 g males, approx. 20 g females
- Housing: individually in stainless steel wire mesh cages, identified by tail tattoo
- Diet (e.g. ad libitum): Purina Certified Rodent Chow Brand Animal Diet #5002, ad libitum, except during exposure
- Water (e.g. ad libitum): Elizabethtown Water Company, ad libitum, except during exposure
- Acclimation period: 27 days


ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21-23
- Humidity (%): 53 +/- 14
- Photoperiod (hrs dark / hrs light): 12 hrs light/12 hrs dark


IN-LIFE DATES: From: Jan. 23, 1990 To: Jan. 20, 1992

Route of administration:

inhalation: vapour

Type of inhalation exposure (if applicable):

whole body

Vehicle:

unchanged (no vehicle)

Details on exposure:

GENERATION OF TEST ATMOSPHERE / CHAMBER DESCRIPTION
- Exposure apparatus: 10,000 l glass and stainless steel exposure chamber
- Method of holding animals in test chamber: individual cages
- Source and rate of air: chamber supplied air, 2000-2130 lpm
- Method of conditioning air: Test substance in a Protectoseal laboratory can passed through a fluid metering pump into teflon tubing to a coiled glass rod in the volatilization generator. Nitrogen was also fed into the volitization generator. A heating element was positioned in the center of the glass coil to aid volatilization. The nitrogen and test substance mixture then entered the exposure chamber.
- Air flow rate: 2000-2130 lpm
- Air change rate: 4.7-5.0 min.
- Method of particle size determination: TSI Aerodynamic Particle Sizer
- Treatment of exhaust air: Air was exhausted through a HEPA filter, charcoal filter, and into a MOCO incinerator. A charcoal drum was used as a back-up in case of incinerator failure.

TEST ATMOSPHERE
- Brief description of analytical method used: GC
- Samples taken from breathing zone: yes, monthly

Analytical verification of doses or concentrations:

yes

Details on analytical verification of doses or concentrations:

Hourly samples were taken from the test chamber and analyzed using a MIRAN 1A Ambient Air Analyzer. In addition, samples were taken monthly and analyzed using GC.

Duration of treatment / exposure:

2 yrs, total of 504 exposures

Frequency of treatment:

6 hrs/day, 5 days/week

Remarks:

Doses / Concentrations:
0, 900, 3000, 9000 ppm
Basis:
other: target concentration

Remarks:

Doses / Concentrations:
0.039, 900, 3000, 9018 ppm (0, 3168, 10560, 31680 mg/m3)
Basis:
analytical conc.

No. of animals per sex per dose:

50 per sex/per group

Control animals:

yes, sham-exposed

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice daily
- Cage side observations: mortality, toxicological and pharmacological signs


DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: prior to test and weekly thereafter

BODY WEIGHT: Yes
- Time schedule for examinations: 3 times pretest, weekly for first 13 weeks, monthly thereafter


FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
2 times pretest, weekly for first 13 weeks, monthly thereafter


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: pretest, termination


HAEMATOLOGY: Yes
- Time schedule for collection of blood: pretest, month 12, month 18, termination
- Anaesthetic used for blood collection: No
- Parameters checked: differential leucocyte counts

Sacrifice and pathology:

GROSS PATHOLOGY: Yes
nasal cavity, cranial cavity, brain, spinal cord, thoracic cavity, abdominal cavity, pelvic cavity, and neck

HISTOPATHOLOGY: Yes
lungs, abdominal aorta, adrenals, bone, bone marrow, brain, esophagus, exorbital lacrimal gland, eyes, gonads, gall bladder, heart, intestine, kidneys, larynx, liver, lymph nodes, nasopharyngeal tissues, nerves, pancreas, pituitary, prostate, salivary gland, seminal vesicles, skin, spinal cord, spleen, stomach, thymic region, thyroid, trachea, urinary bladder, uterus, gross lesions, tissue masses

Statistics:

Body weight, body weight change, and mean food consumption were statistically analyzed.

