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Description of key information

Key value for chemical safety assessment

Acute toxicity: via oral route

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Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: according to guideline and GLP
Qualifier:
according to
Guideline:
OECD Guideline 423 (Acute Oral toxicity - Acute Toxic Class Method)
GLP compliance:
yes
Test type:
acute toxic class method
Species:
rat
Strain:
Wistar
Sex:
female
Details on test animals and environmental conditions:
TEST ANIMALS
- Age at study initiation:10-12 weeks
- Weight at study initiation: 165-192 g
- Fasting period before study: 16-24 h
- Housing:
- Diet ad libitum
- Water ad libitum
- Acclimation period: 5 d

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22
- Humidity (%): 55
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12 / 12
Route of administration:
oral: gavage
Vehicle:
other: corn oil with the aid of acetone
Details on oral exposure:
Rats received single oral dose by gavage.
For oral administration lactofen was melted at 70 °C and formulated in corn oil with the aid of 10 % acetone (dried with molecular sieve). the applied formulations were well mixed before administration. The formulations for administration were prepared at room temperature. The administration volume was 10 ml/kg bw
Doses:
3 females 2000 mg/kg bw
3 females 300 mg/kg bw
3 females 300 mg/kg bw
No. of animals per sex per dose:
3 females
Control animals:
no
Details on study design:
Rats received single oral dose by gavage.
For oral administration lactofen was melted at 70 °C and formulated in corn oil with the aid of 10 % acetone (dried with molecular sieve). The applied formulations were well mixed before administration. The formulations for administration were prepared at room temperature. The administration volume was 10 ml/kg bw
The starting dose level should be that which is most likely to produce mortality in some of the dosed animals. Absence or presence of compound-related mortality of the amimals dosed at one step will determine the rext step.
no further testing is needed
dosing of three additional animals wth the the same dose
dosing of three addional animals at the next higher or lower dose level
Statistics:
The LD50 was estimated according to OECD Guideline for testing of chemicals No. 423
Sex:
female
Dose descriptor:
LD100
Effect level:
ca. 2 000 mg/kg bw
Remarks on result:
other: the clinical signs were piloerection, abdominal position, labored breathing
Sex:
female
Dose descriptor:
LD0
Effect level:
ca. 300 mg/kg bw
Remarks on result:
other: the substance was tolerated without clinical signs
Sex:
female
Dose descriptor:
approximate LD50
Effect level:
ca. 500 mg/kg bw
Mortality:
all animals dosed with 2000 mg/kg bw died
all animals dosed with 300 mg/kg bw survived the treatment
Clinical signs:
2000 mg/kg bw:
piloerection, abdominal position, labored breathing
300 mg/kg bw
no clinical signs
Body weight:
no toxicological effects on body weight or body weight gain in animals treated with 300 mg/kg bw
Gross pathology:
2000 mg/kg bw : urinary bladder enlargedm liver spoted, kidneys pale spotted
300 mg/kg bw: no particular findings
Other findings:
no data
Conclusions:
According to OECD Guideline 423 the LD50 cut-off of lactofen is 500 mg/kg bw
Executive summary:

Female Wistar rats were tested for acute oral toxicity according to OECD TG 423 and GLP. All animals dosed with 2000 mg/kg bw died during the observation period; the clinical signs were piloerection, abdominal position and labored breathing, The gross pathological examination revealed enlarged urinary bladderm spotted liver and pale spoted kidneys. The dose of 300 mg /kg bw was tolerated without any findings. According to OECD Guideline 423 the LD50 cut-off of lactofen is 500 mg/kg bw

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
500 mg/kg bw
Quality of whole database:
2 Studies are available. Overall, the cut-off LD50 of 500 mg/kg will be used for risk assessment although this value might be to conservative, based on the atrificial formulation of the test item in this study.

