Neodecanoic acid, iron salt

Endpoint summary

Description of key information

No data on repeated dose toxicity from studies conducted with the target substance, Neodecanoic acid, iron salt, are available. Therefore, data from suitable read-across partners Iron trichloride hexahydrate and Neodecanoic acid was used to assess the specific toxicity of Neodecanoic acid, iron salt. For details and justification of read-across please refer to the report attached in section 13 of IUCLID.

In sub-chronic (90-day) repeated dose toxicity studies with both Iron trichloride hexahydrate and Neodecanoic acid, effects on body weight were observed in rats. The study conducted with Neodecanoic acid is chosen as the one, from which the dose descriptor for risk assessment is chosen. A NOAEL of 700 mg/kg bw/day (HD) based on Neodecanoic acid could be derived, which corresponds to a NOAEL of 772 mg/kg bw/day for the target substance Neodecanoic acid, iron salt.

Key value for chemical safety assessment

Toxic effect type:

dose-dependent

Repeated dose toxicity: via oral route - systemic effects

Link to relevant study records

Reference

Reference 1

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

For details and justification of read-across please refer to the attached report in section 13 of IUCLID.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

effects observed, treatment-related

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

Water consumption and compound intake (if drinking water study):

effects observed, treatment-related

Ophthalmological findings:

not examined

Haematological findings:

effects observed, treatment-related

Clinical biochemistry findings:

effects observed, treatment-related

Urinalysis findings:

not examined

Behaviour (functional findings):

not examined

Immunological findings:

not examined

Neuropathological findings:

not examined

Histopathological findings: neoplastic:

not examined

Other effects:

not examined

Details on results:

- Mortality: None of the animals in any of the groups died during the 13-week period of the study.
- Body weight: There was a statisitcally significant dose related decrease in male body weight (1% level of significance) at 0.5% and above and a statisitcally significant decrease in female body weight at 2% (1% level) and 1% (5% level). Decreased on body weight for male rats were of the order of 46%, 26% and 10% of controls for the 2%, 1% and 0.5% dose levels, respectively. In females there was a 20% reduction at 2% and a 6% reduction at 1%.
- Water consumption: There was a significant suppression in the intake of drinking water observed in groups given concentrations of 0.5% or more (no further detail).
- Haematology: Males of the treated groups had significantly increased red blood cell counts (no further details).
- Clinical Chemistry: Higher levels of serum iron were observed in males (control: 102 ± 5 g/dl; 0.12%: 107 ± 11 g/dl; 0.25%: 109 ± 8  g/dl; 0.5%: 129 ± 22  g/dl; 1.0%: 139 ± 10 g/dl; 2.0%: 156 g/dl).
- Gross pathology: No findings reported.

Key result

Dose descriptor:

NOAEL

Effect level:

0.5 other: % w/v in drinking water

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Key result

Critical effects observed:

no

Table 1_Doses: The dose of feric chloride in mg/kg bw/day was calculated from the drinking water intake and the final weight of male and female rats

Dose of ferric chloride hexahydrate		Final weight (kg)		Final daily water intake (mL/d)		Dose (mg/kg bw/day)
%	mg/L	Males	Females	Males	Females	Males	Females
0	0	0.35	0.195	23.5	15	0	0
0.12	1.2	0.345	0.19	23	14	80	88
0.25	2.5	0.34	0.185	21	13	154	176
0.5	5.0	0.325	0.175	18	11	277	314
1.0	10.0	0.3	0.175	16.5	10	550	571
2.0	20.0	0.195	0.145	12	7.5	1231	1034

Conclusions:

In conclusions, the NOAEL for iron trichloride derived from a 90-day repeated dose toxicity study in rats was 0.5% (equivalent to 277 and 314 mg/kg bw/day iron trichloride hexahydrate in males and females).