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Histopathological findings: neoplastic:

effects observed, treatment-related

Details on results:

CLINICAL SIGNS AND MORTALITY
85% of control males and 80% of control females survived. Results for treatment groups were similar.

BODY WEIGHT AND WEIGHT GAIN
There were no statistically significant differences in body weight or body weight gains in male mice. Females in the 9018 ppm group had significantly reduced weight gain (14%).

FOOD CONSUMPTION AND COMPOUND INTAKE
The 9000 ppm group males had lower food consumption in 29 of 35 measurements. Food consumption was also lower then controls in the 9018 ppm females for 19 of the first 20 measurements.

OPHTHALMOSCOPIC EXAMINATION
No treatment related effects were seen.

HAEMATOLOGY
No treatment related effects were noted.

GROSS PATHOLOGY
Increases in liver masses and nodules were seen in 9018 ppm females. There was also a dose related increase in uterine cysts.

HISTOPATHOLOGY: NON-NEOPLASTIC
Females in the 9018 ppm group had a dose related decrease in the severity and incidence of cystic endometrial hyperplasia, and uterine cysts. There was also an increase in proliferative lesions of the pituitary in all female treatment groups, however, this did not seem to be dose related. These effects may have been due to hormonal imbalances due to treatment.

HISTOPATHOLOGY: NEOPLASTIC
There was a dose related increase in hepatocellular adenomas and carcinomas in females. There was a statistically significant increase in benign tumors, but not in malignant tumors. Incidence in 9018 ppm females was similar to control males.

Key result

Dose descriptor:

NOAEC

Effect level:

3 000 ppm

Sex:

female

Remarks on result:

other: Effect type: carcinogenicity

Key result

Dose descriptor:

LOAEC

Effect level:

9 018 ppm

Sex:

female

Basis for effect level:

other: Increase in liver masses and nodules, however liver masses and tumors in B6C3F1 mice are known to be sensitive to body weight changes, especially in female B6C3F1 mice (NTP 2004)

Remarks on result:

other: Effect type: carcinogenicity

Key result

Dose descriptor:

NOAEC

Effect level:

9 018 ppm

Sex:

male

Remarks on result:

other: Effect type: carcinogenicity

Significant Results of Oncegenicity Study in Mice

	0 ppm	900 ppm	3000 ppm	9018 ppm
Macroscopic Incidence of Uterine Cysts
No. Examined	50	50	49	50
Uterine Cysts	21	18	14	11
Liver Neoplasia Females
No. Examined	50	50	49	50
Hepatocellular Adenomas	4	6	4	10
Hepatocellular Carcinoma	3	2	5	6
Total Neoplasms	7	8	9	16
Liver Neoplasia Males
No. Examined	49	50	50	50
Hepatocellular Adenomas	10	5	7	10
Hepatocellular Carcinoma	7	11	10	3
Total Neoplasms	17	16	17	13
Incidence of Cystic Endometrial Hyperplasia
No. Examined	50	32	32	50
No. of Incidences	48	29	27	44
Trace	3	4	3	10
Mild	14	13	8	19
Moderate	23	10	15	15
Severe	8	2	1	0
Pituitary Proliferative Lesions in Females
No. Examined	45	48	48	49
Hyperplasia	2	4	4	6
Adenoma	0	6	7	5
Adenocarcinoma	0	0	1	0
Total Neoplasms	0	6	8	5
Total Proliferative Lesions	2	10	12	11

Conclusions:

Liver tumors in B6C3F1 mice are known to be sensitive to body weight changes, especially in female B6C3F1 mice (NTP 2004). Therefore, the increased incidence of liver masses and nodules in female mice should be interpreted with care. The NOAEC level for oncogenic effects in female mice is 3000 ppm (10560 mg/m3). The LOAEC for female mice was 9018 ppm (31680 mg/m3). No oncogenic effects were seen in male mice. The NOAEC level for oncogenic effects in male mice is 9018 ppm (31680 mg/m3).

