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

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

05 Mar 1985 to 27 Mar 1985

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

comparable to guideline study with acceptable restrictions

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1985

Report date:

1985

Materials and methods

Test guideline

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 410 (Repeated Dose Dermal Toxicity: 21/28-Day Study)

Version / remarks:

1981

Deviations:

yes

Remarks:

An occlusive application was used and no statistical analyses were performed.

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:

other: Crl:CD(SD)BR

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Weight at study initiation: 241 – 362 g
- Housing: exclusive rooms, single housed in suspended stainless steel mesh cages
- Diet: Rat and mouse Maintenance diet, ad libitum
- Water: filtered main water, ad libitum via water bottles
- Acclimation period: about 2 weeks

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 19 - 25
- Humidity (%): 40 - 70
- Air changes (per hr): minimum 12
- Photoperiod (hrs dark / hrs light): 12/12

IN-LIFE DATES: From: 05 Mar 1985 To: 27 Mar 1985

Administration / exposure

Type of coverage:

occlusive

Vehicle:

corn oil

Details on exposure:

TEST SITE
- Area of exposure: non-abraded areas of skin
- % coverage: not less than 10 %

Duration of treatment / exposure:

21 days, 6 hours per day

Frequency of treatment:

Daily

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

20 mg/kg bw/day (actual dose received)

Remarks:

Group 2. Low dose

Doses / concentrations 2

Dose / conc.:

200 mg/kg bw/day (actual dose received)

Remarks:

Group 3. Mid dose

Doses / concentrations 3

Dose / conc.:

2 000 mg/kg bw/day (actual dose received)

Remarks:

Group 4. High dose

No. of animals per sex per dose:

5

Control animals:

yes, concurrent no treatment

Details on study design:

- Rationale for animal assignment: Random

Examinations

Observations and examinations performed and frequency:

CAGE SIDE OBSERVATIONS:
- Time schedule: Daily
- Cage side observations: Viability/mortality (twice daily), detailed behavioural observation (once weekly),

DETAILED CLINICAL OBSERVATIONS:
- Time schedule: Daily, including skin irritation which was assessed according to the scale antioned in Any other information on material and method inlc tables.

BODY WEIGHT: Yes
- Time schedule for examinations: Weekly

FOOD CONSUMPTION: Yes
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/animal/day: Yes

OPHTHALMOSCOPIC EXAMINATION:
- Time schedule for examinations: No

HAEMATOLOGY:
- Time schedule for collection of blood: During the final week
- Anaesthetic used for blood collection: No
- Animals fasted: Yes (18 hours)
- How many animals: All animals
- Parameters: haemoglobin concentration(Hb), mean cell volume (MCV), red blood cell count (RBC) and indices: mean cell haemoglobin (MCH), packed cell volume (PCV), mean cell (haemoglobin concentration MCHC); total and differential white cell count (WBC) , platelet count.

CLINICAL CHEMISTRY:
- Time schedule for collection of blood: During the final week
- Animals fasted: Yes (18 hours)
- How many animals: All animals
- Parameters: glutamate oxaloacetate transaminase (GOT/AST), glutamate pyruvate transaminase (GPT/ALT), alkaline phosphatase (Alk.P), blood urea nitrogen (BUN), glucose, inorganic, bilirubin, creatinine, sodium, total protein (TP), potassium, albumin, calcium, albumin/globulin ratio.

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:

GROSS PATHOLOGY: Yes (see Any other information on material and method inlc tables)
HISTOPATHOLOGY: Yes (see Any other information on material and method inlc tables)

Results and discussion

Effect levels

1

Dose descriptor:

NOAEL

Remarks:

Local

Effect level:

> 2 000 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Remarks on result:

other:

Remarks:

No effects observed

2

Dose descriptor:

NOAEL

Remarks:

Systemic

Effect level:

200 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

organ weights and organ / body weight ratios

Target system / organ toxicity

Critical effects observed:

no

Any other information on results incl. tables

ANALYSIS OF FORMULATIONS

The results obtained during the first week of the study were slightly lower than expected (83 - 88 % of nominal). The samples were analysed again and the results obtained were considered to be satisfactory (90 – 94 %) of normal). The values obtained at week 3 were also considered to be acceptable (94 – 96 %).

 

MORTALITY

There were no deaths during the study.

 

CLINICAL OBSERVATIONS

There were no treatment-related clinical changes.

 

SKIN IRRITATION

There was no evidence skin irritation at the application site in any of the treated animals.

 

BODY WEIGHT

There were no treatment-related changes in body weight gain

FOOD CONSUMPTION

Mean food consumptions of test and control groups remained closely comparable and there were no treatment-related changes.

 

HAEMATOLOGY

There were no haematological changes associated with treatment.

 

CLINICAL CHEMISTRY

Clinical chemistry parameters were unaffected by treatment.

 

ORGAN WEIGHTS

A slight increase in absolute and relative liver weights of about 19 per cent was observed in the group 4 animals when compared with the respective control value. This change was considered to be treatment-related. There were no other

changes in absolute or relative organ weights associated with treatment.

