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Description of key information

The pivotal repeated dose study was a 52 week study by the oral route with the analogous substance ammonium sulphate.  In male and female rats, dietary administration of ammonium sulphate resulted in an increase in absolute and relative kidney weights  at the high dose level for both sexes. Absolute spleen weights were decreased and relative liver weights were increased in high dose males only. The NOAEL for these effects was 0.6% in the  diet, which is equivalent to 256 and 284 mg/kg bw/d in males and females, respectively.  The study was performed to methods equivalent to OECD 453, with few deviations. The deviations noted probably arise as a result of the publication of this data in a journal format as opposed to a study report.

Key value for chemical safety assessment

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records
Reference
Endpoint:
chronic toxicity: oral
Remarks:
combined repeated dose and carcinogenicity
Type of information:
experimental study
Adequacy of study:
weight of evidence
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
comparable to guideline study with acceptable restrictions
Justification for type of information:
REPORTING FORMAT FOR THE ANALOGUE APPROACH

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
In accordance with REACH Annex XI, Section 1.5, of Regulation (EC) No. 1907/2006 (REACH) the standard testing regime may be adapted in cases where a grouping or read-across approach has been applied.

The similarities may be based on:
(1) a common functional group
(2) the common precursors and/or the likelihood of common breakdown products via physical or biological processes, which result in structurally similar chemicals; or
(3) a constant pattern in the changing of the potency of the properties across the category
Diammonium dihydrogenpyrophosphate is a soluble inorganic salt consisting of pyrophosphate anions and ammonium cations. Similarities between the source chemical (ammonium sulphate) and the target chemical (diammonium dihydrogenpyrophosphate) are based on the following:
(1) The source chemical (ammonium sulphate) and the target substance (diammonium dihydrogenpyrophosphate) are structurally similar substances. Both are soluble ammonium salts. In vivo both substances will be (bio)transformed into their respective ionic forms; ammonium cations and either phosphate or sulphate anions. Exposure to the non-common compound, the sulphate ions, will not result in toxicological effects at the dose levels tested. Similarly, the effects of different phosphate moieties are not considered to be toxicologically significant due to in vivo (bio) transformation.
(2) The common breakdowns product (ammonium ions) are immediately transformed into urea by the liver and do not exist in the blood in relevant amounts unless in case of liver failure. Exposure to the non-common compound, the sulphate ion, will not result in toxicological effects. Similarly, the effects of phosphate and sulphate are not considered to be toxicologically significant and as such the ammonium ion is the key moiety for assessment of the systemic toxicity of diammonium dihydrogenpyrophosphate. The effects of the target compound (diammonium dihydrogenpyrophosphate) are expected to be equal to the effects of the source substance (ammonium sulphate) for the property under consideration.

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
See read-across justification report attached.

3. ANALOGUE APPROACH JUSTIFICATION
See read-across justification report attached.

4. DATA MATRIX
See read-across justification report attached.

Qualifier:
equivalent or similar to guideline
Guideline:
OECD Guideline 453 (Combined Chronic Toxicity / Carcinogenicity Studies)
Deviations:
yes
Remarks:
No opthalmological evaluation performed, clinical signs not reported in the study report, no haematology or clinical chemistry measurements made during the study.
Principles of method if other than guideline:
Male and female F344 rats were exposed to various concentrations of ammonium sulfate in the diet over a period of either 52 weeks (chronic toxicity study) or 104 weeks (carcinogenicity study).
GLP compliance:
not specified
Limit test:
no
Species:
rat
Strain:
Fischer 344/DuCrj
Sex:
female
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Japan (Atsugi, Japan)
- Age at study initiation: 5 weeks
- Weight at study initiation: 100-150 g
- Fasting period before study: no data
- Housing: 3 or 4 rats per cage
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 1 week

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 24 ± 1 °C
- Humidity (%): 55 ± 5 %
- Air changes (per hr): 18
- Photoperiod (hrs dark / hrs light): 12/12

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on oral exposure:
PREPARATION OF DOSING SOLUTIONS:

DIET PREPARATION
- Rate of preparation of diet (frequency): test diet replaced ever 2 weeks
- Mixing appropriate amounts with (Type of food): powdered basal diet (CRF-1)
- Storage temperature of food: under refrigeration

