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Repeated dose toxicity: dermal

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Administrative data

Endpoint:
sub-chronic toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Guideline study, well documented. Key study for ICCA Robust Summary: follow-up study of Project No. 38H0294/8255, 25 March 1985, relevant toxicological endpoints and application route.

Data source

Referenceopen allclose all

Reference Type:
study report
Title:
Unnamed
Year:
1985
Report date:
1985
Reference Type:
other: TSCATS
Title:
Unnamed
Year:
1985
Report date:
1985

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 411 (Subchronic Dermal Toxicity: 90-Day Study)
GLP compliance:
yes
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Formamide
EC Number:
200-842-0
EC Name:
Formamide
Cas Number:
75-12-7
Molecular formula:
CH3NO
IUPAC Name:
formamide
Details on test material:
- Name of test material (as cited in study report): formamide
- Analytical purity: >99.5%
- Impurities: metahnol approx. 0.1%; ammonium formate approx. 0.1%; iron approx. 0.1%; water approx. 0.02%

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Dr . Karl Thomae GmbH, Biberach/Riss, Germany
- Weight at study initiation: average weights 245 g (males) and 205 g (females)
- Fasting period before study: no
- Housing: singly
- Diet (ad libitum): Kliba 343-A-Rat/mouse maintenance diet of Klingental-46 mühle AG, CH-4303 Kaiseraugst
- Water: tap water ad libitum
- Acclimatisation period: 7 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Type of coverage:
semiocclusive
Vehicle:
water
Details on exposure:
Route of Administration: dermal
TEST SITE
- Area of exposure: max. 10% of the body surface
- Type of wrap if used: porous gauze dressing and a non irritating tape.
- Time intervals for shavings or clipplings: at least twice a week .


REMOVAL OF TEST SUBSTANCE
- Washing (if done): the test substance was washed off with luke- warm water .
- Time after start of exposure: after the 6-hour exposure period


TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 0.26 mL per 100 g rat body weight
- Concentration (if solution):
30 mg/kg bw/day: 1%
100 mg/kg bw/day: 3.3%
3000 mg/kg bw/day: 100%
- Constant volume or concentration used: yes


USE OF RESTRAINERS FOR PREVENTING INGESTION: no; wrapping prevented ingestion
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The concentrations of the various formamide-water solutions and the test substance stability were determined by GC at the beginning, in the middle and at the end of the study .
Duration of treatment / exposure:
90 days
Frequency of treatment:
6 h/day; 5 days/week
Doses / concentrations
Remarks:
Doses / Concentrations:
30, 100, 3000 mg/kg/d
Basis:

No. of animals per sex per dose:
Groups at 0, 30, and 100 mg/kg bw/day: 10/sex/dose
Groups at 3000 mg/kg bw/day: 20/sex/dose
Control animals:
yes, concurrent vehicle
Details on study design:
Post-exposure period: none
Positive control:
not required

Examinations

Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: twice a day on working days, once a day during weekends


DETAILED CLINICAL OBSERVATIONS: No
- Time schedule:


BODY WEIGHT: Yes
- Time schedule for examinations: all animals were weighed once weekly .


FOOD CONSUMPTION:
- Food consumption for each animal determined: Yes. Weekly.


WATER CONSUMPTION: No data


OPHTHALMOSCOPIC EXAMINATION: Yes
- Time schedule for examinations: at the beginning of the study and at the end of the administration period.
- Dose groups that were examined: control and high dose groups.


HAEMATOLOGY: Yes
- Time schedule for collection of blood: at 5, 8 and 12 weeks after the beginning of administration in all animals.
- Anaesthetic used for blood collection: No data
- Animals fasted: Yes. Sampling took place in the afternoon at the end of the exposure period.
- How many animals: all animals on test.
- Parameters checked:
- hemoglobin
- erythrocyte count
- hematocri t
- mean hemoglobin content per erythrocyte
- mean cell volume
- mean corpuscular hemoglobin concentration
- platelet count
- leukocyte count
- Carboxyhemoglobin


CLINICAL CHEMISTRY: No


URINALYSIS: No


NEUROBEHAVIOURAL EXAMINATION: No
Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes (fixation) No further histopathology was performed as no compound related new findings could be detected gross pathologically that had not been observed previously in the first experiment with Formamide .
Statistics:
Clinical examinations and Pathology: means and standard deviation were calculated. The statistical evaluation was carried out using a
t-Test generalized by WILLIAMS.
Hematology: means and standard deviation were calculated. T-test was used for the statitistical evaluation.