Executive summary:

Iron trichloride hexahydrate (98.5% purity) was administered to Fischer 344 rats (10/sex/dose) in their drinking water for 13 weeks, at concentrations of 0.12, 0.25, 0.5, 1.0 and 2.0 % FeCl3 (equivalent to approximately 80, 154, 277, 550 and 1231 mg/kg bw/day in male rats, 88, 176, 314, 571 and 1034 mg/kg bw/day in female rats). All deaths and clinical signs of toxicity were recorded. Body weights were measured weekly. At the end of the dosing period, all survivors were killed for haematological, clinical chemistry and pathological exminations. All major organs and tissues were examined microscopically. There were no deaths or clinical signs of toxicity. There was a significant reduction in body weight gains at the two highest doses at the end of the treatment period. Treated males had increased levels of serum iron and higher red blood cell counts compared with controls. The NOAEL for iron trichloride derived from a 90-day repeated dose toxicity study in rats was 0.5% (equivalent to 277 and 314 mg/kg bw/day iron trichloride hexahydrate in males and females, or 584 and 662 mg/kg bw/day Neodecanoic acid, iron salt in males and females referring to the iron content, respectively).

This information is used in a read-across approach in the assessment of the target substance.For details and justification of read-across please refer to the read-across report attached to IUCLID section 13.

Reference 2

Endpoint:

sub-chronic toxicity: oral

Type of information:

read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

weight of evidence

Justification for type of information:

For details and justification of read-across please refer to the report attached in section 13 of IUCLID.

Reason / purpose for cross-reference:

read-across source

Clinical signs:

no effects observed

Mortality:

no mortality observed

Description (incidence):

No unscheduled deaths occured during the study.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

At study initiation female rats exposed to 1000 mg/kg/d showed significantly decreased body weight gain during the first week (gains averaged 23 g compared with 41 g in controls), and subsequent weight loss in the second week (gains of -1 g compared with 8 g in controls). Male rats also showed significant decreases in weight gain (average of 104 g compared with 118 g in controls) and week two (average of 19 g compared with 35 g in controls). Based on concerns for animal welfare the decision was taken to reduce the highest tested dose to 700 mg/kg/d at that point.
At terminal sacrifice body weight gain was significantly decreased in female rats at all doses. Control females averaged 108 grams of weight gain over 90 days of exposure, while neodecanoic acid exposed groups averaged weight gains of 87, 93, and 81 grams per rat in the 100, 300, or 700 mg/kg/day groups, respectively.
Terminal body weights were significantly decreased in female rats exposed to 700 mg/kg/d neodecanoic acid (average 265 g, P < 0.05) compared to controls (average 292 g).
Body weight gain and terminal body weight were not significantly affected by neodecanoic acid exposure for male rats.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

Among female rats group mean food consumption on a g/animal basis was significantly decreased in most weeks for the 700 mg/kg/d exposed group, and occasionally for some weeks in rats exposed to 300 mg/kg/d. However, when food consumption was considered on a g/kg/d basis there was no significant effect of neodecanoic acid on food consumption.
Among male rats group mean food consumption on a g/animal basis was significantly decreased in some weeks, but without any consistent time or dose pattern. No statistically significant differences were found when food consumption was considered on a g/kg/d basis.

Food efficiency:

no effects observed

Water consumption and compound intake (if drinking water study):

not examined

Ophthalmological findings:

no effects observed

Haematological findings:

effects observed, treatment-related

Description (incidence and severity):

In males only: Lymphocyte counts increased for all doses (1.25 to 1.58× control), but not significantly (p ≤ 0.001) until 1000/700 mg/kg/day. This corresponded with significantly increased (p ≤ 0.05 at 300 mg/kg/day and p ≤ 0.001 at 1000/700 mg/kg/day) white blood cell counts (1.20 to 1.51× control). Basophil counts significantly increased (p ≤ 0.001) in the 1000/700 mg/kg/day group compared to control (from 0.02 ± 0.009 to 0.05 ± 0.009 x10^3/uL).
In females only: At 1000/700 mg/kg/day, decreases in hemoglobin (0.94× control) and hematocrit (0.94× control);
In both males and females: red cell distribution width increased (1.08 to 1.17× control); and increases in blood urea nitrogen (BUN; 1.38× control; males only) and creatinine (1.33× control; males only) were considered test item related.
All of these changes were considered non-adverse due to their relatively small magnitude.