Acute toxicity: via inhalation route

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Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Principles of method if other than guideline:
The acute inhalation toxicity of PPG-844 was assessed by exposing 10 rats (5 males and 5 females), for a period of 4 hours, to an atmosphere containing a respirable aerosol of the test substance. The animals were observed for mortality, clinical signs, food and water consumption. At the end of the 14-day observation period the rats were subjected to a detailed macroscopic examination.
GLP compliance:
yes
Test type:
standard acute method
Species:
rat
Strain:
Wistar
Sex:
male/female
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
head only
Vehicle:
other: 10% acetone
Analytical verification of test atmosphere concentrations:
yes
Duration of exposure:
4 h
Concentrations:
Group 1 (control)
Group 2 (vehicle control)
Group 3 (PPG-844)

Atmosphere concentration of PPG-844:
By gravimetric analysis: 3.6 g/m³
By HPLC analysis: 3.4 g/m³
No. of animals per sex per dose:
5 mala and 5 female animals per group
Control animals:
yes
Sex:
male/female
Dose descriptor:
LC50
Effect level:
> 3.4 mg/L air
Based on:
test mat.
Exp. duration:
4 h

Mortality: There were no deaths related to exposure to PPG-844

Clinical signs: a) during exposure: no adverse signs were visible b) brown staining of the fur and poor groming was noted in the rats exposed to PPG-844. These signs persisted for 2 days (males) or 11 days (females).

Body weight: no effect

Food consumption: reduced for all groups on the day following exposure

Water consumption: markedly increased water consumption for 5 days (males) or 3 days (females)

Macroscopic pathology: no abnormalities were seen in any rat

Executive summary:

The acute inhalation toxicity of PPG-844 was assessed by exposing 10 rats (5 males and 5 females), for a period of 4 hours, to an atmosphere containing a respirable aerosol of the test substance. The animals were observed for mortality, clinical signs, food and water consumption. At the end of the 14-day observation period the rats were subjected to a detailed macroscopic examination.

LC50 (4 hours) for PPG-844: In excess of 3.4 g/m³ which was the highest attainable aerosol concentration.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LC50
5 300 mg/m³
Quality of whole database:
LC50 was > 5.30 mg/l, highest attainable aerosol concentration.

Acute toxicity: via dermal route

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Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP guideline study
Qualifier:
according to
Guideline:
other: 43 FR 37336, Part 163.81-2
Principles of method if other than guideline:
The test article was applied to the clipped and abraded skin of 5 male and 5 female albino rabbits at a dose level of 2 grams per kg bw. the animals were observed for mortality, clinical signs and body weight gain. A gross necropsy was performed of all animals sacrifieced on day 14.
GLP compliance:
yes
Test type:
standard acute method
Limit test:
yes
Species:
rabbit
Strain:
New Zealand White
Sex:
male/female
Type of coverage:
occlusive
Vehicle:
unchanged (no vehicle)
Duration of exposure:
24 hours
Doses:
2000 mg/kg bw
No. of animals per sex per dose:
5 male and 5 female animals were applied a dose of 2000 mg/kg bw
Control animals:
not specified
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 2 000 mg/kg bw
Based on:
test mat.

All animals survived the 14-day duration of the study.

One female gained body weihgt consistantly from day 0 to day 14. One male and one other female lost body weight from day 0 to day 7. The remaining 4 males and 3 females lost body weight from day 0 to day 7 and regained at least 40% of this lost body weight from day 7 to day 14.

Very slight and/or well defined erythema was observed for all animals from days 1 or 2 as late as day 11. No other dermal reactions were observed during the study.

Gross necropsy examinations revealed solitary or multiple, red or red-brown discolorations of the skin at the test sites of one male and 3 females. A diffuse, green discoloration of the lung was also observed upon necropsy examination of one ot these females. Necropsy examination of one other male revealed a solitary, tan depression on the stomach. No other abnormalities were observed upon necropsy examinations of all animals sacrificed on day 14.

Executive summary:

The test article was applied to the clipped and abraded skin of 5 male and 5 female albino rabbits at a dose level of 2 grams per kg bw. the animals were observed for mortality, clinical signs and body weight gain. A gross necropsy was performed of all animals sacrifieced on day 14. All animals survived the 14-day duration of the study.

