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Administrative data

Description of key information

The NOAEL for oral toxicity in rats was 1500 mg/kg bw/d in a 14 day range-finding study and 1000 mg/kg bw/d in a combined repeated dose/reproductive toxicity study. Low toxicity is also predicted for the inhalation and dermal routes of exposure.

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
Remarks:
combined repeated dose and reproduction / developmental screening
Type of information:
experimental study
Adequacy of study:
key study
Study period:
23 October 1991 to 6 January 1992
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Study performed according to internationally accepted test guidelines but not according to GLP.
Reason / purpose:
reference to same study
Qualifier:
according to
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Version / remarks:
Draft March 1990
GLP compliance:
no
Remarks:
The report states that the study was conducted according to the principles of GLP, but the work was not certified and was not subject to Quality Assurance review .
Limit test:
no
Species:
rat
Strain:
other: Crl:CD (SD) BR VAF/Plus
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River UK Ltd.
- Age at study initiation: (P) Males 12 wks ±1 day, Females (sexually mature, virgin) 7 weeks ±1day;
- Weight at study initiation: (P) Males: 440-446 g; Females: 224-228 g
- Fasting period before study: overnight
- Housing: pre-mating; suspended stainless steel cages equipped with solid sides and wire grid front, back, floor, and top. During mating male and female pairs were housed in plastic breeding cages (North Kent Plastics, RM2 type).
- Acclimatisation period: 1 week
- Diet : Biosure Laboratory Animal Diet No. 1 ad libitum
- Water : tap water ad libitum

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 21
- Humidity (%): 55
- Air changes (per hr): not specified
- Photoperiod (hrs dark / hrs light): 12/12

Five males and five females were supplied for health check purposed. They were killed within 24 hours of arrival and subjected to routine macroscopic examination.
Route of administration:
oral: gavage
Vehicle:
other: 1% methylcellulose
Details on oral exposure:
The test material was ground in a mortar with a small volume of 1% methylcellulose until a smooth paste was formed. The formulation was then gradually made up to volume and mixed using a high speed homogeniser. A series of suspensions were then made to give the required concentrations. Formulations were prepared daily and dosed on the day of preparation.
Analytical verification of doses or concentrations:
no
Details on analytical verification of doses or concentrations:
Analytical verification of doses was not carried out.
Duration of treatment / exposure:
Males: 7 weeks; Females: 9 weeks.
Frequency of treatment:
Daily
Remarks:
Doses / Concentrations:
0, 500, and 1000 mg/kg/day
Basis:
actual ingested
No. of animals per sex per dose:
10 rats/sex/dose
Control animals:
yes
Details on study design:
A range finding study was conducted prior to the main study, the limit dose of 1000 mg/kg bw/d was established as a suitable high dosage level. As this study was a combined repeated dose toxicity/reproduction study, females were exposed to the test substance for 9 weeks until post partum day 4 when they were sacrificed (non-pregnant females were also sacrificed at week 9). Males were sacrificed after 7 weeks exposure.
Controls were concurrent but it is not stated whether they were unexposed, or administered the vehicle alone.
Positive control:
A positive control was not included.
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily


BODY WEIGHT: Yes
- Time schedule for examinations: recorded at allocation to groups, commencement of treatment and thereafter weekly. Females also weighed daily from the commencement of the mating period until parturition and Days 0 and 4 post partum.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study):
- Food consumption for each animal determined and mean daily diet consumption calculated as g food/kg body weight/day: Yes, measured during the pre-treatment and pre-mate period for males and females, during the post mate period for males and post partum for females. Water intake was only measured by visual observation, and could therefore not be subjected to statistical analysis.


HAEMATOLOGY: Yes, assessed after two weeks of treatment, and again after 5 weeks treatment in females
- Anaesthetic used for blood collection: Light ether anaethesia
- Animals fasted: Yes, overnight
- Parameters examined: PCV, haemoglobin, RBC, MCHC, MCV, total and differential WBC, platelets, examination for abnormal cell morphology, thrombotest, reticulocyte count.


CLINICAL CHEMISTRY: Yes, assessed after two weeks of treatment, and again after 5 weeks treatment in females.
- Animals fasted: Yes, overnight
- Parameters examined: Glucose, GPT, GOT, CPK, gammaGT, total protein albumin, globulin, urea nitrogen, AP, total bilirubin, creatine, sodium, potassium, calcium, inorganic phosphorus, chloride, cholesterol.