Stability of ammonium sulphate in the solid pellet diet was evaluated and no decomposition was confirmed after storageunder refrigeration or at room temperature for 2 weeks.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Recapture rates for ammonium sulfate from the admixed diet at each concentration level were confirmed to be 95.4-98.7%.
Duration of treatment / exposure:
52 or 104 weeks
Frequency of treatment:
Continuously (in diet)
Remarks:
Doses / Concentrations:
42, 256, 1527 mg/kg bw/day (males) 48, 284, 1490 mg/kg bw/day (females)
Basis:
other: actual ingested during 52-week chronic study. Calculated on the basis of food consumption and body weight
Remarks:
Doses / Concentrations:
0.1, 0.6, 3.0%
Basis:
other: nominal in diet, 52-week chronic toxicity study
Remarks:
Doses / Concentrations:
564.1, 1288.2 mg/kg bw/day (males); 649.9, 1371.4 mg/kg bw/day (females)
Basis:
other: actual ingested during 104-week carcinogenicity study. Calculated on the basis of food consumption and body weight
Remarks:
Doses / Concentrations:
0, 1.5, 3%
Basis:
other: nominal in diet, 104-week carcinogenicity toxicity study
No. of animals per sex per dose:
52-week chronic toxicity study: 10 animals per sex per dose group
104-week carcinogenicity study: 50 animals per sex per dose group
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: selected on basis of a 13-week dietary study in which rats were administered diets containing 0%, 0.38%, 0.75%, 1.5% and 3.0%. Reduced bodyweight gains and diarrhea were noted in males at the 3.0% dose level. NOAEL estimated to be 866 mg/kg/day (males) and 1975 mg/kg/day (females)
Observations and examinations performed and frequency:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily


BODY WEIGHT: Yes
- Time schedule for examinations: every 2 weeks until week 10 and every 5 weeks thereafter

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


FOOD EFFICIENCY:
- Body weight gain in kg/food consumption in kg per unit time X 100 calculated as time-weighted averages from the consumption and body weight gain data: No data

OPHTHALMOSCOPIC EXAMINATION: YNo data


HAEMATOLOGY: Yes
- Time schedule for collection of blood: at termination of study (52 weeks) No data from carcinogenicity study
- Anaesthetic used for blood collection: Yes (ether)
- Animals fasted: Yes
- How many animals: 10 per group
- Parameters checked: red blood cell count (RBC), hemoglobin concentration (Hb), hematocrit (Ht), mean corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular hemoglobin concentration (MCHC), platelet count (Plt) and white blood cell count (WBC). Differential leukocyte counts and the reticulocyte count (Ebl).

CLINICAL CHEMISTRY: Yes
- Time schedule for collection of blood: at termination of study (52 weeks) No data from carcinogenicity study
- Animals fasted: Yes
- How many animals: 10 per group
- Parameters checked: total protein (TP), albumin (Alb), albumin/globulin ratio (AIG), total bilirubin (T-bil), total cholesterol (T-Cho), triglyceride (TG), blood urea nitrogen (BUN), creatinine (Cre), calcium (Ca), inorganic phosphorus (IP), sodium (Na), potassium (K), chloride Cl), aspartate transaminase (AsT), alanine transaminase (AlT), alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (gamma-GTP)

