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Please be aware that this old REACH registration data factsheet is no longer maintained; it remains frozen as of 19th May 2023.

The new ECHA CHEM database has been released by ECHA, and it now contains all REACH registration data. There are more details on the transition of ECHA's published data to ECHA CHEM here.

Diss Factsheets

Administrative data

Description of key information

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
sub-chronic toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Fully reported study performed under GLP and using a standard test method.
Qualifier:
according to guideline
Guideline:
EPA OPP 82-1 (90-Day Oral Toxicity)
GLP compliance:
yes
Limit test:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals or test system and environmental conditions:
42 days old at start of treatment: bodyweights males 175-195g, females 145-178g. Individually housed; animal room 19-23C, 30-80% humidity, 12h dark/light cycle. Food and water provided ad lib.
Route of administration:
oral: gavage
Vehicle:
water
Remarks:
(distilled)
Details on oral exposure:
Gavage dosing at 5 ml/kg dose volume.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Stability (up to14 days) and homogeneity of formulated doses was confirmed. Achieved concentrations were confirmed by analysis of samples taken weekly to Week 4, then in Weeks 7, 10 and 13.
Analytical method: after addition of a colour reagent to diluted samples and heating (70C, 1h), absorbance at 492nm was determined.
Duration of treatment / exposure:
91 or 92 days (staggered termination).
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
200 mg/kg
Basis:
other: ingested dose (corrected for active ingredient)
Remarks:
Doses / Concentrations:
500 mg/kg
Basis:
other: ingested dose (corrected for active ingredient)
Remarks:
Doses / Concentrations:
1000 mg/kg
Basis:
other: ingested dose (corrected for active ingredient)
No. of animals per sex per dose:
20 males, 20 females
Control animals:
yes, concurrent vehicle
Details on study design:
Samples from 10M, 10F/group taken for haematology, clinical chemistry and urinalysis.
Positive control:
No
Observations and examinations performed and frequency:
Twice daily cageside observations. Detailed weekly observations including bodyweight.
Opthalmoscopy: pretest and at termination.
Blood samples taken at termination, after fasting: full haematology and clinical chemistry.
Urinalysis: at termination.
Sacrifice and pathology:
Macroscopic observations at necropsy.
Organ weights: adrenals, brain, heart, kidneys, liver, lungs, ovaries, pituitary, spleen, testes with epididymides, thyroid/parathyroids, uterus.

Tissues collected: weighed organs plus aorta (thoracic), bone and bone marrow (sternum/femur), oesophagus, eyes with optic nerve, intestine (caecum, colon, ileum, jejunum, rectum), lacrymal gland, lymph nodes, mammary gland, sciatic nerve, pancreas, prostate, salivary glands, seminal vesicles, skeletal muscle, skin spinal cord (cervical, thoracic, lumbar), stomach, thymic region, trachea, urinary bladder, uterus with cervix, gross lesions.

Histopathology: all collected tissues from control and high-dose groups plus decedents. Kidneys, liver, lungs, stomach, adrenals, gross lesions for other test groups.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
2 males died at 1000 mg/kg/day. Excessive salivation seen at 500 and 1000 mg/kg/day.
Mortality:
mortality observed, treatment-related
Description (incidence):
2 males died at 1000 mg/kg/day. Excessive salivation seen at 500 and 1000 mg/kg/day.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
decreased in males dosed at 1000 mg/kg/day.
Food consumption and compound intake (if feeding study):
no effects observed
Ophthalmological findings:
no effects observed
Haematological findings:
effects observed, treatment-related
Description (incidence and severity):
Haemoglobin, haematocrit and erythrocyte counts were significantly decreased, leucocyte counts increased at 1000 mg/kg/day (both sexes); erythrocytes were significantly decreased in males at 500 mg/kg/day.
Clinical biochemistry findings:
no effects observed
Description (incidence and severity):
At 1000 mg/kg/day glucose, total protein, albumin and globulin significantly decreased, albumin/globulin ratio increased. Total protein, globulin and albumin/globulin ration were reduced at 500 mg/kg (and glucose decreased in males).
Urinalysis findings:
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Description (incidence and severity):
Absolute and relative adrenal weights increased significantly at 1000 and at 500 (males only) mg/kg/day. In females absolute and relative liver weights increased significantly at 1000 and 500 mg/kg/day, pituitary weights decreased at 1000 mg/kg/day.
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Stomach lesions (nodules, masses, swelling) seen at 1000 mg/kg/day.
Histopathological findings: non-neoplastic:
effects observed, treatment-related
Description (incidence and severity):
Necrotising gastritis of forestomach and/or glandular stomach seen at 500 and 1000 mg/kg/day (severe at 1000 mg/kg/day).
Details on results:
Homogeneity and stability of test doses plus achieved concentrations (within 20% of nominal values) were confirmed by analysis.
Dose descriptor:
NOEL
Effect level:
200 mg/kg bw/day (actual dose received)
Based on:
act. ingr.
Sex:
male/female
Basis for effect level:
other: Based on stomach lesions and associated clinical pathology parameters observed at 500 and 1000 mg/kg/day.
Critical effects observed:
not specified
Conclusions:
Daily oral dosing of rats at 200 mg/kg/day produced no effects considered treatment-related: this is concluded to be the NOEL.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
subchronic
Species:
rat
Quality of whole database:
Due to the number of subchronic and subacute toxicity studies available and the reliability (Klimisch 1) of the selected key subchronic study, overall database quality is high.

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Link to relevant study records
Reference
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.
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
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.
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).
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.
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.
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).
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.
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).
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).
Critical effects observed:
not specified

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.

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.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
200 mg/kg bw/day
Study duration:
subacute
Species:
rabbit
Quality of whole database:
This study using a close chemical analogue found no evidence of systemic toxicity, but

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Data from a number of subacute and subchronic oral toxicity studies are available. Significant dermal absorption is not expected and acute dermal toxicity testing identified no systemic toxicity: repeat-dose dermal testing is thus not required. Significant inhalation exposure is not expected due to low vapour pressure and limited possibilities for such exposure: repeat-dose testing by this route is therefore also not required.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Three subchronic oral toxicity studies are available. Two (1 using gavage, 1 dietary administration) found no significant toxicity at the maximum dosages tested (300 and 100 mg/kg/day respectively). However the selected key (gavage) study clearly identified the fore- and glandular stomach as a primary target organ and demonstrated a NOEL for this and other effects at 200 mg/kg/day.

Justification for selection of repeated dose toxicity inhalation - systemic effects endpoint:
Study not required (in accordance with REACH Annex IX column 2).

Justification for selection of repeated dose toxicity inhalation - local effects endpoint:
Study not required (in accordance with REACH Annex IX column 2).

Justification for selection of repeated dose toxicity dermal - systemic effects endpoint:
Subacute dermal toxicity study of a close chemical analogue: 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). Chronic toxicity study not required (in accordance with REACH Annex IX column 2).

Justification for selection of repeated dose toxicity dermal - local effects endpoint:
Study not required (in accordance with REACH Annex IX column 2).

Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: stomach

Justification for classification or non-classification

The available repeat-dose oral toxicity studies indicate relatively low systemic toxicity: the concluded NOAEL and identified target organ do not meet the criteria for Specific Target Organ Toxicity (STOT) classification under the CLP Regulation (1272/2008, as amended).