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Administrative data

Description of key information

DAP exhibits low to moderate acute oral and inhalation toxicity, with low acute dermal toxicity in rodents.

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:
disregarded due to major methodological deficiencies
Study period:
1976-11-10
Reliability:
3 (not reliable)
Rationale for reliability incl. deficiencies:
other: Although this concerns a well-documented publication, the results are not unequivocally interpretable.
Principles of method if other than guideline:
Method: Dogs were housed in individual wire mesh cages, and were fed once daily with Agway Food (700g g/dog/day), while water was available ad libitum. After an overnight fast, each dog received 800 mg test material/kg body weight by gavage. This was the LD50 dose calculated from studies in the rat. Feed and water were then made available to the dogs. Dogs were observed carefully for the next 8 hours and frequently each day thereafter for 8 days.
GLP compliance:
no
Test type:
acute toxic class method
Limit test:
no
Species:
dog
Strain:
not specified
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Weight at study initiation:
Dog number 1201 = 11.5 kg
Dog number 1202 = 14.8 kg
Dog number 1203 = 15.7 kg
Dog number 1204 = 9.1 kg
Dog number 1205 = 7.4 kg

- Fasting period before study: Overnight
- Housing: Individual Wire Mesh Cages
- Diet: Agway Dog Food once daily (700g/dog/day)
- Water: ad libitum
Route of administration:
oral: gavage
Vehicle:
not specified
Details on oral exposure:
No details provided in report
Doses:
800 mg/kg bw
No. of animals per sex per dose:
3 Males numbered 1201, 1202, and 1203.
2 Females numbered 1204 and 1205.
Control animals:
no
Details on study design:
After an overnight fast, each dog received diallyl phthalate (800 mg/kg bw ) by gavage. This was the LD50 dose calculated from studies in the rats. Feed and water were then made available to the dogs. Dogs were observed carefully for the next 8 hours and frequently each day thereafter for 8 days.
Statistics:
No details provided in report
Dose descriptor:
LD50
Effect level:
ca. 800 mg/kg bw
Mortality:
Dog 1204 died 9 hr after dosing due to pulmonary edema and dog 1205 died 26 hr after dosing.
Clinical signs:
After dosing all five dogs vomited within 2 hours of treatment. Emesis first occured approximately 1.3 hours following dosing (0.6-2.1 hr. range) and recurred in all dogs at intervals throughout the day. Autopsy of the second dog, which died after 26h following dosing, revealed widespread gastrointestinal bleeding with possible jaundice. The other 3 dogs returned to normal behaviour within  a week.
Body weight:
- Final body weight:
Dog number 1201 = 11.2 kg
Dog number 1202 = 15.1 kg
Dog number 1203 = 14.8 kg
Dog number 1204 = 9.1 kg
Dog number 1205 = 6.9 kg
Other findings:
The urine was dark yellow for 5 days post dosing but appeared normal, thereafter. Defecation was normal except for dark stools in dog 1201 until 5 days post dosing. Appetite returned rapidly post treatment except in dog 1201 which did not eat normal quantities of food for 4 days. The results of clinical chemistry, urinalyses and hemaogical tests performed 4 days post treatment are presented in table 4 of the attached report.

Haematological and urine analyses were within the normal range in all survivors four days following treatment. Plasma pH however, was lower than normal in all dogs and this was accompanied by low chloride, and marginally depressed sodium and potassium content of the plasma.

SGPT levels were elevated in all dogs: SGOT and SAP were elevated in 2 of the 3 remaining dogs. The dog with the lowest values (1202 M) presumably had vomitted most or all of the compound within 3 hours after treatment, since no additional observations of vomiting were detected. The other 2 dogs, with higher blood enzyme levels had sufficient emetic stimulation to cause vomiting beyond 6 hours following treatment.