URINALYSIS: No

NEUROBEHAVIOURAL EXAMINATION: No

Sacrifice and pathology:
GROSS PATHOLOGY: Yes
HISTOPATHOLOGY: Yes
Brain, lungs, heart, spleen, liver, adrenals, kidneys and testes were weighed. As for adrenals, kidneys and testes, weights of each side were separately recorded and the total of both sides was used for calculation of group mean and SD values.
In addition to these organs, the nasal cavity, trachea, aorta, pituitary, thyroids, parathyroids, salivary glands, tongue, esophagus, stomach, duodenum, jejunum, ileum, caecum, colon, rectum, pancreas, urinary bladder, epididymides, prostate, seminal vesicles, ovaries, uterus, vagina, mammary glands, skin, mesenteric and submandibular lymph nodes, thymus, sternum, femur including bone marrow, sciatic nerve, trigeminal nerve, spinal cord (cervical, thoracic and lumber cords), eye, Harderian gland and thigh muscle. All organs and tissues in the control and 3.0% group animals were histopathologically examined. Additionally, macroscopically abnormal sites in the 0.1% and 0.6% group animals in the chronic study and all organs and tissues of the 1.5% animals in the carcinogenicity study were also histopathologically examined.
Statistics:
Variance in data for body weights, hematology, serum biochemistry and organ weights were checked for homogeneity by Bartlett test. When the data were homogeneous, one-way analysis of variance (ANOVA) was used. In the heterogeneous cases, the Kruskal-Wallis test was applied. When statistically significant differences were indicated, Dunnett's multiple test was employed for comparison between control and treated groups. Final survival rates and the incidences of tumor and non-neoplastic lesions were compared with the Fisher's exact probability test or the Mann-Whitney's U-test.
Clinical signs:
effects observed, treatment-related
Mortality:
mortality observed, treatment-related
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
effects observed, treatment-related
Food efficiency:
not examined
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:
effects observed, treatment-related
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Histopathological findings: neoplastic:
no effects observed
Details on results:
CLINICAL SIGNS AND MORTALITY
In the chronic toxicity study (52 weeks), no mortality was found in any groups throughout the treatment period.
In the carcinogenicity study (104 weeks), the survival rate of control, 1.5% and 3.0% groups were 88%, 78% and 76%, respectively, for males, and 76%, 80% and 80%, respectively, for females, and no significant differences were observed among the groups.

BODY WEIGHT AND WEIGHT GAIN
No test substance-related changes in bodyweight were observed.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
A tendency for increase of food intake in the male 3.0% group in the chronic toxicity study was noted. No effects were noted in the other test groups.

HAEMATOLOGY
No significant variation was found in the erythrocytic parameters and platelets among the groups in the chronic toxicity test. Some slight changes were found in WBC parameters but this was not significant and was not considered to be dose-dependent.

CLINICAL CHEMISTRY
No dose-related alterations were found in any of the serum biochemical parameters in the chronic toxicity study.

ORGAN WEIGHTS
Absolute and relative kidney weights were increased or showed a tendency for increase at 3.0% in both sexes in the chronic toxicity study. Absolute spleen weights were decreased and relative liver weights were increased in the 3.0% male dose group. No dose-related changes were found in the other organs.

GROSS PATHOLOGY
There were no obvious macroscopic findings in any group in either the chronic toxicity or carcinogenicity studies, except for massive, nodular or focal lesions suggesting neoplastic change in the carcinogenicity study.

HISTOPATHOLOGY: NON-NEOPLASTIC
There were no obvious macroscopic findings in any of the groups tested in the chronic toxicity or carcinogenicity studies.
In the carcinogenicity study, non-neoplastic and neoplastic lesions were noted in the control and treatment groups, with no significant inter-group difference in their incidences or severity.
In the chronic toxicity study several non-neoplastic lesions were noted in the control and the 3.0% groups and there were no differences in their incidences between the groups in either sex.
Strain-related increases in some lesions were noted in all groups but there were no test substance-related increases in lesions.

Dose descriptor:
NOAEL
Effect level:
256 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male
Basis for effect level:
other: Based on 0.6% dose level. Increased absolute and relative kidney weights in the high dose group. In the high dose group a decrease in absolute spleen weights and an increase in relative liver weights were noted.
Dose descriptor:
NOAEL
Effect level:
284 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
female
Basis for effect level:
other: Based on 0.6% dose level. Increased absolute and relative kidney weights in the high dose group. In the high dose group a decrease in absolute spleen weights and an increase in relative liver weights were noted.
Critical effects observed:
not specified

Table 1

Final body weight, food consumption and the amount of ammonium sulfate intake in rats fat diet containing ammonium sulfate for 52 weeks

 

Dose level (%)

Final body weight (g)

Food consumption (g/rat/day)

Intakes of ammonium sulfate (mg/kg b.w./day)