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

In males only: At ≥ 300 mg/kg/day were total cholesterol increased (1.13 to 1.51× control; at 300 mg/kg/day). Consistent with kidney effects confirmed by histopatholgy as alpha 2u nephropathy, blood urea nitrogen (1.38× control) and creatinine (1.33× control) were significantly increased.
All of these changes were considered non-adverse due to their relatively small magnitude. Increased blood urea nitrogen and creatinine correlated with the histologic changes in the kidney of male rats. All other differences between control and treated mean values, including those that were statistically significant, were considered not test item related as they lacked a dose relationship and/or there was general overlap between individual control and treated values.

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

Immunological findings:

no effects observed

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

Among female rats there were significant increases in liver weight on an absolute basis and brain-weight relative basis at 700 mg/kg/d, and relative basis at 300 mg/kg/d and above. Adrenal gland weights were significantly decreased on an absolute basis at all doses, and relative to brain weight at 700 mg/kg/d, but not relative to body weight. Heart weights were unaffected by neodecanoic acid on a brain weight-relative and absolute basis, but significantly increased at all doses on a body weight-relative basis. However, the increase in heart weight did not appear dose responsive (0.379%, 0.353%, and 0.359% relative to body weight in the 100, 300, and 700 mg/kg/d groups compared with 0.331% in controls).
Among male rats there were significant increases in liver weight on an absolute, body weight-relative, and brain weight-relative basis at 300 mg/kg/d and above. Adrenal gland weights were significantly increased on an absolute basis at 100 and 700 mg/kg/d (non-significant, but marginally, increased at 300 mg/kg/d), relative to body weight only at 700 mg/kg/d, and relative to brain weight at all doses. Heart weights were marginally increased, but not significantly, by neodecanoic acid on an absolute and brain weight-relative basis, but significantly increased at 700 mg/kg/d on a body weight-relative basis. Prostate and seminal vesicle weights were significantly decreased in rats exposed to 700 mg/kg/d neodecanoic acid on an absolute and brain weight-relative basis, but not body-weight relative. Testes weights appeared unaffected. The most marked organ weight changes occurred in the kidney of male rats, with increased weights observed at all doses on an absolute and relative (both brain and body weight) basis, and increasing in a pattern consistent with a dose response. Alpha-2u nephropathy was expected in male rats exposed to neodecanoic acid, which was supported by histopathological confirmation as described in the respective section.

Gross pathological findings:

effects observed, treatment-related

Description (incidence and severity):

Among female rats there were no remarkable gross pathology findings that occurred more than sporadically as single findings without any clear dose response pattern.
Among male rats the majority exposed to 700 mg/kg/d were reported to have findings in the kidney (abnormal color, enlarged, or masses), and a single rat exposed to 300 mg/kg/d was reported to have a dilated pelvis (a finding not reported for any rats at the 700 mg/kg/d exposure). Other gross pathology findings were sporadic and not clearly treatment related.

Neuropathological findings:

no effects observed

Histopathological findings: non-neoplastic:

effects observed, treatment-related

Description (incidence and severity):

Generalized hepatocellular hypertrophy was present in males and females at 1000/700 mg/kg/day. The enlarged hepatocytes had increased brightly eosinophilic granular cytoplasm, most notable in males with marked hypertrophy.
In male rats only: Increased hyaline droplets in the proximal tubular epithelium, tubular degeneration and regeneration and/or granular casts in all male rat kidneys at
≥100 mg/kg/day. The hyaline droplets were eosinophilic on hematoxylin and eosin staining and bright red with Mallory's Heidenhain stain, which enhanced visualization of the angular hyaline inclusions. Small scattered hyaline droplets are normally found in the proximal tubules of male rats. The hyaline droplets were larger and more numerous in males treated with the test article compared with controls, with a dose effect on incidence and severity. These findings were consistent with test item-induced alpha 2u-globulin nephropathy.

Histopathological findings: neoplastic:

effects observed, non-treatment-related

Description (incidence and severity):

A single 1000/700 mg/kg/day exposed male rat developed a renal tumor (4064S1) characterized as "malignant nephroblastoma, unilateral, incidental". This neoplasm is not uncommon in rats of this age and was considered spontaneous and not test item-related

Other effects:

not specified

Dose descriptor:

LOEL

Effect level:

>= 93 - <= 105 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

body weight and weight gain

Dose descriptor:

NOEL

Effect level:

>= 658 - <= 1 134 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

body weight and weight gain

Dose descriptor:

LOEL

Effect level:

>= 268 - <= 318 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

organ weights and organ / body weight ratios

Dose descriptor:

