Diallyl phthalate

Endpoint summary

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 for cross-reference:

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 or test system 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:

no adverse effect observed

Dose descriptor:

NOAEL

50 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

Klimisch 2

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.