Male

0

410.9 ± 12.3

13.9

-

0.1

428.6 ± 17.6

13.6

42

0.6

416.7 ± 23.7

13.4

256

3.0

400.5 ± 15.1

15.7

1527

Female

0

207.4 ± 13.5

8.4

-

0.1

220.3 ± 8.7

8.6

48

0.6

219.2 ± 13.6

8.4

284

3.0

212.7 ± 24.4

8.6

1490

 

Table 2

Haematology in male rats fed diet containing ammonium sulfate for 52 weeks (number of animals = 10)

 

Dose level (%)

 

 

 

0 (Control)

0.1

0.6

3.0

RBC 1010/L

841.0 ± 39.3

875.0 ± 35.5

842.0 ± 22.3

868.0 ± 40.2

Hb g/dL

13.6 ± 1.0

14.3 ± 0.7

13.9 ± 0.4

14.1 ± 0.5

Ht %

43.6 ± 1.9

45.7 ± 2.0

44.1 ± 1.0

44.9 ± 2.1

MCV fL

51.8 ± 0.6

52.2 ± 0.6

52.4 ± 0.5

51.7 ± 1.0

MCH pg

16.2 ± 0.7

16.4 ± 0.3

16.5 ± 0.3

16.2 ± 0.4

MCHC g/dL

31.3 ± 1.5

31.3 ± 0.6

31.6 ± 0.5

31.3 ± 0.6

Plt 1010/L

65.6 ± 5.7

70.3 ± 6.1

66.5 ± 4.9

65.4 ± 11.6

Ebl count/200 WBC

2.4 ± 2.0

3.9 ± 2.2

3.1 ± 1.7

2.4 ± 1.6

WBC 108/L

51.8 ± 16.6

44.7 ±13.5

46.1 ± 8.1

49.6 ± 13.5

Differential cell count (%)

Band

0.0 ± 0.0

0.0 ± 0.0

0.0 ± 0.0

0.0 ± 0.0

Seg

36.4 ± 4.7

44.5 ± 9.0*

43.6 ± 4.1

39.9 ± 8.2

Eosino

2.1 ± 1.3

1.9 ± 0.8

2.7 ± 2.0

1.9 ± 0.8

Baso

0.0 ± 0.0

0.0 ± 0.0

0.0 ± 0.0

0.1 ± 0.2

Lympho

61.1 ± 3.8

53.2 ± 9.0

53.4 ± 4.0*

57.8 ± 8.5

Mono

0.4 ± 0.7

0.4 ± 0.6

0.4 ± 0.5

0.5  

Each value represents the mean ± SD

*Significantly different from the control atp< 0.05

Table 3

Haemathology in female rats fed diet containing ammonium sulfate for 52 weeks (number of animals = 10)

 

Dose level (%)

 

 

 

0 (Control)

0.1

0.6

3.0

RBC 1010/L

770.0 ± 83.8

792 ± 44.3

742.0 ± 29.1

744.0 ± 40.2

Hb g/dL

13.4 ± 1.5

14.0 ± 0.8

13.0 ± 0.4

13.0 ± 1.0

Ht %

43.6 ± 4.5

44.7 ± 2.2

42.2 ± 1.5

42.3 ± 2.1

MCV fL

56.6 ± 0.3

56.5 ± 0.4

56.8 ± 0.3

56.9 ± 0.4

MCH pg

17.4 ± 0.6

17.7 ± 0.4

17.5 ± 0.6

17.5 ± 0.7

MCHC g/dL

30.7 ± 1.1

31.4 ± 0.7

30.8 ± 1.0

30.7 ± 1.3

Plt 1010/L

61.3 ± 4.3

62.6 ± 3.7

60.0 ± 2.8

60.1 ± 5.1

Ebl count/200 WBC

7.3 ± 4.2

8.3 ± 3.0

6.5 ± 3.1

8.5 ± 3.4

WBC 108/L

31.1 ± 6.5

28.8 ± 3.0

24.0 ± 2.9*

28.5 ± 9.7

Differential cell count (%)