OTHER: Organ weights: adrenals, brain, epididymides, heart, kidneys, liver, lungs, ovaries, prostrate, testes, thymus, spleen.
Sacrifice and pathology:
Animals were subject to gross necropsy at study termination. The following tissues were examined histologically (* denotes tissues examined from control and high dose groups only): adrenals*, brain*, epididymides*, heart*, kidneys*, liver*, lungs, mammary gland, macroscopically abnormal tissues, ovaries*, pituitary*, prostate*, seminal vesicles*, spleen*, testes*, thymus, thyroids, uterus* and vagina*.
Other examinations:
No other examinations were reported.
Statistics:
ANOVA followed by Williams' test, or Kruskal-Wallis 'H' statistic followed by Shirley's test where appropriate.
Clinical signs:
effects observed, treatment-related
Description (incidence and severity):
: observations of pales faeces are not considered to be of toxicological significance
Mortality:
mortality observed, treatment-related
Description (incidence):
: observations of pales faeces are not considered to be of toxicological significance
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Food efficiency:
not examined
Water consumption and compound intake (if drinking water study):
no effects observed
Ophthalmological findings:
not examined
Haematological findings:
no effects observed
Clinical biochemistry findings:
no effects observed
Urinalysis findings:
not examined
Behaviour (functional findings):
not examined
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
not examined
Details on results:
CLINICAL SIGNS AND MORTALITY
There were no clinical signs associated with treatment, and there were no deaths during the study.

BODY WEIGHT AND WEIGHT GAIN
The bodyweight gain of treated males was similar to that of controls throughout the study. Females given 1000 mg/kg/day showed reduced gain during pregnancy but recovered post partum.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
No effects of treatment on food intake were apparent over the time periods of measurement.

HAEMATOLOGY
There were no changes in the haematological and biochemical parameters measured that were clearly indicative of a reaction to treatment. Clinical chemistry data are shown in Table 1.

ORGAN WEIGHTS
There were no differences in organ weights that indicated any treatment-related effects.

HISTOPATHOLOGY: NON-NEOPLASTIC
There were no differences or changes noted at histopathological examination that indicated any treatment-related effects.
Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No effects were observed at the highest (limit) dose level
Critical effects observed:
not specified

Clinical Chemistry data

 

 

 

Protein

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Group

No. of animals

Glucose (mg/dl)

Total (g/dl)

Alb (g/dl)

Glob (g/dl)

Urea Nitr (mg/dl)

Creatitine (mg/dl)

AP mU/ml

GPT mU/ml

GOT mU/ml

gamma GT mU/ml

CPK mU/ml

Bilirubin (mg/dl)

Na mEq/l

K mEq/l

Ca mEq/l

P mEq/l

Cl mEq/l

Chol mg/dl

Control males

10

159

6.3

2.9

3.3

15

0.5

304

27

60

<1

142

<0.1

142

3.6

5.4

4.6

100

53

500mg/kg/day males

10

154

6.4

3

3.5

16

0.5

354

29

65

<1

93

<0.1

141

3.8

5.5

4.5

100

55

1000 mg/kg/day males

10

161

6.4

2.9

3.5

16

0.5

356

32

72

<1

130

<0.1

142

3.7

5.4

4.2

101

56

 

 

 

 

 

 

 

 

 

 

 

 

 

F

 

 

 

 

 

 

Control fem

10

161

6.7

3.3

3.4

15

0.5

320

26

53

<1

125

<0.1

140

3.4

5.6

4.2

101

68

500mg/kg/day fem

10

160

6.6

3.2

3.3

17

0.6

340

23

51

<1

125

<0.1

141

3.4

5.4

3.8

103

65

1000 mg/kg/day fem

10

161

6.7

3.3

3.5

17

0.6

351

27

56

<1

137

0.1

141

3.6

5.6

4.3

102

65

 

 

 

 

 

 

 

 

 

 

 

 

 

F

 

 

 

 

 

 

week 5

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

 

