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Description of key information

Key value for chemical safety assessment

Acute toxicity: via oral route

Link to relevant study records
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
20 July to 5 November 1999
Reliability:
1 (reliable without restriction)
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
Deviations:
not specified
Qualifier:
according to
Guideline:
EU Method B.1 tris (Acute Oral Toxicity - Acute Toxic Class Method)
Deviations:
not specified
GLP compliance:
yes
Test type:
acute toxic class method
Limit test:
yes
Test material information:
Composition 1
Species:
rat
Strain:
other: Wistar Crl:(WI) BR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: Approximately 7 weeks old
- Weight at study initiation: Within 20% of sex mean
- Fasting period before study: Overnight prior to dosing until approximately 3-4 hours after administration of the test substance.
- Housing: Group housing of 3 animals per sex per cage in polycarbonate cages containing purified sawdust as bedding material.
- Diet (e.g. ad libitum): Free access to standard pelleted laboratory animal diet (Carfil Quality BVBA, OUd-Turnhour, Belgium).
- Water (e.g. ad libitum): Free access to tap water
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21˚C
- Humidity (%): 50%
- Air changes (per hr): 15 Air changes per hour
- Photoperiod (hrs dark / hrs light): 12 hours of artificial fluorescent light/12 hours dark.
Route of administration:
oral: gavage
Vehicle:
polyethylene glycol
Details on oral exposure:
VEHICLE
- Amount of vehicle (if gavage): 10mL/kg
- Justification for choice of vehicle: The vehicle was selected based on a pretest performed at NOTOX.

DOSAGE PREPARATION (if unusual): Formulations (w/w) were prepared within 4 hours prior to dosing. Homogeneity was accomplished to a visually acceptable level.

CLASS METHOD (if applicable)
- Rationale for the selection of the starting dose: Toxicity of the test substance was assessed by stepwise treatment of groups of 3 animals.
Doses:
200 mg/kg
2000 mg/kg
No. of animals per sex per dose:
3 Animals
Control animals:
not specified
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: Twice daily
- Necropsy of survivors performed: Yes, by asphyxiation using oxygen/carbon dioxide procedure.
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: Twice daily viability/mortality; body weights Days 1 (pre-admin), 8 and 15 and at death; clinical signs were taken on day 1 and once daily thereafter, until day 15.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 200 - < 2 000 mg/kg bw
Based on:
test mat.
Mortality:
The incidence of mortality is reported in Table No. 1 below.

Two females and two males were found dead on days 2 and 4 and on days 4 and 5, respectively. The two other animals (one female and one male) were sacrificed moribund on day 7 and day 5, respectively, as indicated by the combination of clinical signs and considerable body weight loss observed in these animals.
Clinical signs:
Within the 200 mg/kg dose group, signs of alopecia and/or scabs (in the neck) became apparent in two females during week 2. Based on the time of occurrence, these findings were considered not related to treatment and of no toxicological significance.

Within the 2000 mg/kg dose group lethargy was observed in all males on day 1. From day 2 (males) or day 3 (females) clinical signs became apparent among the animals, including hunched posture, uncoordinated movements, piloerection, ventro-lateral recumbency, lethargy, tremors, slow breathing, red staining of the snout, dehydration and emaciation. No clinical signs of toxicity were apparent in one female prior to its death on day 2.
Body weight:
All animals treated at 2000 mg/kg surviving for several days showed considerable body weight loss. The fact that over 20% body weight loss was observed, the animals were sacrificed; they being moribund was one of the criteria for this decision.
Gross pathology:
Reduced spleen and thymus size was found among the 2000 mg/kg treated animals, at macroscopic post mortem examination.

