1-[1,3-bis(hydroxymethyl)-2,5-dioxoimidazolidin-4-yl]-1,3-bis(hydroxymethyl)urea

Repeated dose toxicity: dermal

Administrative data

Endpoint:

short-term repeated dose toxicity: dermal

Type of information:

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

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Read-across to a well reported subacute toxicity study performed using a close chemical analogue which shows close structural similarity and also releases formaldehyde via hydrolysis. (Both the registered substance and the analogue are highly water-soluble reaction products of formaldehyde and a substituted urea (organic compound found in nature: both are readily hydrolysed, releasing formaldehyde). Source study conducted in accordance with current practice at the time: limited tissue list examined microscopically.

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

1973

Report date:

1973

Materials and methods

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

21-day rabbit dermal toxicity study with haematology and urinalysis plus limited organ weights at necropsy and micropathology (protocol adapted from a US EPA recommendation).

GLP compliance:

no

Remarks:

Pre-GLP study

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

N,N''-methylenebis[N'-[3-(hydroxymethyl)-2,5-dioxoimidazolidin-4-yl]urea]

EC Number:

254-372-6

EC Name:

N,N''-methylenebis[N'-[3-(hydroxymethyl)-2,5-dioxoimidazolidin-4-yl]urea]

Cas Number:

39236-46-9

IUPAC Name:

N',N'''-methylenebis{1-[3-(hydroxymethyl)-2,5-dioxoimidazolidin-4-yl]urea}

Test material form:

solid: particulate/powder

Remarks:

migrated information: powder

Details on test material:

Fine white powder

Test animals

Species:

rabbit

Strain:

other: described as albino rabbits

Sex:

male/female

Details on test animals or test system and environmental conditions:

Initial bodyweights: males 2.19-3.38 kg, females 1.94-3.42 kg.
Individually housed, with free access to food and water.

Administration / exposure

Type of coverage:

occlusive

Vehicle:

unchanged (no vehicle)

Details on exposure:

Test substance applied to the dorsal skin (at least 10% of body area, initially shaved, then reclipped as necessary) daily for 6h/day, 5 days/week over a 3-week period.

Analytical verification of doses or concentrations:

no

Duration of treatment / exposure:

3 weeks (5 days/week).

Doses / concentrations

Remarks:

Doses / Concentrations:
20, 45, 90, 200 mg/kg/day.
Basis:
nominal per unit body weight

No. of animals per sex per dose:

5 males, 5 females.

Control animals:

yes, sham-exposed

Details on study design:

In each group, skin at the test site was abraded in 3 females, 2 males (test sites at the remaining 3 males, 2 females were left as intact skin). Local skin reactions were scored as well as systemic toxicity parameters.

Positive control:

Not required.

Examinations

Observations and examinations performed and frequency:

Bodyweights were recorded and blood plus urine samples collected pretreatment and at study termination.

Sacrifice and pathology:

Examinations at necropsy included measurement of liver, kidney and spleen weights as well as recording of any macroscopic abnormalities.

Other examinations:

Stained sections of lungs, liver, kidneys, spleen, bladder, test site skin and adjacent normal skin plus macroscopic abnormalities were examined microscopically.
Haematology parameters investigated: white blood cells, differential count, haemoglobin, haematocrit.
Urinary parameters investigated: pH, specific gravity, albumin, glucose, ketones, bile, occult blood.

Results and discussion

Results of examinations

Clinical signs:

no effects observed

Description (incidence and severity):

A single female dosed at 90 mg/kg/day died on Day 18 of the test period. This was not attributed to treatment with the test substance. No adverse reactions to treatment were reported.

Dermal irritation:

effects observed, treatment-related

Description (incidence and severity):

Cses of localised slight to mild acute or chronic dermatitis (sometimes with ulceration or pustule formation) were observed. At intact skin test sites, this was seen in 2 animals at 45 mg/kg/day and 4 at 200 mg/kg/day.

Mortality:

no mortality observed

Description (incidence):

A single female dosed at 90 mg/kg/day died on Day 18 of the test period. This was not attributed to treatment with the test substance. No adverse reactions to treatment were reported.

Body weight and weight changes:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

not examined

Urinalysis findings:

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Description (incidence and severity):

except for test site skin lesions in 3/5 males, 1/5 females treated at 200 mg/kg/day. These were superficial and judged to be reversible (and similar changes were seen in one control animal).

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

cases of local local test site dermatitis at higher dose levels.

Details on results:

Light to mild superficial dermatitis, sometimes with focal ulceration and/or pustules, was seen at intact skin test sites in some animals treated at 200 mg/kg/day, and (by microsopic examination only) in one male treated at 45 mg/kg/day. Similar responses were seen in a few animals treated at abraded skin test sites. Daily skin reaction scores during the treatement period never exceeded 1 for erythema (very slight), and were all 0 for oedema (none seen).

Effect levels

1

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: NOAEL for systemic toxicity: no observed effect on bodyweight, haematology, urine, organ weights or pathology other than skin at test sites.

2

Dose descriptor:

LOAEL

Effect level:

45 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

other: Based on local reaction at test sites (for intact skin, seen in 2 animals at this dosage and 3 at 200 mg/kg/day).

3

Dose descriptor:

LOAEL

Effect level:

200 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: Based on local reaction at test sites (in intact skin, seen only in 1 female treated at this dosage).

Target system / organ toxicity

Critical effects observed:

not specified

Any other information on results incl. tables

No evidence of systemic toxicity was observed. A high incidence of pulmonary oedema was seen in lung sections from all groups including controls but this was not associated with any other lung abnormalities and was considered unrelated to treatment.

Applicant's summary and conclusion

Conclusions:

This study found no evidence of systemic toxicity when rabbits were treated dermally (6h/day under occluded dressing) with the tested chemical analogue at dosages up to 200 mg/kg/day. Localised skin reactions were observed. Based on the close similarity of chemical structure and properties, it is predicted that the registered substance would show a similar pattern of toxicological response.

Executive summary:

Rabbits dosed dermally for 15 days (within a 3 -week period) showed local reactions indicative of a mild inflammatory response. In the absence of clinical chemistry tests and with only limited haematology investigations and micropathology list, the observed absence of systemic toxicity at the maximum tested dosage does not provide definitive evidence of low toxicity.