NOEL

Effect level:

>= 93 - <= 105 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

female

Basis for effect level:

organ weights and organ / body weight ratios

Dose descriptor:

LOEL

Effect level:

>= 261 - <= 305 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

organ weights and organ / body weight ratios

Dose descriptor:

NOEL

Effect level:

>= 92 - <= 102 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

organ weights and organ / body weight ratios

Dose descriptor:

LOEL

Effect level:

>= 92 - <= 102 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

gross pathology

organ weights and organ / body weight ratios

Remarks on result:

other:

Remarks:

Effect not relevant to humans

Dose descriptor:

LOEL

Effect level:

>= 658 - <= 1 134 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

organ weights and organ / body weight ratios

Dose descriptor:

NOEL

Effect level:

>= 261 - <= 305 mg/kg bw/day (actual dose received)

Based on:

test mat.

Sex:

male

Basis for effect level:

organ weights and organ / body weight ratios

Critical effects observed:

no

Lowest effective dose / conc.:

268 mg/kg bw/day (actual dose received)

System:

hepatobiliary

Organ:

liver

Critical effects observed:

yes

Lowest effective dose / conc.:

92 mg/kg bw/day (actual dose received)

System:

urinary

Organ:

kidney

Treatment related:

yes

Dose response relationship:

yes

Relevant for humans:

no

Liver weights were signficantly increased in a treatment-related manner in both male and female rats. Histopathology indicates liver hypertrophy, not hyperplasia, suggestive of an adaptive increase in metabolic capacity to increase clearance. Combined seminal vesicle and prostate weight was signficantly decreased on an absolute and brain weight-relative basis, but not body weight-relative. No histopathology difference was observed between the control and 1000/700 mg/kg/day group, suggesting the effect is not treatment related.

In male rats only, kidney weights, gross pathology and histopathology (including immunohistochemistry confirmation) indicate the occurrence of alpha2u globulin nephropathy. While it is an adverse effect for the male rat, it is well established as not relevant to humans.

Group/sex	2M	3M	4M	2F	3F	4F
Dose (mg/kg/day)	100	300	1000/700	100	300	1000/700
Kidney
Absolute weight (%)	19	19	39^b	-	-	-
vs. body weight (%)	12	19	49	-	-	-
vs. brain weight (%)	16	19	39	-	-	-
Liver
Absolute weight (%)	-	12	34	-	-	28
vs. body weight (%)	-	12	44	-	12	40
vs. brain weight (%)	-	13	34	-	-	28

^a Statistically significant difference between mean values for test item-treated and control groups.

^bGroup 4 n=9 due to renal tumor in 1/10.

-= not test item-related.

Conclusions:

Test article exposure resulted in liver hypertrophy, suggestive of adaptive increase in metabolism to increase test article clearance (non-adverse effect), and alpha 2u globulin nepropathy in male rats only (not human relevant effect). The results can be considered conclusive but not sufficient for classification. The human relevant NOAEL for the study is 700 mg/kg/day, corresponding to 772 mg/kg/d for Neodecanoic acid, iron salt, taking into account the relative iron content of the target substance.

Executive summary:

In this subchronic toxicity study (according to OECD 408), neodecanoic acid was administered to 10-12 Sprague-Dawley rats/sex/dose (n >= 10 per group) via the diet with target exposures of 0, 100, 300, or 1000/700 mg/kg/d for 13 weeks. The highest dose at study initiation targeted 1000 mg/kg/d, but was reduced to 700 mg/kg/d for animal welfare reasons following the second week of exposure.

Body weight gain was signficantly reduced in female rats in all exposure groups, but terminal body weights were signficantly different from controls only for the 1000/700 mg/kg/d exposure group. Body weight gain and terminal body weight were not significantly affected in male rats. Liver weights were significantly increased in both sexes at target exposures of 300 mg/kg/d and greater. Histopathology indicated 1000/700 mg/kg/day exposure resulted in generalized liver hypertrophy, not hyperplasia.

In male rats only, there were significant increases in kidney weight in all neodecanoic acid exposed groups, with weights increasing with exposure. Gross pathology findings in male rats were also consistent with a treatment-related effect. Histopathology findings were consistent with alpha2u globulin nephropathy, an effect not relevant to humans.