 

MACROSCOPIC NECROPSY FINDINGS

All rats had fur loss on the abdominal skin, accompanied in some cases by sores. The severity was similar in all groups. These abdominal skin lesions were probably associated with the occlusion technique. The only finding in the internal viscera was occasional cases of hydronephrosis in the right kidney. There were no findings of any unusual nature or incidence to suggest any gross toxic effect.

 

MICROSCOPIC PATHOLOGY FINDINGS

Minor changes such as low grade hypergranulosis and acanthosis were present in samples of skin from the site of application of the corn oil vehicle in group 1 rats.

Histopathological changes in the treated skin site of group 4 rats were similar to those in group 1. There was no evidence of increased irritation associated the with application of the test article in corn oil.

The most common finding in the liver of both control and treated rats was minor foci of leucocyte accumulation. minimal hepatocellular hypertrophy was probably present in a few animals, as suggested by the slightly increased liver weights but this was difficult to define with certainty against the normal background variations based on the histopathology of relatively few animals. There was no evidence of any degenerative changes in either the liver or kidney to suggest any systemic toxicity due to test article application.

 

Table 1 Overview of results

Dose (mg/kg bw/day)	0	0	20	20	200	200	2000	200	dr
	m	f	m	f	m	f	m	f
Mortality	none
Clinical signs	No treatment-related findings
Body Weight	No treatment-related findings
Food consumption	No treatment-related findings
Haematology	No treatment-related findings
Clin. Chemistry
ALAT						d		d
ASAT						d		d
Urinalysis	Not performed
Organ weights
liver					d^r		i^a,r	i^a,r
gonads					d^r		d^a,r
kidneys							d^a,r
Pathology
Macroscopy	no treatment-related findings
Microscopy
liver: hypertrophy	0/5	0/5	0/5	0/5	0/5	0/5	2/5	3/5
kidney: hydronephrosis	0/5	1/5	2/5	0/5	1/5	1/5	1/5	0/5

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

a absolute organ weight

r relative organ weight

Applicant's summary and conclusion

Conclusions:

Based on increased liver weights and concomitant liver hypertrophy of half of the test animals, the systemic NOAEL is set at 200 mg/kg bw/day. Since no adverse local effects were observed, the local NOAEL is set at >2000 mg/kg bw/day.

Executive summary:

An OECD TG 410-like study as performed in compliance with GLP to assess the subacute dermal toxicity. Groups of 5 male and 5 female Crl:CD(SD)BR rats were dermally exposed to 20, 200 and 2000 mg/kg test item under occlusive conditions for 21 days - 6 hours/day. An additional group was treated with the corn oil vehicle alone and acted as controls. Twice daily all animals were examined to detect any which were dead or moribund.All animals were examined once daily for clinical changes including skin irritation. Individual body weights were recorded on the first day of the test and at weekly intervals throughout the study. Individual food consumption was recorded at weekly intervals throughout the study. Individual blood samples were collected from the orbital sinus of all animals (after an 18 hours fast) during the final week of the study. Laboratory analysis (haematology and clinical chemistry) were performed on individual blood samples. The animals were killed by an intraperitoneal injection of pentobarbitone sodium solution and exsanguination, following about 19 hours without food. A full macroscopic examination was made.

No treatment-related local skin effects were observed. One control animal, four animals given 20 mg/kg and one animal given 200 mg/kg showed slight, mainly reversible erythema. No treatment-related effects were observed on mortality, clinical observations, body weight, food consumption and haematology. In clinical chemistry analyses, females given 200 and 2000 mg/kg showed decreased levels of ASAT (80 % and 82 % of control, respectively) and ALAT (65 and 60 % of control, respectively). These changes were not considered to be treatment-related, since decreases were observed and no dose-response relationship was noted. In both males and females of the 2000 mg/kg dose group, increased absolute liver weights (122 % of control) and relative liver weights (119 % of control) were noted. Male rats given 2000 mg/kg showed decreased absolute weights of the gonads (94 % of control) and kidneys (91 % of control). In male rats given 200 and 2000 mg/kg, decreased relative weights of the gonads (94 % and 92 % of control, respectively) and the kidneys (94 % and 89 % of control, respectively) were seen.

At necropsy, no treatment-related changes were observed. Histopathology showed mild renal hydronephrosis in the control group (1/10) and 20 mg/kg group (2/10). Mild to moderate renal hydronephrosis was seen in 2/10 rats of the 200 mg/kg dose group, and the symptom was severe in one animal of the highest dose group. Hypertrophy of the liver was observed in 5 rats of the highest dose group. In the absence of histopathological correlates at 200 mg/kg, the slight decreases in relative gonad and kidney weight at 200 mg/kg were not considered toxicologically relevant.

Based on increased liver weights and concomitant liver hypertrophy of half of the test animals, the systemic NOAEL is set at 200 mg/kg bw/day. Since no adverse local effects were observed, the local NOAEL is set at >2000 mg/kg bw/day.