Table 1:

Dose Level (mg/kg) Mortality Sex Date of Treatment
200 0/3 females 20-Jul-99
200 0/3 males 22-Jul-99
2000 3/3 females 27-Jul-99
2000 3/3 males 29-Jul-99
Interpretation of results:
harmful
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under the current test conditions the oral LD50 value for the test substance is within the following range 200-2000 mg/kg body weight.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
200 mg/kg bw

Acute toxicity: via inhalation route

Endpoint conclusion
Endpoint conclusion:
no study available

Acute toxicity: via dermal route

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Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
12 August to 3 November 1999
Reliability:
1 (reliable without restriction)
Reference:
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 402 (Acute Dermal Toxicity)
Deviations:
not specified
Qualifier:
according to
Guideline:
EU Method B.3 (Acute Toxicity (Dermal))
Deviations:
not specified
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
other: Wistar Crl:(WI) BR
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Deutschland, Sulzfeld, Germany
- Age at study initiation: Approx. 9 weeks old
- Weight at study initiation: Did not exceed +/- 20% of sex mean.
- Housing: Individually housed in polycarbonated cages containing purified saw dust as bedding material.
- Diet (e.g. ad libitum): Free access to standard pelleted laboratory animal diet (Carfil Quality BVBA, Oud-Turnout, Belgium).
- Water (e.g. ad libitum): Free access to tap-water.
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21˚C
- Humidity (%): 50%
- Air changes (per hr): Approximately 15 air changes per hour.
- Photoperiod (hrs dark / hrs light): 12 hours of artificial light/12 hours dark

IN-LIFE DATES: From: 12 August 1999 To: 26 August 1999
Type of coverage:
semiocclusive
Vehicle:
polyethylene glycol
Details on dermal exposure:
TEST SITE
- Area of exposure: Back of animals
- % coverage: 10%
- Type of wrap if used: Surgical gauze patch, successively covered with aluminium foil and Coban flexible bandage. A piece of Micropore tape was additionally used for fixation of the bandages to females only.

REMOVAL OF TEST SUBSTANCE
- Washing (if done): Water
- Time after start of exposure: 24 hours

TEST MATERIAL
- Amount(s) applied (volume or weight with unit): 10 mL/kg body weight
Duration of exposure:
24 hours
Doses:
2000 mg/kg
No. of animals per sex per dose:
5 Males and 5 Females
Control animals:
not required
Details on study design:
- Duration of observation period following administration: 15 days
- Frequency of observations and weighing: Observations - twice daily, body weights - days 1 (pre-administration), 8 and 15.
- Necropsy of survivors performed: Yes, Sacrificed by asphyxiation using an oxygen/carbon dioxide procedure.
- Other examinations performed: clinical signs, body weight, organ weights, histopathology, other: Clinical signs - On day 1 of dosing and once daily thereafter, until day 15.
Statistics:
Not performed
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.
Mortality:
No mortality occurred
Clinical signs:
Scabs and scales were seen in the treated skin-area of one female between days 2 and 8.

Red staining of the fur in the neck appeared in another female on day 9 and persisted until termination. Based on the incidence and time of occurrence, this finding was considered not related to treatment and of no toxicological significance.
Body weight:
Changes reported in body weight gain in males and females were within the range expected for rats used in this type of study and were not considered indicative of toxicity.
Gross pathology:
No abnormalities were found at macroscopic post mortem examination of the animals.
Interpretation of results:
practically nontoxic
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
Under current test conditions the LD50 value for test substance exceeds 2000 mg/kg body weight.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw

Additional information

Justification for selection of acute toxicity – oral endpoint
GLP study conducted according to OECD Guideline 423 and EU Method B.1. Under the current test conditions the oral LD50 value for Pymordiol is within the following range 200-2000 mg/kg body weight.

Justification for selection of acute toxicity – dermal endpoint
CLP study conducted according to OECD Guideline 402 and EU Method B.3. Under current test conditions the LD50 value for test substance exceeds 2000 mg/kg body weight.

Justification for classification or non-classification

Based on acute oral LD50 greater than 200 but less than 2000 mg/kg bw, this substance might either be classified as EU CLP Acute Oral Tox Cat 3 (if the LD50 is less than 300 mg/kg bw) or Acute Oral Tox Cat 4 (if LD50 is greater than 300 mg/kg bw).

Precautionarily, this substance is therefore classified as Acute Oral Tox Cat 3, H301.