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Toxicological information

Acute Toxicity: oral

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Administrative data

Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Study period:
9 August 1985 - 23 August 1985
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: Study conducted in accordance with GLP requirements and OECD 401 method.
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1985
Report Date:
1985

Materials and methods

Test guideline
Qualifier:
according to
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
yes
Remarks:
The variation in volume of dosing; that recommendation was not part of that guideline.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
- Name of test material (as cited in study report): AHTN (Tonalid)
- Substance type: pure active substance
- Physical state:pure active substance dissolved in isopropyl myristate

Test animals

Species:
rat
Strain:
other: Cpb:Wu;Wistar
Sex:
male/female
Details on test animals and environmental conditions:
Young adult, SPF—bred albino rats (Cpb:Wu;Wistar random) were used. They were obtained from the Central Institute for the Breeding of Laboratory Animals TNO, Zeist, the Netherlands. The body weights of the males varied from 245 to 283 g, those of the females from 162 to 187 g. The rats were kept under the environmental conditions of the Institute’s animal house for 1 week prior to the test.
Species: albino ratis, male: weight 245-283 g and female: weight 162-187 g.Test conditions: temperature: 22 =/-2 degreesCelsius. Relative humidity; 40-60 % 12 hours light/12 hours dark. Food: cereal-based diet.

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
other: isopropyl myristate (IPM)
Doses:
17.5% Tonalid in IPM. Dose: 4.00, 4.80, 5.76, 6.91, 8.29 ml/kg body weight euivalent to 700, 840, 1008, 1209, 1451 g/kg body weight.
No. of animals per sex per dose:
10 (5 male and 5 female)
Control animals:
no
Statistics:
The LD5O was calculated according to the method of Weil, C.W., Biometrics 8 (1952) 249-263

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
920 mg/kg bw
95% CL:
> 795 - < 1 066
Mortality:
Deaths occurred between 6 hours and 8 days after dosing.
Clinical signs:
Within a few hours after dosing the rats showed sluggishness and piloerection. - Later on haematuria was observed until 2 days after treatment. After a few days, moreover, encrustations around eyes and nostrils, and signs of’ emaciation were observed. These latter phenomena persisted in all surviving rats during the first post—treatment week.
In the second post—treatment week the survivors recovered gradually and looked quite healthy again at the end of the observation period.
Body weight:
The individual body weights on day 7 revealed growth retardation or weight loss of all survivors. On day 14 the body weight of most of the rats was normal again for rats of this strain and age.
Gross pathology:
Macroscopic examination at autopsy of the rats that died in the first few post—treatment days revealed blood—stained urine in the bladder of all rats. In the rats that died thereafter and in those that survived the observation period no treatment—related gross alterations were found.

Any other information on results incl. tables

Table 1 Body weight and mortality rate in rats after a single oral dose administration in rats

Bodyweights on day (g) Mortality
Dose Males Females Males Females
mg/kg bw 0 days 7 days 14 days 0 days 7 days 14 days
700 268 280 315 172 171 191 1/5 0/5
840 254 212 273 170 157 170 4/5 0/5
1008 266 235 287 178 150 196 3/5 4/5
1209 257 250 304 174 152 175 4/5 3/5
1451 260 - - 173 - - 5/5 5/5

Applicant's summary and conclusion

Interpretation of results:
Category 4 based on GHS criteria
Remarks:
Migrated information Criteria used for interpretation of results: EU
Conclusions:
After treatment, the rats showed sluggishness, piloerection, haematuria, encrustations around eyes and nostrils & signs of emaciation. Deaths occurred between 6 hours and 8 days after treatment. The oral LD50 of Tonalid was found to be 920 mg per kg body weight with 795 and 1066 as the 95% confidence limits.
Executive summary:

Groups of five male and five female young adult albino rats were administered by gavage 4.00, 4.80, 5.76, 6.91 or 8.29 ml/kg bw of a 17.5% (w/v) solution of AHTN (Tonalid®; purity =98%; equivalent to doses of 700, 840, 1008, 1209 and 1451 mg/kg bw AHTN) in isopropyl myristate and observed for 14 days. Within a few hours, signs of sluggishness and piloerection were seen. Later on haematuria, encrustrations around eyes and nostrils and signs of emaciation were observed. Death occurred between 6 hours and 8 days of dosing at which time survivors recovered gradually looking healthy at the end of the observation period. Macroscopic examination at autopsy of the rats that died in the first few days revealed blood stained urine in the bladder. No other treatment-related gross alterations were seen in these or other animals. An LD50 of 920 mg/kg bw was calculated.

 

Source: EU Risk Asssessment Report AHTN, Luxembourg, Office for Official Publications of the European Communities, ECB (May 2008)