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Acute Toxicity: oral

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Endpoint:
acute toxicity: oral
Type of information:
read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
1985
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Not specified if conducted to GLP.
Justification for type of information:
Using the study with formic acid as a read across to the reaction mass of 2,2-bis(formyloxymethyl) propane-1,3-diyl diformate and formic acid is considered to be justified as formic acid is the main component of this reaction mass. The primary effect following exposure to the reaction mass of 2,2-bis(formyloxymethyl)propane-1,3-diyl diformate and formic acid will be due to the caustic properties of formic acid.
Cross-referenceopen allclose all
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
1985
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Remarks:
Not specified if conducted to GLP.
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
- Name of test material (as cited in study report): Ameisensäure 99%
- Analytical purity: 99%
Species:
rat
Strain:
other: Bor: WISW
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: F. Winkelmann, 4799 Borchen, Germany
- Weight at study initiation: males 126 g, females 117 g
- Fasting period before study: 16 h prior to dosing
- Housing: 1 to 5 rats per cage in Macrolon cages
- Diet: complete diet ad libitum
- Water: free access to tap water ad libitum



ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20
- Humidity (%): 65
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 0.41 to 0.82 mL/kg bw


DOSAGE PREPARATION: undiluted


Doses:
501, 631, 794, 1000 mg/kg bw
No. of animals per sex per dose:
10
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily observations for clinical signs; body weight was recorded before treatment, and on days 1, 7, and 14 thereafter
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
The LD50 was calculated according to Litchfield and Wilcoxon  (1949)
Sex:
male/female
Dose descriptor:
LD50
Effect level:
730 mg/kg bw
95% CL:
618 - 863
Remarks on result:
other: neat formic acid
Mortality:
Deaths occurred within 8 days after dosing; cf. tabulated detail information in the field “Remarks on results". The combined oral LD50 for male and female rats was 730 mg/kg bw.

Clinical signs:
Clinical signs were noted 30 minutes after dosing. Symptoms included  unkempt fur, hunched posture, stagger, aggressiveness, dyspnea, sedation  and ataxia, lateral and abdominal position, convulsions, bloody noses,  blood in urine. At later times hypothermia, body weight loss and pale  limbs were additionally noted.  Symptoms subsided and were absent in all animals but one which showed  symptoms until the end of the observation period.
Body weight:
Body weight gain was decreased in a dose-related manner; cf. tabulated detail information in the field “Remarks on results". 
Gross pathology:
Dead animals:  Hyperemia of the stomach and intestines. Mottled livers and kidneys.
Sacrificed animals:  Hyperemia of the stomach. Mottled livers and discoloration of kidneys and  pancreas

Mortality
The combined LD50 for male and female rats was 730 mg/kg bw.

=========================================================
Dose              Mortality         Death occurred 
(mg/kg bw)    (No. dead/exposed)       after    
               male       female  
---------------------------------------------------------    
 501          0/5         1/5        within 1 hour
 631          2/5         2/5        within 24 hours
 794          1/5         5/5        within 8 days
1000          4/5         4/5        within 48 hours
=========================================================

Clinical signs
Clinical signs were noted 30 minutes after dosing. Symptoms included  unkempt fur, hunched posture, stagger, aggressiveness, dyspnea, sedation  and ataxia, lateral and abdominal position, convulsions, bloody noses,  blood in urine. At later times hypothermia, body weight loss and pale  limbs were additionally noted. 
Symptoms subsided and were absent in all animals but one which showed  symptoms until the end of the observation period.

Body weight gain was decreased in a dose-related manner 

=========================================
Dose              Mean body weight gains  
(mg/kg bw)      within 14 days post dosing  
                 (g; males and females)
-----------------------------------------   
 501                56.1
 631                45.9  
 794                28.3  
1000               - 3.4
=========================================

Gross pathology
Dead animals: 
Hyperemia of the stomach and intestines. Mottled livers and kidneys.

Sacrificed animals: 
Hyperemia of the stomach. Mottled livers and discoloration of kidneys and  pancreas.

