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Administrative data

Description of key information

Information is only available for repeated oral dose toxicity. No data is available for dermal toxicity or toxicity through inhalation.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
short-term repeated dose toxicity: oral
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
8 - 21 September 1976
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study is well documented and reliable but exposure duration is 14 days instead of 28 days as required by the REACH regulation.
Reason / purpose:
reference to same study
Principles of method if other than guideline:
No specific guidelines followed, study was a preliminary study for the 13 week study (see cross reference).
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Fischer 344
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Frederick Cancer Research Center (Frederick, MD)
- Acclimation period: 18 d
- Age at study initiation: 10 wk
- Method of Identification: Ear tag
- Housing: 2-3 per cage, Polycarbonate (Lab Same as single- Products. Garfield, NJ. administration studies and Hazleton Systems, Aberdeen, MD)
- Bedding:Ab-sorb-dri ( Lab Products; Garfield, NJ)
- Diet: Purina Lab Chow@ (ground); provided ad libitum
- Water (e.g. ad libitum): Tap water in bottles, acidified to pH 2.5 with HCl; provided ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 23 ± 1;
- Humidity (%):30-70;
- Air changes (per hr): 12-15
- Photoperiod (hrs dark / hrs light): 12/12


IN-LIFE DATES: necropsy date: 22 September 1976
Route of administration:
oral: gavage
Vehicle:
corn oil
Details on oral exposure:
Dosing solution: 50 mg/ml. Different volumes were administered to achieve the various doses; vehicle controls received the same dose volume as did the 600 mg/kg animals.
Analytical verification of doses or concentrations:
no
Duration of treatment / exposure:
14 d.
Frequency of treatment:
Once daily.
Remarks:
Doses / Concentrations:
0,50,100,200,400, 600 mg/kg bw
Basis:
actual ingested
No. of animals per sex per dose:
5
Control animals:
yes, concurrent vehicle
Positive control:
Not applicable
Observations and examinations performed and frequency:
- Type and Frequency of Observation: Observed once daily for mortality; weighed on d 0,7,14.
- Necropsy of survivors performed: yes.
Sacrifice and pathology:
No pathology performed.
Other examinations:
No tissues examined microscopically.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
All the rats died at 600 mg/kg bw and 3/5 males and 1/5 females died at 400 mg/kg bw. Clinical effects were limited to inactivity occasionally occurring at 100 and 600 mg/kg bw. No clinical signs were observed in other dose groups.
Mortality:
mortality observed, treatment-related
Description (incidence):
All the rats died at 600 mg/kg bw and 3/5 males and 1/5 females died at 400 mg/kg bw. Clinical effects were limited to inactivity occasionally occurring at 100 and 600 mg/kg bw. No clinical signs were observed in other dose groups.
Body weight and weight changes:
effects observed, treatment-related
Description (incidence and severity):
Males initially lost weight at 400 mg/kg bw; mean body weight gains for males at 200 or 400 mg/kg bw and for females at 400 mg/kg bw appeared to be lower than those of the vehicle controls.
Ophthalmological findings:
not examined
Haematological findings:
not examined
Clinical biochemistry findings:
not examined
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
effects observed, treatment-related
Description (incidence and severity):
Dark, mottled lungs and distended stomachs males and females at >= 400 mg/kg bw. Enlarged cecums and spleen in both sexes at 200 mg/kg and enlarged cecums in males at 50 and 100 mg/kg. Abnormalities of liver in both sexes >=50 mg/kg bw.
Histopathological findings: non-neoplastic:
not examined
Histopathological findings: neoplastic:
not examined
Dose descriptor:
other: LC50
Effect level:
350 mg/kg bw (total dose)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: See attached figure presenting the dose-response relation for estimation of the LC50.
Dose descriptor:
other: LC0
Effect level:
200 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Dose descriptor:
LOEL
Remarks:
Abnormalities in liver
Effect level:
50 mg/kg bw/day (nominal)
Based on:
test mat.
Sex:
male/female
Critical effects observed:
not specified

TABLE: Survival and mean body weights of rats in the fourteen-day repeated-administration gavage studies of diallylphthalate

Dose

Survival

Mean body weights (grams)

Initial

Interim

Final

Change

MALE

0

5/5

128

161

191

63

50

5/5

128

169

186

58

100

5/5

128

161

182

54

200

5/5

128

169

169

41

400

2/5

128

112

124

-4

600

0/5

128

(d)

(d)

-

FEMALE

0

5/5

103

119

134

31

60

5/5

103

121

131

28

100

5/5

103

121

136

33

200

5/5

103

121

133

30

400

4/5

103

97

111

8

600

0/5

103

(d)

(d)

-

 

Conclusions:
The liver appeared to be the main target organ of diallyl phthalate exposure in rats. Gross examination showed visible effects on the liver even at the lowest dose of 50 mg/kg bw tested (LOEC). Other organs affected were spleen (>= 200 mg/kg bw) and lungs (>= 400 mg/kg bw). No dose related mortality was observed at and below 200 mg/kg bw (LC0).
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
50 mg/kg bw/day
Study duration:
subchronic
Species:
rat
System:
hepatobiliary
Organ:
liver

Repeated dose toxicity: inhalation - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: inhalation - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - systemic effects

Endpoint conclusion
Endpoint conclusion:
no study available

Repeated dose toxicity: dermal - local effects

Endpoint conclusion
Endpoint conclusion:
no study available

Additional information

Evaluation of the key value for repeated oral dose toxicity is based on a series of studies in rats. Studies with mice have also been added, but these show a higher tolerance for oral DAP exposure compared to rats. In rats, the liver appeared to be the primary target organ with changes observed at and above 50 mg/kg/day for males and 100 mg/kg/day for females in the 90-day study. However, the features identified in the subchronic oral rat study at 50 mg/kg/day were termed "hepatocellular alterations characterised by hepatocellular basophillia, cellular and nuclear hypertrophy and nuclear hyperchromatism". There were only mild alterations at 100 mg/kg/day and the 25 mg/kg/day histopathological examination was not performed because of the "absence (or presence of only minimal) hepatic changes at 50 mg/kg/day". The description in the study report of a low incidence of minimal (or absent) hepatic changes confirms the identification of the NOAEL at 50 mg/kg/day.


Repeated dose toxicity: via oral route - systemic effects (target organ) digestive: liver

Justification for classification or non-classification

Specific Target Organ Toxicity: Repeated. STOT-RE is assigned on the basis of findings of ‘significant’ or ‘severe’ toxicity. In this context ‘significant’ (Category 2) means changes which clearly indicate functional disturbance or morphological changes which are toxicologically relevant. ‘Severe’ (Category 1) effects are generally more profound or serious than ‘significant’ effects and are of a considerably adverse nature which significantly impact on health. Both factors have to be evaluated by weight of evidence and expert judgement. Classification in Category 2 is applicable when significant toxic effects observed in a 90-day repeated-dose study conducted in experimental animals are seen to occur within guidance value ranges which are presented in the "Guidance on the Application of the CLP Criteria" Page 482 (noting that these are guidance values intended for guidance purposes). For a 90 day study significant effects are seen at dose levels between 10 and 100 mg/kg/day. In the results of the key study, described above, an NOAEL of 50 mg/kg/day has been selected (on the basis of the absence of or minimal hepatic changes) and the alterations at 100 mg/kg/day are described as mild. Consequently, the changes described are not considered to be significant (changes which clearly indicate functional disturbance or morphological changes which are toxicologically relevant) and therefore a classification of STOT Repeated Exposure Category 1 or 2 is not justified.