The elevation of the liver enzymes (SGOT, SGPT and SAP) is indicative of hepatotoxicity. These enzymes appear in plasma as a result of liver cell damage. The marked elevation of SAP suggests possible obstructive jaundice and intrahepatic cholestasis: however, no obvious jaundice was seen in the surviving dogs.
Interpretation of results:
Category 4 based on GHS criteria
Remarks:
Migrated information: Results indicate at least category IV.
Conclusions:
Since all five dogs vomited shortly after dose administration, the actual dose ingested was most likely lower than the 800 mg/kg bw applied. As two out of five dogs died, the ingested dose approximates the LD50 of diallyl phthalate for dogs. Hence, considering the range between 300 and 2000 mg/kg bw for Toxicity category IV, diallyl phthalate should be classified as such.
Executive summary:

A single, oral administration of D.A.P. (800 mg/kg) to 3 male and 2 female dogs was followed by episodes of emesis for up to 8 hours post treatment. Both females on test died. Female 1204 died of pulmonary edema hours after receiving D.A.P. Female 1205 died 26 hours after treatment with widespread gastrointestinal bleeding and possible jaundice. Dog 1204 had not vomitted until 2 hours post treatment while 1205 had had 5 recorded episodes or emesis. Elevated liver enzyme levels were found in all surviving dogs four days following treatment with D.A.P. These findings indicate hepatocellular damage with possible obstructive jaundice and intrahepatic cholestasis.

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
656 mg/kg bw
Quality of whole database:
Klimisch 2

Acute toxicity: via inhalation route

Link to relevant study records
Reference
Endpoint:
acute toxicity: inhalation
Type of information:
experimental study
Adequacy of study:
key study
Study period:
No details provided in report
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
guideline study with acceptable restrictions
Qualifier:
equivalent or similar to
Guideline:
OECD Guideline 433 draft (Acute Inhalation Toxicity: Fixed Concentration Procedure) (not officially approved)
Deviations:
no
GLP compliance:
no
Species:
rat
Strain:
Sprague-Dawley
Sex:
male/female
Details on test animals and environmental conditions:
Supplier: Charles River Breeding Laboratories, Wilmington, Massachusetts
Received: March 25, 1980
Pre-exposure body weights: 256-288 g (males); 227-247 g (females)
Route of administration:
inhalation: aerosol
Type of inhalation exposure:
whole body
Vehicle:
air
Remarks:
(Dry air, flow rate 15 L per minute)
Details on inhalation exposure:
- The test material was placed in a 500 ml graduated cylinder connected to an FMI fluid metering pump (Model ARPG 201 with a 1/3 inch piston set to deliver at 60%. The test material was fed directly into a Round Spray Atomizing Nozzle mounted inside the 100 liter plexiglass chamber housing the test animals. Dry air, at a flow rate of 15 liters per minute, was passed through the atomizer to generate the aerosol. The exlosure lasted for four hours.
- The air temperature and humidity were monitored continuosly using a wet bulb/dry bulb hygrometer, during the exposure and readings were recorded hourly.
- The nominal exposure concentration was 67.2 mg/L
- The mean airborne concentration was 4.47 mg/L which represents 7% of the nominal exposure concentration
- The average aerodynamic mass median diameter of the aerosol particles was 2.51µm, with a geometric standard deviation range of 2.39 to 3.60 (See Table 2 of the attached report)
- The mean temperature in the chamber during the test material exposure was 69°F and the mean relative humidity was 85%
Analytical verification of test atmosphere concentrations:
yes
Remarks:
Gas Chromatography-analysis of samples on charcoal tubes taken hourly during exposure
Duration of exposure:
4 h
Concentrations:
- The nominal exposure concentration was 67.2 mg/L
- The mean airborne concentration was 4.47 mg/L which represents 7% of the nominal exposure concentration
No. of animals per sex per dose:
5
Control animals:
no
Details on study design:
- Duration of observation period following administration:
- Frequency of observations and weighing: Air temperature and humidity were monitored continuosly during the exposure and readings were recorded hourly. Samples of the chamber atmosphere were taken at approximately 1, 2, 3 and 4 hours into the exposure. Particle size distribution samples were taken at approximately 30 minute intervals during the exposure.
- Necropsy of survivors performed: yes (Gross necropsy examinations were performed as soon as posstble after death on all animals dying spontaneously)
- Other examinations performed: clinical signs, body weight and histopathology (tissues for histopathological examination: lungs, liver, kidneys and any gross lesions)