Band

0.0 ± 0.0

0.0 ± 0.0

0.0 ± 0.0

0.0 ± 0.0

Seg

32.4 ± 16.6

26.3 ± 6.6

27.0 ± 3.6

26.0 ± 4.0

Eosino

1.1 ± 1.0

1.5 ± 0.9

1.8 ± 1.3

1.0 ± 0.7

Baso

0.0 ± 0.0

0.0 ± 0.0

0.0 ± 0.0

0.0 ± 0.0

Lympho

66.0 ± 16.4

71.5 ± 6.3

70.4 ± 4.7

72.4 ± 4.2

Mono

0.5 ± 0.5

0.7 ± 0.6

0.8 ± 0.5

0.6 ± 0.6

Each value represents the mean ± SD

*Significantly different from the control atp< 0.05

 

Table 4

Serum biochemistry in male rats diet containing ammonium sulfate for 52 weeks (number of animals=10)

 

 

Dose level (%)

 

 

 

0 (Control)

0.1

0.6

3.0

TP g/dL

7.3 ± 0.3

7.3 ± 0.3

7.5 ± 0.3

7.1 ± 0.3

Alb g/dL

4.8 ± 0.2

4.8 ± 0.2

4.9 ± 0.2

4.7 ± 0.3

A/G

1.9 ± 0.1

2.0 ± 0.1*

1.9 ± 0.1

2.0 ± 0.1*

T-Bil mg/dL

0.1 ± 0.1

0.2 ± 0.1

0.3 ± 0.1**

0.1 ± 0.0

T-Cho mg/dL

119 ± 12

127 ± 13

133 ± 15

115 ± 16

TG mg/dL

129 ± 28

155 ± 50

174 ± 57

123 ± 44

BUN mg/dL

18.9 ± 1.7

20.1 ± 1.6

18.4 ± 1.0

18.5 ± 1.5

Cre mg/dL

0.36 ± 0.03

0.33 ± 0.02*

0.32 ± 0.02**

0.36 ± 0.02

IP mg/dL

10.6 ± 0.2

10.8 ± 0.2

10.9 ± 0.4

10.8 ± 0.5*

IP mg/dL

5.1 ± 0.4

5.0 ± 0.5

4.5 ± 0.3**

4.9 ± 0.4

Na mEQ/L

142 ± 3

143 ± 2

143 ± 4

143 ± 5

K mEQ/L

4.3 ± 0.3

4.5 ± 20*

4.6 ± 0.3

4.4 ± 0.3

Cl mEQ/L

102 ±3

104 ± 19*

104 ± 2

102 ± 3

AsT IU/L

88 ± 4

109± 43

134 ± 45**

88 ± 21

AlT IU/L

55 ± 7

79± 1.0

97 ± 39**

57 ± 18

ALP IU/L

354 ± 75

391 ±

418 ± 46

375 ± 48

ɣ- GTP IU/L

5.0 ± 3.0

5.0 ±

7.0 ± ± 2.0

7.0 ± 2.0

Each value represents the mean ± SD

 

*Significantly different from the control atp< 0.05

**Significantly different from the control at p < 0.01

Table 5

Serum biochemistry in femalerats diet containing ammonium sulfate for 52 weeks (number of animals=10)

 

Dose level (%)

 

 

 

0 (Control)

