Ethyl [2-(4-phenoxyphenoxy)ethyl]carbamate

Repeated dose toxicity: inhalation

Administrative data

Endpoint:

short-term repeated dose toxicity: inhalation

Type of information:

experimental study

Adequacy of study:

key study

Study period:

20 Apr 1987 to 17 Jun 1987

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1987

Report date:

1987

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 412 (28-Day (Subacute) Inhalation Toxicity Study

Version / remarks:

May 1981

GLP compliance:

yes

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ethyl [2-(4-phenoxyphenoxy)ethyl]carbamate

EC Number:

276-696-7

EC Name:

Ethyl [2-(4-phenoxyphenoxy)ethyl]carbamate

Cas Number:

72490-01-8

Molecular formula:

C17 H19 N O4

IUPAC Name:

ethyl [2-(4-phenoxyphenoxy)ethyl]carbamate

Test animals

Species:

rat

Strain:

Wistar

Remarks:

KFM-Han

Sex:

male/female

Administration / exposure

Route of administration:

inhalation: aerosol

Type of inhalation exposure:

nose only

Vehicle:

other: ethanol

Mass median aerodynamic diameter (MMAD):

3 µm

Geometric standard deviation (GSD):

1.9

Duration of treatment / exposure:

6 hours/day

Frequency of treatment:

5 days/week, total of 21 exposures

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

10 mg/m³ air (nominal)

Remarks:

Group 2: Low dose, equivalent to 11 mg/m³ air (actual concentration)

Doses / concentrations 2

Dose / conc.:

100 mg/m³ air (nominal)

Remarks:

Group 3: Mid dose, equivalent to 99 mg/m³ air (actual concentration)

Doses / concentrations 3

Dose / conc.:

1 000 mg/m³ air (nominal)

Remarks:

Group 4: High dose, equivalent to 1050 mg/m³ air (actual concentration)

No. of animals per sex per dose:

5

Control animals:

yes, concurrent no treatment

Results and discussion

Effect levels

1

Key result

Dose descriptor:

NOAEL

Remarks:

Local

Effect level:

> 1 000 mg/m³ air (nominal)

Based on:

test mat.

Sex:

male/female

Remarks on result:

other: no local effects observed. Equivalent to 1050 mg/m³ air (actual concentration)

2

Key result

Dose descriptor:

NOAEL

Remarks:

Systemic

Effect level:

100 mg/m³ air (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

clinical biochemistry

food consumption and compound intake

organ weights and organ / body weight ratios

Remarks on result:

other: Equivalent to 99 mg/m³ air (actual concentration)

Target system / organ toxicity

Key result

Critical effects observed:

no

Any other information on results incl. tables

Exposure system monitoring

The particle size distribution determined using a Mercer Impactor. The mean (standard deviation) of the percentage of the aerosol sampled which was collected on the 3 µm (mass median aerodynamic diameter) stage or less was found to be 97.4 % (SD = 1.91).

The temperature and oxygen content measurements showed no unusual excursions. The humidity measurements were discontinued after two days due to the alcohol solvent affecting the sensor and thereby the humidity readings.

Mortality: All rats survived the study periods.

Clinical signs: No signs of toxicity were seen during the study.

Food consumption: Food was slightly in the high dose male animals at the end of the treatment period. The food consumption for all other groups were similar for the male and female animals.

Body weights: Body weight gains were slightly reduced in the high dose (group 4) male animals. This was noted as well in reduced terminal body in the group 4 males. The body weights for all other groups were similar for the male and female animals.

Ophthalmoscopy: No treatment-related effects were noted.

Haematology: The of haematological data indicated no changes of toxicological significance at the end of exposure for the treated groups, nor at the end of the treatment-free recovery period for group 4.

Treatment-unrelated: All differences in the results of the haematology parameters were considered to be incidental and of normal biological variation when compared to that of the controls.

Clinical biochemistry: For biochemical data no changes of toxicological significance were noted at the end of exposure for the treated groups; however a slightly increased potassium level (by 22%) and chloride level (by 5%) for males, and slightly increased albumin level (by 11 % and total protein level (by 9%) for females was noted for group 4 when compared to controls. These findings were considered to be of an adaptive nature due to the treatment and found to be reversible at the end of the treatment-free (recovery) period.

Treatment- unrelated: All other differences in the results of the clinical biochemistry parameters were considered to be incidental and of normal biological variation when compared to that of the controls.