Statistics:
No details provided in report
Key result
Sex:
male/female
Dose descriptor:
LC100
Effect level:
4.47 mg/L air
Exp. duration:
4 h
Mortality:
On day 1, 4 out of 5 males died and all females died. The remaining male died the following day.
Clinical signs:
other: Reddening of nasal tissues (mucosal surfaces, nasal turbinates), lung lobes and liver in all animals. Further observations were vascularized and friable brain, reddening of brain tissue, kidney medulla and/or the glandular surface of stomach.
Body weight:
Only the male rat, which died on day 2 was weighed and its body weight had decreased from 270 to 235 g.
Gross pathology:
No data presented.

- During the exposure period, all visible animals exhibited closed eyes, reduced activity, labored breathing, and wet and matted fur. Some lacrimation and salivation were observed and one female exhibited chromodacryorrhea. Observations of abnormal signs commenced at the 15-minute interval of exposure and disappeared by exposure termination or during the four-hour post-exposure periodexcept laboured breathing, which persisted until death.

- During the post-exposure period mucoid nasal discharge, laboured breathing with occasional gasping, wet and matted fur, purple skin coloration, flushed skin, stained fur around the eyes, nose and/or mouth, dilated pupils, loss of pupillary reflexes, and rough, dry and/or dull corneal surfaces were most frequently observed. Lacrimation, salivation, shallow breathing, dry rales, uncoordinated movement, general poor condition, lack of grip, prostration, yellow stained ano-genital fur, brown stained ano-genital fur miosis, and corneal opacity were observed less frequently. A complete list of exposure and post-exposure observations is presented in Table 3 (although not attached in the reprot).

- By the 480 -minute interval, one of ten rats died. By the morning of Day 1 eight more animals had died, and the surviving animal died after observation on Day 1. Observations for this animal on Day 1 include reduced activity yellow stained ano-genital fur, general poor condition, laboured breathing, damp and matted fur, cool body, purple skin coloration, and lack of grip and support on all limbs.

- Necropsy examination revealed lung and nasal turbinate discoloration in four males and all females which were considered related to exposure. Other abnormal necropsy findings were obscured by post-mortem changes.

Interpretation of results:
Category 4 based on GHS criteria
Conclusions:
- Exposure to the test material produced immediate signs of irritation and 100% mortality by Day 1. Necropsy examination revealed discoloration of the nasal turbinates and lungs.
- A group of Sprage-Dawley rats was exposed to an aerosol of compound ''D'' for four hours at a nominal concentration of 67.2 mg/l. Direct chamber measurements indicated a mean airborne concentration of the test material - 4.47 mg/l with an average aerodynamic mas median diameter of 2.51µm.
- Exposure to the test material produced immediate signs of irritation and 100% mortality by Day 1. Necropsy examination revealed discoloration of the nasal turbinates and lungs.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
discriminating conc.
Value:
580 mg/m³