0.1

0.6

3.0

TP g/dL

7.5 ± 0.3

7.7 ± 0.5

7.8 ± 0.4

7.6  ± 0.7

Alb g/dL

5.4 ± 0.3

5.5 ± 0.4

5.6 ± 0.4

5.5 ± 0.4

A/G

2.5 ± 0.2

2.6 ± 0.1

2.6 ± 0.2

2.6 ± 0.2

T-Bil mg/dL

0.2 ±0.1

0.3 ± 0.1

0.3 ± 0.2

0.4 ± 0.3

T-Cho mg/dL

123 ± 6

129 ± 8

129 ± 16

134 ± 13

TG mg/dL

84 ± 24

126 ± 36

121 ± 40

126 ± 67

BUN mg/dL

21.8 ± 6.7

1836 ± 1.2

17.1 ± 1.6*

19.1 ± 2.2

Cre mg/dL

0.36 ± 0.04

0.33 ± 0.02*

0.34 ± 0.03

0.33 ± 0.02*

IP mg/dL

10.5 ± 0.3

10.6 ± 0.4

10.7 ± 0.2

10.7 ± 0.4

IP mg/dL

4.0 ± 0.7

4.4 ± 0.5

4.3 ± 0.5

4.1 ± 0.6

Na mEQ/L

142 ± 1

144 ± 5

142 ± 1

142 ± 1

K mEQ/L

4.0 ± 0.4

4.2 ± 0.2

4.1 ± 0.2

4.0 ± 0.2

Cl mEQ/L

103 ± 3

104 ± 4

104 ± 1

101 ± 2

AsT IU/L

68 ± 7

63 ± 5

64 ± 5

64 ± 6

AlT IU/L

35 ± 6

36 ± 4

33 ± 2

33 ± 4

ALP IU/L

165 ± 35

150 ± 9

134 ± 19*

141 ± 21

ɣ- GTP IU/L

<2 

<2 

< 2

<2

Each value represents the mean ± SD

*Significantly different from the control atp< 0.05

 

Table 6

Organ weights of male rats fed diet containing ammonium sulfate for 52 weeks (number of animals =10)

 

Dose level (%)

 

 

 

0 (Control)

0.1

0.6

3.0

Body weight (g)

410.9 ± 12.3

428.6 ± 17.6

416.7 ± 23.7

400.5 ± 15.1

Absolute (g)

 

 

 

 

Brain

2.04 ± 0.05

2.03 ± 0.07

2.05 ± 0.05

2.04 ± 0.05

Lungs

1.20 ± 0.09

1.23 ± 0.21

1.16 ± 0.07

1.13 ± 0.06

Heart

1.09 ± 0.08

1.10 ± 0.07

1.08 0.05

1.08 ± 0.07

Spleen

0.73 ± 0.05

0.72 ± 0.04

0.83 ± 0.36

0.68 ± 0.04*

Liver

9.62 ± 0.58

9.92 ± 0.73

10.26 ± 0.63

10.0 ± 0.85

Adrenals

0.03 ± 0.01

0.04 ± 0.01

0.04 ± 0.00

0.04 ± 0.00

Kidneys

2.35 ± 0.25

2.32 ± 0.11

2.42± 0.11

2.51± 0.11*

Relative (g/100 g b.w.)

Brain

0.50 ± 0.02

0.47 ± 0.02

0.49 ± 0.04

0.51 ± 0.02

Lungs

0.29 ±0.02

0.29 ± 0.04

0.28 ± 0.02

0.28 ± 0.01

Heart

0.26 ± 0.02

0.26 ± 0.02

0.26 ± 0.02

0.27 ± 0.01

Spleen

0.18 ± 0.01

0.17 ± 0.01

0.20 ± 0.08

0.17 ± 0.01

Liver

2.34 ± 0.13

2.31 ± 0.09

2.46± 0.10

2.50 ± 0.16*

Adrenals

0.01 ± 0.00

0.01 ± 0.00

0.01 ± 0.00

0.01 ± 0.00

Kidneys

0.83 ± 0.04

0.76 ± 0.03*

0.78 ± 0.07

0.82 ± 0.04

Each value represents the mean ± SD

*Significantly different from the control atp< 0.05

 

Table 7

Organ weight of female rats fed diet containin ammonium sulfate for 52 weeks (number of animals= 10)

 

Dose level (%)

 

 

 

0 (Control)

0.1

0.6

3.0

Body weight (g)

207.4 ± 13.49

220.3 ± 8.68

219.2 ± 13.62

212.7 ± 24.39

Absolute (g)

Brain

1.86 ± 0.04

1.83 ± 0.04

1.83 ± 0.05

1.82 ± 0.05

Lungs

0.82 ± 0.06

0.79 ± 0.10

0.83 ± 0.12

0.79 ± 0.05

Heart

0.65 ± 0.05

0.67 ± 0.05

0.70 ± 0.03

0.67 ± 0.05

Spleen

0.44 ± 0.04

0.44 ± 0.02

0.45 ± 0.03

0.45 ± 0.07

Liver

4.44 ± 0.26

4.66 ± 0.35

4.69 ± 0.40

4.89 ± 0.42

Adrenals

0.04 ± 0.00

0.04 ± 0.01

0.04 ± 0.01

0.04 ± 0.01

Kidneys

1.25 ± 0.07

1.35 ± 0.08*

1.35 ± 0.09

1.39 ± 0.08**

Relative (g/100 g b.w.)