Executive summary:

The purpose of this study was to determine the oncogenic effect of inhalation exposure of commercial hexane. Groups of 50 male and 50 female mice were exposed to 0, 900, 3000, or 9018 ppm (0, 3168, 10560, 31680 mg/m3) of test substance for 6 hrs/day, 5 days/week, for 2 yrs. During the study, the animals were examined for clinical signs, mortality, body weight, opthamological, and food consumption effects. At study termination, animals were sacrificed and gross pathology and histopathology performed. Mortalities of exposure groups were consistant with control groups. Histopathology revealed increased liver masses and nodules in female mice at the 9018 ppm exposure group. Liver tumors in B6C3F1 mice are known to be sensitive to body weight changes, especially in female B6C3F1 mice (NTP 2004). Therefore, the increased incidence of liver masses and nodules in female mice should be interpreted with care. The NOAEC level for oncogenic effects in female mice is 3000 ppm (10560 mg/m3). The LOAEC for female mice was 9018 ppm (31680 mg/m3). No oncogenic effects were seen in male mice. The NOAEC level for oncogenic effects in male mice is 9018 ppm (31680 mg/m3).

 

NTP. 2004. NTP Technical Report on the Toxicology and Carcinogenesis Studies of Stoddard Solvent IIC (CAS No. 64742-88-7) in F344/N Rats and B6C3F1 Mice (Inhalation Studies). NIH Publication No. 04-4453.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEC

10 560 mg/m³

Study duration:

chronic

Species:

mouse

Quality of whole database:

2 key read across studies from a structural analogue available for assessment.

Carcinogenicity: via dermal route

Endpoint conclusion

Endpoint conclusion:

no study available

Justification for classification or non-classification

Based on available read across data, Hydrocarbons, C6-C10 (even numbered), n-alkanes, isoalkanes, >5% n-hexane is not classified as carcinogenic under the new Regulation (EC) 1272/2008 on classification, labeling and packaging of substances and mixtures (CLP).

Additional information

No standard carcinogenicity studies are available for Hydrocarbons, C6-C10 (even numbered), n-hexane, isoalkanes, >5% n-hexane. However, data is available for a structural analogue, hexane and presented in the dossier. This data is read across to Hydrocarbons, C6-C10 (even numbered), n-alkanes, isoalkanes, >5% n-hexane based on analogue read across and a discussion and report on the read across strategy is provided as an attachment in IUCLID Section 13.

Commercial hexane

A key study examined the oncogenic effect of inhalation exposure from commercial hexane (API, 1995a). Groups of 50 male and 50 female rats were exposed to 0, 900, 3000, or 9016 ppm of test substance for 6 hrs/day, 5 days/week, for 2 yrs. Mortalities of exposure groups were consistant with control groups. Body weight gain was significantly reduced in exposure groups. Histopathology revealed dose-related effects in the nasoturbinal tissue in all exposure groups. Therefore, there was no NOAEC level for local irritation effects. The LOAEC level for both sexes was 900 ppm. No oncogenic effects were seen in the exposure groups. The NOAEC for systemic effects was 9016 ppm in rats of both sexes.

 

In a key carcinogenic study the oncogenic effect of inhalation exposure of commercial hexane was determined (API, 1995b). Groups of 50 male and 50 female mice were exposed to 0, 900, 3000, or 9018 ppm (0, 3168, 10560, 31680 mg/m3) of test substance for 6 hrs/day, 5 days/week, for 2 yrs. Histopathology revealed increased liver masses and nodules in female mice at the 9018 ppm exposure group. Liver tumors in B6C3F1 mice are known to be sensitive to body weight changes, especially in female B6C3F1 mice, as referenced in NTP 2004. Therefore, the increased incidence of liver masses and nodules in female mice should be interpreted with care. The NOAEC level for oncogenic effects in female mice is 3000 ppm (10560 mg/m3). The LOAEC for female mice was 9018 ppm (31680 mg/m3). No oncogenic effects were seen in male mice. The NOAEC level for oncogenic effects in male mice is 9018 ppm (31680 mg/m3).