Acute toxicity: via dermal route

Link to relevant study records
Reference
Endpoint:
acute toxicity: dermal
Type of information:
experimental study
Adequacy of study:
key study
Study period:
Date of Study Report: August 25, 1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Basic data given: comparable to guidelines/standards
Qualifier:
according to
Guideline:
other: 16CFR 1500.40
Deviations:
not specified
GLP compliance:
no
Test type:
standard acute method
Limit test:
no
Species:
rabbit
Strain:
other: albino
Sex:
not specified
Details on test animals and environmental conditions:
The acute dermal toxicity study (single exposure) was conducted on adult albino rabbits selected from healthy, acclimated animals.
Type of coverage:
not specified
Vehicle:
not specified
Details on dermal exposure:
No details provided in report
Duration of exposure:
No details provided in report
Doses:
200, 2000 and 5000 mg/kg
No. of animals per sex per dose:
30 rabbits used in total (no details provided whether they were male or female)
Control animals:
not specified
Details on study design:
No details provided in report
Statistics:
No details provided in report
Preliminary study:
N/A
Sex:
not specified
Dose descriptor:
LD50
Effect level:
3 300 mg/kg bw
Based on:
test mat.
Mortality:
No details provided in report
Clinical signs:
No details provided in report
Body weight:
No details provided in report
Gross pathology:
No details provided in report
Other findings:
No details provided in report

Results:

 

Dosage Level

(mg/kg)

No.*Rabbits

Dosed

Deaths

Day

1

2

3

4

5

6

7

8

9

10

11

12

13

14

Mortality after 14 Days

200

10

3

0

0

0

0

0

0

0

0

0

0

0

0

0

3/10

2000

10

1

0

0

1

0

0

0

1

0

0

0

1

0

0

4/10

5000

10

1

2

3

0

0

0

0

0

0

0

0

0

0

0

6/10

* Administered as received.

Interpretation of results:
study cannot be used for classification
Remarks:
Migrated information
Conclusions:
The approximate acute Dermal LD50 obtained for the test material identified above is 3300 mg/kg of body weight estimated by interpolation from the probit response curve.
Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
LD50
Value:
3 300 mg/kg bw

Additional information

The acute oral LD50 equals the LD50 found for female rats in "Single administration study in F344/N rat (NTP, 1985)", which appeared to be more sensitive than their male counterparts.

The key study for dermal toxicity included three dose levels of 200, 2000 and 5000 mg/kg bw. The LD50 was calculated to be 3300 mg/kg bw, but three rabbits died at 200 mg/kg bw. Remarkably, all three rabbits died on the first day of exposure, whereas only one rabbit had died at each of the other dose levels, which were an order of magnitude higher. Further rabbits that died at 5000 mg/kg bw, were recorded dead on the following days, while those at 2000 mg/kg bw died during the 14 -day observation period. As no data were present for treatment controls, the results of this study should be viewed with caution, although other studies largely corroborated this value (these studies had lower Klimisch scores, however).

In an acute inhalation study in the rat an LC50 of 8.3 mg/l (8300mg/m3) was identified for a 1 hour exposure. The LC1 of 580 mg/m3 was calculated by the authors and this is considered the most sensitive starting point for deriving a DNEL. While a second acute inhalation study identified an LC 100 of 4470 mg/m3 for 4 hours exposure, the LC50 of 8.3 mg/l for one hour would correspond to an LC50 at 4 hours of 2075mg/m3 (see below, assuming a simple linear relationship) indicating that the use of the LC1 for one hour in determining a DNEL is conservative.

Justification for classification or non-classification

Acute oral toxicity: Classification as Category 4, LC50 is between 300 and 2000 mg/kg b.w.

Acute dermal toxicity: No classification as the LD50 > 2000 mg/kg bw, the upper limit for classification.

Acute toxicity for inhalation: Classification as Category 4; motivation is firstly based on 4470 mg/m3 inducing 100 % mortality in a 4 -h exposure study, which confirms that the LC50 of DAP for inhalation is below 5 mg/l. Secondly, based on the secondary source data from ToxiGenics' study 420-0402 with an overall LC50 for rats which was 8300 mg/m3 after 1 hour of exposure, the LC50 value for the 4h-exposure would correspond with 2075 mg/m3 (assuming a simple linear relationship between time and LC50). The lowest 1h-LC50 value was 5200 mg/m3 for female rats, corresponding with 1300 mg/m3 extrapolated to 4 h exposure (again, assuming a simple linear relationship). These values indicate that the LC50 of DAP for inhalation is between 1000 and 5000 mg/m3, the limits for classification as Category 4.