Brain

0.90 ± 0.05

0.83 ± 0.04

0.84 ± 0.05

0.86 ± 0.09

Lungs

0.39 ±0.04

0.36 ± 0.05

0.38 ± 0.06

0.37 ± 0.04

Heart

0.31 ± 0.02

0.31 ± 0.03

0.32 ± 0.03

0.32 ±0.02

Spleen

0.21 ± 0.03

0.20 ± 0.01

0.21 ± 0.02

0.21 ±0.03

Liver

2.15 ± 0.17

2.11 ± 0.13

2.14 ± 0.18

2.31 ± 0.18

Adrenals

0.02 ± 0.00

0.02 ± 0.00

0.02 ± 0.00

0.02 ± 0.00

Kidneys

0.60 ±0.01

0.61 ±0.04

0.61 ± 0.06

0.66 ±0.05

Each value represents the mean ± SD

*Significantly different from the control atp< 0.05

**Significantly different from the control at p < 0.01

 

Table 8

 

Histopathological finding in male rats fed diet containing ammonium sulfate for 52 weeks (number of animal=10)

 

Organs

Lesions

Grade

Dose level (%)

0 (Control)

3.0

Liver

Bile duct proliferation

+

9

8

Necrosis, focal

++

+

1

1

2

4

Pancreas

Acinar cell atrophy focal

+

4

2

Kidney

Basophilic tubules

+

1

2

Chronic nephropathy

+

0

1

Heart

Myocarditis, focal

+

6

6

Tongue

Mononuclear cell infiltration

+

1

0

Rectum

Erosion

+

1

0

Pituitary

Basophilic cell hyperplasia, diffuse

+

1

0

Adrenal

Pheochromocytoma, malignant

 

0

1

Prostate

Luminal dilatation

+

5

6

Spinal cord

Calcification

+

1

1

Adipose

Tissue in abdominal cavity

Necrosis, focal

+

1

1

 

 

Table 9

Histopathological findings in female rats fed diet containing ammonium sulfate for 52weeks (number of animals=10)

Organs

Lesions

Grade

Dose level (%)

0 (Control)

3.0

Liver

Bile duct proliferation

+

0

3

Granuloma

+

3

2

Altered hepatocellular foci

+

7

9

Spleen

Increased extramedullary hematopoiesis

+

1

0

Pancreas

Acinar cell atrophy, focal

+

1

0

Heart

Myocarditis, focal

+

1

2

Tongue

Mononuclear cell infiltration

+

1

2

Pituitary

Cyst

+

1

2

Adenoma, anterior lobe

 

0

2

Thyroid

C-cell hyperplasia

 

1

0

Uterus

Endometrial stromal polyp

 

1

0

Harderian gland

Mononuclear cell infiltration

+

3

0

 

Conclusions:
The authors concluded that the no observed adverse effect level of ammonium sulphate was the 0.6% diet, which is equivalent to 256 and 284 mg/kg bw/d in males and females, respectively, and the compound is non-carcinogenic under the conditions of the study.
Endpoint conclusion
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
256 mg/kg bw/day
Study duration:
chronic
Species:
rat
Quality of whole database:
Studies on analogous substances are available to asess the repeated dose toxicity over 28 days, 90 days and 52 weeks. All studies are considered to be Klimisch reliabiltiy 2 and are presented as part of a weight of evidence in accordance with Annex XI, section 1.2 of Regulation (EC) No. 1907/2006 (REACH).

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

Justification for classification or non-classification

 

 

Specific target organ toxicity (CLP Regulation) – repeated exposure (STOT RE)

Chronic toxicity, oral:

The effects of diammonium dihydrogenpyrophosphate are likely to be consistent with those seen in the ammonium sulphate study presented in this dossier.

In accordance with Regulation (EC) no. 1272/2008 the criteria for classification as a specific target organ toxicant (STOT-RE) via the oral route are not met. Since effects were seen at exposure levels greater than the cut-off value for classification (100 mg/kg bw) no classification is required.