Conclusions:
The combined LD50 for male and female rats was determined to be 730 mg/kg bw.
Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Study period:
November 15, 1989 to February 15, 1990
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Qualifier:
according to guideline
Guideline:
other: EEC Guideline 84/449/EEC
GLP compliance:
yes
Test type:
fixed dose procedure
Limit test:
yes
Specific details on test material used for the study:
- Name of test material (as cited in study report): 2,2,-Bis-(hydroxymethyl)-1,3-propandiol (pentaerythritol)
- Substance type: white crystals
- Physical state: solid
- Analytical purity: 99%, confirmed by gas chromatography
- Lot/batch No.: 885/C
- Stability under test conditions: yes, confirmed by the sponsor
- Storage condition of test material: closed container at room temperature
- Other: ph 4-5 (60 g/L H2O, 20°C)
Species:
rat
Strain:
other: Bor: WISW (SPFCpb)
Sex:
male/female
Details on test animals or test system and environmental conditions:
The animals were male and female Bor: WISW (SPFCpb) rats, obtained from Winkelmann Versuchstierzucht GmbH & Co. Males were 11 weeks old at the start of treatment with a body weight range of 219-225 g. Females were 12 weeks old at the start of treatment with a body weight range of 159-179 g.
They were housed individually in Macrolon Cages (Type II), with animal bedding chips. They were fed a standard diet ad libitum (ssniff R, ssniff Spezialfutter GmbH), and tap water was provided ad libitum (Stadtwerke Bielefeld Municipal Works).
The room temperature was maintained at 20.0-22.5°C, and relative humidity was 40-60%. Artificial lighting was provided for 12 hours per day.
Animals were randomised to treatment groups on arrival using a computerised random figure generator. The rats were individually identified colour codes and ear notches. They rats were acclimatised for at least 5 days.

Route of administration:
oral: gavage
Vehicle:
other: aqueous tylose (1%)
Details on oral exposure:
The rats were fasted for approximately 16 hours prior to administration. The test substance was administered as a single oral dose by gavage, in aqueous tylose (1%). The test substance was suspended in the vehicle immediately prior to dosing using an ultraturrax homogeniser. The administration volume was set to 21.5 ml/kg. The content of the suspension was 237 mg/ml.
Doses:
5110 mg/kg
No. of animals per sex per dose:
5 males and 5 females
Control animals:
no
Details on study design:
The rats were observed continuously for the first 4-6 hours after administration, then once daily thereafter for 14 days. Mortality was checked twice daily (am and pm) on weekdays, and once daily on weekends and national holidays. The body weights were recorded at the beginning of the study, and 7 and 14 days after administration.
At the end of the observation period, all surviving animals were sacrificed for gross necropsy (animals that died during the observation period were also necropsied). Macroscopical examination included external appearance, body orifices, body cavities and their contents.
Statistics:
Statistical analyses were not required.
Preliminary study:
No preliminary study was reported.
Sex:
male/female
Dose descriptor:
LD50
Effect level:
> 5 110 mg/kg bw
Based on:
test mat.
Remarks on result:
other: No deaths
Mortality:
No mortality occurred during the study.
Clinical signs:
The only sign of toxicity was diarrhoea, recorded in 3 rats (2 males and 1 female) 7 hours after dosing. All other rats appeared normal.
Body weight:
There was no effect of treatment on bodyweight; all rats gained weight throughout the observation period.
Gross pathology:
No abnormal findings were detected at gross necropsy.
Other findings:
No other findings were reported.

The acute oral LD50 of pentaerythritol in rats is > 5110 mg/kg bw.

Conclusions:
Pentaerythritol is of low acute oral toxicity. The acute oral LD50 of pentaerythritol in rats was found to be >5110 mg/kg bw, under the conditions of this study.
Executive summary:

Pentaerythritol was studied for acute toxicity after single oral administration in rats. The test substance was suspended in aqueous tylose (1%) and administered to a group of three rats. The single dose level was 5110 mg/kg bw, the administration volume was 21.5 ml/kg bw; the content of the suspension was 237 mg/ml. No deaths occurred. The only sign of toxicity was diarrhoea, recorded in all rats at 7 hours after gavage administration. At necropsy, no abnormal findings were found. The acute oral LD50 in the rat was therefore found to be >5110 mg/kg bw under the conditions of this study.