Combined prostate and seminal vesicle weights were decreased in male rats exposed to 1000/700 mg/kg/d neodecanoic acid on an absolute and brain weight-relative basis, but not body weight-relative. This was not correlated with any histopathology findings, thus the effects do not appear treatment-related.

The study results indicate a human relevant NOAEL for Neodecanoic acid of 700 mg/kg/d (HD), corresponding to 772 mg/kg/d for Neodecanoic acid, iron salt, taking into account the relative iron content of the target substance.

This information is used in a read-across approach in the assessment of the target substance. For justification of read-across please refer to the attached read-across report (see IUCLID section 13).

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

772 mg/kg bw/day

Study duration:

subchronic

Species:

rat

Quality of whole database:

OECD guideline study performed under GLP according to OECD Guideline 408.

Repeated dose toxicity: inhalation - systemic 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

No data on repeated dose toxicity are available for the target substance Neodecanoic acid, iron salt, itself. Thus, available data from the suitable read-across substances Neodecanoic acid and Iron trichloride hexahydrate were used to assess the specific toxicity of Neodecanoic acid, iron salt in a read-across approach. For details on the read-across rationale please refer to IUCLID section 13.

In a 13-week sub-chronic oral repeated dose toxicity study in Fischer 344 rats Iron trichloride hexahydrate (98.5% purity) was administered to Fischer 344 rats (10/sex/dose) in drinking water at concentrations of 0.12, 0.25, 0.5, 1.0 and 2.0% (equivalent to calculated values of approximately 80, 154, 277, 550 and 1231 mg/kg bw/day in male rats and 88, 176, 314, 571 and 1034 mg/kg bw/day in female rats). There were no deaths or clinical signs of toxicity. There was a significant reduction in body weight gains at the two highest doses at the end of the treatment period. Treated males had increased levels of serum iron and higher red blood cell counts compared with controls. The NOAEL was 0.5 % (equivalent to 277 and 314 mg/kg bw/day Iron trichloride hexahydrate in males and females, respectively. These values are equivalent to 584 and 662 mg/kg bw/day for males and females, respectively, based on recalculation according to the molecular weight of the target substance neodecanoic acid, iron salt).

In another sub-chronic oral repeated dose toxicity study performed according to OECD Guideline 408, Neodecanoic acid was administered to 10-12 Sprague-Dawley rats/sex/dose (n >= 10 per group) via the diet with target exposures of 0, 100, 300, or 1000/700 mg/kg bw/day for 13 weeks. The highest dose at study initiation targeted 1000 mg/kg bw/day but was reduced to 700 mg/kg bw/day for animal welfare reasons following the second week of exposure. Body weight gain was significantly reduced in female rats in all exposure groups, but terminal body weights were significantly different from controls only for the 1000/700 mg/kg bw/day exposure group. Body weight gain and terminal body weight were not significantly affected in male rats. Liver weights were significantly increased in both sexes at target exposures of 300 mg/kg bw/day and greater. Histopathology indicated 1000/700 mg/kg bw/day exposure resulted in generalized liver hypertrophy, not hyperplasia.

In male rats only there were significant increases in kidney weight in all Neodecanoic acid exposed groups, with weights increasing with exposure. Gross pathology findings in male rats were also consistent with a treatment-related effect. Histopathology findings were consistent with alpha2u globulin nephropathy, an effect not relevant to humans. Combined prostate and seminal vesicle weights were decreased in male rats exposed to 1000/700 mg/kg bw/day neodecanoic acid on an absolute and brain weight-relative basis, but not body weight-relative. This was not correlated with any histopathology findings; thus the effects do not appear treatment related. The study results indicate a human relevant NOAEL of 700 mg/kg bw/day (HD) for Neodecanoic acid, which corresponds to a NOAEL of 772 mg/kg bw/day for the target substance Neodecanoic acid, iron salt.

This study was judged relevant for the assessment of repeated dose toxicity, since it was performed under GLP and comprehensively covers and describes effects relevant for the derivation of a NOAEL.

Justification for classification or non-classification

Based on the available data from the read-across partners, the target substance neodecanoic acid, iron salt does not warrant classification for specific target organ toxicity in accordance to CLP Regulation 1272/2008.