 

Sacrifice and pathology:

Organ weight and organ weight ratios

The following statistically significant changes in absolute and relative organ weights noted in group 4 as compared to controls:

In males: Lungs displayed increased ratios in group 4. Liver displayed increased ratios in group 4.

In females: Liver displayed increased weights and ratios in group 4. Kidneys displayed increased ratios in group 4.

These changes were not considered to be of toxicological significance as there were no correlates of these changes with the histological and biochemical findings.

Macroscopic findings:The macroscopic findings recorded were unremarkable.

Microscopic findings: No treatment related microscopic findings were recorded.

The various spontaneous microscopic findings recorded are within the normal range observed at these ages and in this strain of rat. They may be attributed to sub-clinical illness, spontaneous congenital abnormalities or physiological status.

Table 1 Overview of results

Dose (mg/m3)	1.5	1.5	11	11	99	99	1050	1050	dr
	m	f	m	f	m	f	m	f
Mortality	none
Clinical signs	No treatment-related findings
Body Weight							d
Food consumption							d
Ophthalmoscopy	No treatment-related findings
Haematology
haemoglobin								ic
Clin. Chemistry
bilirubin, total							dc
potassium							ic
chloride							ic
albumin								ic
protein, total								ic
calcium							dc
urea						dc
sodium						dc
Organ weights
lungs							ic^r
liver							ic^r	ic^a,r
testes							ic^r
kidneys								ic^r
adrenal						dc^a,r
Pathology
Macroscopy	No treatment-related findings
Microscopy	No treatment-related findings

dr dose related

dc/ic statistically significantly decreased/increased compared to the controls

d/i decreased/increased, but not statistically significantly compared to the controls

^aabsolute organ weight

^rrelative organ weight

Applicant's summary and conclusion

Conclusions:

Based on increased liver and kidney weights and clinical biochemical findings, the systemic NOAEL is set at 99 mg/m3. Since no adverse local effects were observed, the local NOAEL is set at >1050 mg/m3.

Executive summary:

The study was performed in accordance with OECD TG 412 and in compliance with GLP. Four groups of Wistar, KFM-Han rats, each containing 5 males and 5 females, inhaled 1.5, 11, 99 or 1050 mg/m3 test substance using ethanol as vehicle. The exposure was 6 hours per day for 5 days per week for 29 days. The mean particle size of the aerosol sampled which was 3 µm and the GSD 1.9 μm. No mortality occurred. No clinical or ocular abnormalities were observed. Body weight gain was decreased in males at 1050 mg/m3 (terminal body weight 93 % of control) at the end of the exposure period. Also a decrease in food consumption was observed in these males. At haematology, haemoglobin was slightly, but significantly decreased at 1050 mg/m3 in females (94 % of control). Clinical biochemistry investigations showed a dose-dependent and significant decrease in total bilirubin (72 % of control) and a dose-dependent and significant increase in potassium and chloride (122 % and 105 % of control, respectively) in the highest dosed males. Increased potassium may indicate kidney insufficiency. Calcium was slightly but significantly decreased in these males (97 % of control). In the females, urea was significantly decreased at the 99 mg/m3 dose (78 % of control) and sodium was slightly but significantly decreased at the highest dose (99 % of control). Albumin and total protein were both significantly increased at the highest dose level (111 % and 109 % of control, respectively). In the recovery groups, all values were normal again. Relative weights of the lungs, liver and testis were significantly increased in males of the highest dose group (116 %, 114 % and 116 %, respectively). In females of the highest dose group, absolute and relative liver weight were significantly increased (127 % and 134 %, respectively). Relative kidney weight was significantly increased (116 %) at the highest dose. Absolute and relative adrenals weight were significantly decreased (both 81 %) at 99 mg/m3. However, in the absence of any decreases at the high dose level this finding was considered not toxicologically relevant. Changes in relative testes and lung weight might be due to decreased terminal body weight. Macroscopically and microscopically no treatment-related effects were observed. Males of the control group and the 1050 mg/m3 dose group showed similar histopathological findings, namely bronchial associated lymphoid tissue hyperplasia (2/5 and 1/5, resp.) and interstitial pneumonitis (5/5 and 4/5, resp.) of the lungs, and mononuclear inflammatory cell foci (3/5 and 1/5, resp.) of the liver. Females of both the control group and the 1050 mg/m3 dose group showed nephrocalcinosis of the kidneys. Based on increased liver and kidney weights and clinical biochemical findings, the systemic NOAEL is set at 99 mg/m3. Since no adverse local effects were observed, the local NOAEL is set at >1050 mg/m3.