Therefore the LD50 is > 2000 mg(kg bw (rabbit, m+f)

Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LD50
2 000 mg/kg bw
Quality of whole database:
Effects observed at 2000 mg/kg but not deaths reported; LD0 >/= 2000 mg/kg

Additional information

Oral:

Female Wistar rats were tested for acute oral toxicity according to OECD TG 423 and GLP. All animals dosed with 2000 mg/kg bw died during the observation period; the clinical signs were piloerection, abdominal position and labored breathing, The gross pathological examination revealed enlarged urinary bladderm spotted liver and pale spoted kidneys. The dose of 300 mg /kg bw was tolerated without any findings. According to OECD Guideline 423 the LD50 cut-off of lactofen is 500 mg/kg bw. In a second acute oral toxicity study conducted 1979 different data were reported. In this study 2/10 animals died at 5000 mg/kg, 1/10 at 2290 kg/kg and 1/10 3620 mg/kg. The LD50 was reported to be > 5000 mg/kg bw.

In the second study the the test item was described as viscose but no vehicle was used and the pure compound was applied. In the recent guidline study the test item was described ar "solid, high viscosity, brown" and had to be melted at 70oC and formulated in corn oil with the aid of 10% acetone. Based on this difference in application the different results seem not inplausible. Overall, the cut-off LD50 of 500 mg/kg will be used for risk assessment and classification although this value might be to conservative, based on the atrificial formulation of the test item in this study.

Inhalation:

The acute inhalation toxicity of lactofen was assessed in two early, limited studies. In the first study 10 rats (5 males and 5 females) were exposed for a period of 4 hours, to an atmosphere containing a respirable aerosol of the test substance. The animals were observed for mortality, clinical signs, food and water consumption. At the end of the 14-day observation period the rats were subjected to a detailed macroscopic examination. The LC50 (4 hours) for lactofen was > 3.4 g/m³; which was the highest attainable concentration. In the second study 10 rats (5 males and 5 females) were exposed for a period of 4 hours, to an atmosphere containing a respirable aerosol (5.30 mg/l) of the test substance. Four of the test animals died during the study. Irregular breathing, damp fur, crusty muzzle, alopcia, salivation, crusty eye, yellow/brown stained fur, nasal discharge, squinting, and poor coat quality were observed among the test animals. No reactions were observed in the control animals during the study. Necropsies revealed no gross lesions in 4 test and 8 control animals. Abnormalities of the lung, small intestine, stomach, external surface, and kidney were observed in the remaining test rats. Under the conditions tested, the LC50 was > 5.30 mg/l; which was the highest attainable aerosol concentration.

Dermal:

In a study conducted according to 43 FR 37336, Part 163.81-2. the test article was applied to the clipped and abraded skin of 5 male and 5 female albino rabbits at a dose level of 2 grams per kg bw. The animals were observed for mortality, clinical signs and body weight gain. A gross necropsy was performed of all animals sacrificed on day 14. The test article was held in contact with the skin by adhesive tape, and masking tape. After a 24-hour exposure period, each binder was removed and the test site was wiped (not washed) with gauze sponges moistened with physiological saline. All animals survived the 14-day duration of the study. Reduced body-weight gain was reported for most animals until day 7 or 14. Very slight and/or well defined erythema was observed for all animals from days 1 or 2 as late as day 11. No other dermal reactions were observed during the study. Gross necropsy examinations revealed solitary or multiple, red or red-brown discolorations of the skin at the test sites of one male and 3 females. A diffuse, green discoloration of the lung was also observed upon necropsy examination of one of these females. Necropsy examination of one other male revealed a solitary, tan depression on the stomach. No other abnormalities were observed upon necropsy examinations of all animals sacrificed on day 14; LDo > 2000 mg/kg.


Justification for selection of acute toxicity – oral endpoint
Guideline study

Justification for classification or non-classification

Overall, the cut-off LD50 of 500 mg/kg will be used for risk assessment although this value might be to conservative, based on the atrificial formulation of the test item in this study. Lactofen will be classified according to the EU classification criteria 67/548/EWG with R22 and regulation no. 1272/2008 (GHS) with acute oral cat. 4.

No classification is required for inhalation or dermal exposure because LC50 > 5.30 mg/l (the highest attainable aerosol concentration) and LD50 > 2000 mg/kg, respectively.