Results and discussion

Results of examinations

Clinical signs:
effects observed, treatment-related
Dermal irritation:
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):
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:
effects observed, treatment-related
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Gross pathological findings:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
Groups at 3000 mg/kg bw/day:
- erythema of the skin in both sexes
- reduced general condition, dyspnea, apathy in both sexes
- decreased body weights (both sexes)
- three substance-related deaths (males).

Groups at 100 mg/kg bw/day: no effects noted
Groups at 30 mg/kg bw/day: no effects noted


BODY WEIGHT AND WEIGHT GAIN
Groups at 3000 mg/kg bw/day:
- decreased body weights (both sexes)

Groups at 100 mg/kg bw/day: no effects noted
Groups at 30 mg/kg bw/day: no effects noted


FOOD CONSUMPTION
Groups at 3000 mg/kg bw/day:
- reduced food consumption (both sexes)

Groups at 100 mg/kg bw/day: no effects noted
Groups at 30 mg/kg bw/day: no effects noted


OPHTHALMOSCOPIC EXAMINATION
No effect at either dose


HAEMATOLOGY
Groups at 3000 mg/kg bw/day:
- increase in Hb, erythrocyte count, hematocrit, MCV, mean corpuscular Hb content, and mean corpuscular Hb concentration (both sexes)
- reduction in leukocyte and lymphocyte values in both sexes and platelet count in males
- increase in the number of reticulocytes and of carboxyhemoglobin in both sexes.

Groups at 100 mg/kg bw/day: no effects noted
Note: The following marginal findings were only detected after 12 weeks of treatment and are considered to be incidental:
- reduction in leukocyte values in both sexes,
- platelet count in males,
- and lymphocyte value in females.

Groups at 30 mg/kg bw/day: no effects noted


ORGAN WEIGHTS
Groups at 3000 mg/kg bw/day:
- decrease in absolute organ weights of liver, kidney, spleen, testes and adrenals of males
- increase in relative liver and kidney weights (both sexes) and of the adrenals in males
- increased number of rats with bilateral testicular tubular atrophy.

Groups at 100 mg/kg bw/day: no effects noted
Groups at 30 mg/kg bw/day: no effects noted


GROSS PATHOLOGY
No effects at either dose

Effect levels

Dose descriptor:
NOAEL
Effect level:
100 mg/kg bw/day
Sex:
male/female
Basis for effect level:
other: Clinical signs of toxicity, hematological effects (increased erythron), reduced body and organ weights at 3000 mg/kg bw in this study. Hematological effects at 300 mg/kg bw/day in a preceding 90-day dermal study.

Target system / organ toxicity

Critical effects observed:
not specified

Any other information on results incl. tables

Observations made in the previous study (BASF AG, Project 38H024/8255) could be reproduced for the 3000 mg-group in this follow-up study.




Applicant's summary and conclusion

Conclusions:
Following dermal application of formamide to rats hematological effects (increased erythron) were seen strting at 300 mg/kg bw/day. Clinical signs of toxicity, deaths, reductions in organ and body weights was seen at 3000 mg/kg bw in dermal 90-day rat studies.
Executive summary:

In a subchronic dermal study that was conducted according to OECD guideline 411 and under GLP conditions, formamide was applied to the intact skin of Wistar rats ((0, 30, 100, 3000 mg/kg body weight/day; 10 male and 10 female rats per dose; 20 animals in the high dose groups). Formamide was applied at a constant volume, i.e. it was undiluted at the high dose and diluted with water at the two other dose levels. The control animals received only water.

In groups at 3000 mg/kg bw/day substance related mortality (3/20, only males), clinical signs of toxicity in both sexes (prostration, apathy), reduced food consumption, reduced body weight were seen. Statistically significant changes compared to the controlswere noted as follows: Hematological changes included increases in erythrocyte count, hematocrit, hemoglobin and mean corpuscular hemoglobin content, and reticulocyte counts. Leucocytes were reduced in both sexes and platelets only in males.

Pathological findings included reduced body weights in both sexes; decrease in absolute organ weights of liver, kidney, spleen, testes and adrenals of males; increase in relative liver and kidney weights (both sexes) and of the adrenals in males; increased number of rats with bilateral testicular tubular atrophy.

 

No treatment-related effects were noted in groups at 100 and at 30 mg/kg bw/day.

 

The NOAEL for subchronic dermal administration was therefore established at 100 mg/kg bw/day (BASF, 1985).

 

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