Reason / purpose for cross-reference:
read-across source
Reference
Endpoint:
acute toxicity: oral
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: meets generally accepted criteria. Not GLP, no strain of rat stated.
Principles of method if other than guideline:
Method: other: groups of 5 male rats were given single oral doses of 1.0, 2.15, 4.64, 10.0 or 21.5 g/kg bw and
observed for 7 days, gross autopsy
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Specific details on test material used for the study:
IUCLID4 Test substance: purity was considered to be 100%
Species:
rat
Strain:
not specified
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Weight at study initiation: 175 g
- Fasting period before study: 4 hours
- Housing: in groups
- Diet ad libitum
- Water ad libitum
Route of administration:
oral: gavage
Vehicle:
water
Details on oral exposure:
test substance was given as 10 % or 20 "% or 70 % solution
Doses:
1000 mg/kg bw, 2150 mg/kg bw, 4640 mg/kg bw, 10000 mg/kg bw, 21500 mg/kg bw given as 10 % or 20 % or 70 % solution
No. of animals per sex per dose:
5 males
Control animals:
no
Details on study design:
Food was withheld from rats for a period of 4 hours; rats were observed for 7 days post treatment and gross signs of toxicity were noted, gross autopsy was performed upon rats that died and of the surviving rats at the end of the observation period
Statistics:
moving average method of Weil (1952)
Sex:
male
Dose descriptor:
LD50
Effect level:
ca. 14 700 mg/kg bw
Based on:
other: clinical signs of intoxication from 2150 mg/kg bw onwards and mortality rate at the highest test dose (21500 mg/kg bw) of 5/5 male rats within 24 hours
Mortality:
only at the highest test dose of 21500 mg/kg bw: 5/5 rats died within 24 hours post treatment
no other rat died
Clinical signs:
1000 mg/kg bw : rats appeared normal throughout the observation period
2150 mg/kg bw, 4640 mg/kg bw, 10000 mg/kg bw, 21500 mg/kg bw:
rats appeared depressed, exhibited lacrimation, slow and laboured respiration,
ataxia, and other effects of the limbs
21500 mg/kg bw: additionally depressed and absent placing, righting and pain reflexes
at 43 hours post dosing the surviving rats recovered
Body weight:
no data
Gross pathology:
gross autopsy of the dead rats:
hyperemic and hemorrhagic lungs
irritation of the pyloric portion of the stomach, small intestine (distended and filled with a clear yellowish colored fluid)
and peritoneum, congested kidneys and adrenal
gross autopsy of the survivors #
1000 and 2150 mg/kg bw : rats showed no gross pathothololgical changes
4600 and 10000 mg/kg bw: rats showed hyperemic zones at the periphery of the medulla in the kidneys
Other findings:
Confidence limits could not be calculated due to the "all or none" response (no further data)

RM-Freetext:
Within a couple of hours after the dose, the animals that
received 2.15 g/kg or more showed signs of fatigue, slow
respiration and ataxia. All the animals in the highest dose
group died. Autopsies revealed kidney changes in the three
highest dose groups.

Conclusions:
The LD50 value was determined to be 14700 mg/kg bw
Executive summary:

5 male rats were given single oral doses of 1000, 2150, 4640 10000 or 21500 mg/kg bw and

observed for 7 days. 1000 mg/kg bw was tolerated wihout any harm. Rats of the other groups appeared depressed, exhibited lacrimation, slow and laboured respiration, ataxia, and other effects of the limbs. 21500 mg/kg bw caused the death of all animals within 24 hours. Thus the LD50 value was determined 14700 mg/kg bw (Celanese Corporation 1956).

Data source

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

Materials and methods

Test guideline
Qualifier:
according to guideline
Guideline:
OECD Guideline 401 (Acute Oral Toxicity)
Deviations:
no
GLP compliance:
not specified
Test type:
standard acute method
Limit test:
no

Test material

Constituent 1
Chemical structure
Reference substance name:
Formic acid
EC Number:
200-579-1
EC Name:
Formic acid
Cas Number:
64-18-6
Molecular formula:
CH2O2
IUPAC Name:
formic acid
Constituent 2
Chemical structure
Reference substance name:
Water
Cas Number:
7732-18-5
Molecular formula:
H2O
IUPAC Name:
Water
Constituent 3
Chemical structure
Reference substance name:
Propylidynetrimethanol
EC Number:
201-074-9
EC Name:
Propylidynetrimethanol
Cas Number:
77-99-6
Molecular formula:
C6H14O3
IUPAC Name:
2-ethyl-2-(hydroxymethyl)propane-1,3-diol
Constituent 4
Chemical structure
Reference substance name:
Pentaerythritol
EC Number:
204-104-9
EC Name:
Pentaerythritol
Cas Number:
115-77-5
Molecular formula:
C5H12O4
IUPAC Name:
2,2-Bis(hydroxymethyl)-1,3- propanediol
Test material form:
liquid: viscous