Control fem

10

140

6.5

2.9

3.6

12

0.5

161

26

80

<1

91

0.1

143

3.7

5.3

4

102

44

500mg/kg/day fem

10

133

6.5

3

3.5

11

0.6

184

26

81

<1

103

0.1

142

4

5.4

4.1

101

43

1000 mg/kg/day fem

10

130

6.5

3

3.6

10

5

176

29

78

<2

247

0.1

143

4.1

5.4

4.2

102

47

Conclusions:
There were no findings at either of the dosage levels employed in this study to indicate an immediate requirement for more detailed studies. The NOAEL is considered to be 1000 mg/kg/day.
Executive summary:

The study was conducted to assess the repeated dose oral toxicity and toxicity to reproduction of dipentaerythritol, in accordance with OECD guideline 422 (draft version; 22 March 1990). Sexually mature rats were exposed to dipentaerythritol via oral gavage at 0, 500, and 1000 mg/kg bw/day. Male rats were exposed for 7 weeks prior to sacrifice and necropsy. Females were exposed for 9 weeks until post partum day 4, when they were also sacrificed and subjected to gross necropsy. There were no findings at either of the dosage levels in this study to indicate an immediate requirement for more detailed studies. No effects of treatment were observed on food intake, bodyweight change, haematology, biochemistry, organ weights, post mortem findings and histopathology. The NOAEL is therefore considered to be 1000 mg/kg bw/d.

 

Endpoint conclusion
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Study duration:
subacute
Species:
rat
Quality of whole database:
A 14-day range-finding study and an OECD 422 screening study are available for Di-Penta.

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

Repeated dose oral toxicity: oral

A combined repeated dose toxicity with reproductive toxicity screening test was conducted with di-pentaerythritol in accordance with OECD test method 422 (draft version; 22 March 1990) (Powell et al, 1992). Rats were exposed to di-pentaerythritol via gavage at doses of 0, 500 and 1000 mg/kg bw/d. Male rats were exposed for 7 weeks prior to sacrifice and necropsy. Female rats were exposed for 9 weeks until post partum day 4, when they were also sacrificed and subjected to gross necropsy. There were no findings to indicate an immediate requirement for more detailed studies. No effects of treatment were observed on food intake, body weight change, haematology, biochemistry, organ weights, post mortem findings and histopathology. The NOAEL for this study is therefore considered to be 1000 mg/kg bw/d.

A preliminary range finding study was conducted to determine the toxic effects of di-pentaerythritol on male and female Crl: CD(SD) BR VAF/Plus rats (Powell & Marsden, 1992). Dipentaerythritol was administered by gavage in 1% methylcellulose, at doses of 0, 500, 1000 and 1500 mg/kg bw/d for 14 days. One day after the final dose all surviving rats were sacrificed and subjected to routine macroscopic examination. The only overt clinical change in response to treatment was a few pale faeces observed at 1000 mg/kg bw/d, and more frequently at 1500 mg/kg bw/d, with the females showing the sign on more occasions at each dosage compared to males. These findings are not considered to be of toxicological significance. There were no obvious effects on mean food and water consumption, bodyweight change or the incidence and type of macroscopic changes detected at terminal autopsy. It was concluded that 14 days treatment with dipentaerythritol at doses up to 1500 mg/kg bw/d did not elicit an obvious adverse reaction, and this dose level can be considered to be the NOAEL.

Low toxicity was observed in the preliminary range finding study at dose levels up to 1500 mg/kg bw/d. Low toxicity was also observed in the OECD 422 study at dose levels up to 1000 mg/kg bw/d for treatment periods of up to 9 weeks. On this basis, a repeated dose 90 -day toxicity study in the rat is not considered necessary.

Repeated dose dermal toxicity

A waiver is proposed in line with Column 2 of Annex VIII of the REACH Regulation. The repeated dose toxicity of the substance has been adequately characterised in studies using oral exposure.

Repeated exposure inhalation toxicity

A waiver is proposed in line with Column 2 of Annex VIII of the REACH Regulation. The repeated dose toxicity of the substance has been adequately characterised in studies using oral exposure.


Justification for selection of repeated dose toxicity via oral route - systemic effects endpoint:
Study with the longest treatment period and lowest endpoint

Justification for classification or non-classification

Di-pentaerythritol was shown to be of relatively low toxicity; the results of the oral studies available for di-pentaerythritol do not indicate any severe toxicity and do not show any effects at dose levels of 1500 mg/kg bw or lower. Low toxicity is also predicted for the inhalation and dermal exposure routes. Di-pentaerythritol is therefore not classified for repeated dose toxicity according to Regulation (EC) No 1272/2008.