Test animals

Species:
rat
Strain:
other: Bor: WISW
Sex:
male/female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: F. Winkelmann, 4799 Borchen, Germany
- Weight at study initiation: males 126 g, females 117 g
- Fasting period before study: 16 h prior to dosing
- Housing: 1 to 5 rats per cage in Macrolon cages
- Diet: complete diet ad libitum
- Water: free access to tap water ad libitum



ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20
- Humidity (%): 65
- Photoperiod (hrs dark / hrs light): 12/12

Administration / exposure

Route of administration:
oral: gavage
Vehicle:
unchanged (no vehicle)
Details on oral exposure:

MAXIMUM DOSE VOLUME APPLIED: 0.41 to 0.82 mL/kg bw


DOSAGE PREPARATION: undiluted


Doses:
501, 631, 794, 1000 mg/kg bw
No. of animals per sex per dose:
10
Control animals:
no
Details on study design:
- Duration of observation period following administration: 14 days
- Frequency of observations and weighing: daily observations for clinical signs; body weight was recorded before treatment, and on days 1, 7, and 14 thereafter
- Necropsy of survivors performed: yes
- Other examinations performed: clinical signs, body weight
Statistics:
The LD50 was calculated according to Litchfield and Wilcoxon  (1949)

Results and discussion

Effect levels
Sex:
male/female
Dose descriptor:
LD50
Effect level:
730 mg/kg bw
95% CL:
618 - 863
Remarks on result:
other: neat formic acid
Mortality:
Deaths occurred within 8 days after dosing; cf. tabulated detail information in the field “Remarks on results". The combined oral LD50 for male and female rats was 730 mg/kg bw.

Clinical signs:
Clinical signs were noted 30 minutes after dosing. Symptoms included  unkempt fur, hunched posture, stagger, aggressiveness, dyspnea, sedation  and ataxia, lateral and abdominal position, convulsions, bloody noses,  blood in urine. At later times hypothermia, body weight loss and pale  limbs were additionally noted.  Symptoms subsided and were absent in all animals but one which showed  symptoms until the end of the observation period.
Body weight:
Body weight gain was decreased in a dose-related manner; cf. tabulated detail information in the field “Remarks on results". 
Gross pathology:
Dead animals:  Hyperemia of the stomach and intestines. Mottled livers and kidneys.
Sacrificed animals:  Hyperemia of the stomach. Mottled livers and discoloration of kidneys and  pancreas

Any other information on results incl. tables

Mortality
The combined LD50 for male and female rats was 730 mg/kg bw.

=========================================================
Dose              Mortality         Death occurred 
(mg/kg bw)    (No. dead/exposed)       after    
               male       female  
---------------------------------------------------------    
 501          0/5         1/5        within 1 hour
 631          2/5         2/5        within 24 hours
 794          1/5         5/5        within 8 days
1000          4/5         4/5        within 48 hours
=========================================================

Clinical signs
Clinical signs were noted 30 minutes after dosing. Symptoms included  unkempt fur, hunched posture, stagger, aggressiveness, dyspnea, sedation  and ataxia, lateral and abdominal position, convulsions, bloody noses,  blood in urine. At later times hypothermia, body weight loss and pale  limbs were additionally noted. 
Symptoms subsided and were absent in all animals but one which showed  symptoms until the end of the observation period.

Body weight gain was decreased in a dose-related manner 

=========================================
Dose              Mean body weight gains  
(mg/kg bw)      within 14 days post dosing  
                 (g; males and females)
-----------------------------------------   
 501                56.1
 631                45.9  
 794                28.3  
1000               - 3.4
=========================================

Gross pathology
Dead animals: 
Hyperemia of the stomach and intestines. Mottled livers and kidneys.

Sacrificed animals: 
Hyperemia of the stomach. Mottled livers and discoloration of kidneys and  pancreas.

Applicant's summary and conclusion

Conclusions:
The combined LD50 for male and female rats was determined to be 730 mg/kg bw.
Executive summary:

An OECD guideline No. 401 test was conducted with formic acid. The reaction mass of 2,2-bis(formyloxymethyl) propane-1,3-diyl diformate and formic acid consists of formic acid, propylidynetrimethanol-esters and pentaerythritol-esters.Pentaerythritol and propylidynetrimethanol are demonstrated to be of very low acute toxicity by all routes investigated. Similar low acute toxicity is predicted for their respective esters. The acute toxicity of the reaction mass of 2,2-bis(formyloxymethyl) propane-1,3-diyl diformate and formic acid is therefore driven by the main component: formic acid.