Fatty acids, C18 unsaturated, C12-14 (even numbered) alkyl esters

Endpoint summary

Description of key information

There are reliable three repeated dose oral toxicity studies performed with a constituent of the registration substance and structural analogues avalaible:

1. Subchronic oral toxicity study according to OECD 408 performed with 2-propylheptyl octanoate (CAS No 868839-23-0), structural analogue

NOAEL: 1000 mg/kg bw/d (male/female)

2. Combined repeated dose toxicity study with the reproduction/developmental screening test according to OECD 422 performed with tetradecyl octadec-9-enoate (CAS No 22393-85-7), constituent of the registration substance

NOAEL > 1000 mg/kg bw/d

3. Combined repeated dose toxicity study with the reproduction/developmental screening test according to OECD 422 performed with 8 -methylnonyl octadec-9-enoate (CAS No 59231-34-4), structural analogue

NOAEL 1000 mg/kg bw/d (males), NOAEL 300 mg/kg bw/d (females; based on reducd food consumption and body weight during gestation /lactation)

Key value for chemical safety assessment

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

Study period:

17 Mar - 16 Jun 2006

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
Please refer to cread across justification justification setcion 13.2

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Please refer to cread across justification justification setcion 13.2

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Please refer to cread across justification justification setcion 13.2

3. ANALOGUE APPROACH JUSTIFICATION
Please refer to cread across justification justification setcion 13.2

4. DATA MATRIX
Please refer to cread across justification justification setcion 13.2

Reason / purpose for cross-reference:

read-across source

Clinical signs:

no effects observed

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

1000 mg/kg bw/day, females: increased food intake week 9, 11 (non-adverse)

Food efficiency:

not examined

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

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

effects observed, treatment-related

Description (incidence and severity):

1000 mg/kg bw/day, males: increased albumin level, blood urea nitrogen level (non-adverse)

Urinalysis findings:

effects observed, treatment-related

Description (incidence and severity):

300 mg/kg bw/day, males: decreased pH value (non-adverse)

Behaviour (functional findings):

no effects observed

Immunological findings:

not examined

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Description (incidence and severity):

1000 mg/kg bw/day: increased absolute and relative liver weight (non-adverse)

Gross pathological findings:

no effects observed

Neuropathological findings:

not examined

Histopathological findings: non-neoplastic:

no effects observed

Histopathological findings: neoplastic:

not examined

Details on results:

CLINICAL SIGNS AND MORTALITY
1/10 females in each of the low-, mid- and high dose groups, respectively, died during the laboratory examinations on the last treatment day after blood withdrawal. These deaths are considered to be caused by the ether narcosis and are therefore not treatment-related. No other mortality was noted during the study. The low-dose female that died during ether narcosis had piloerection on Day 72-78. This is considered to be an incidental occurrence. No other animals showed clinical signs.

BODY WEIGHT AND WEIGHT GAIN
There were no statistically significant differences in body weight or body weight gain between the control group and the treatment groups.

FOOD CONSUMPTION
During week 9 and 11, females in the high-dose group showed a statistically significant increase in food consumption, compared to the control group during the same period. As the effect was temporary it is considered to be incidental.

WATER CONSUMPTION
The female in the low-dose group that died during ether narcosis had moderate to severe increased water consumption and diuresis from Day 40 until study termination. This effect is not considered to be treatment-related. No other effects on water consumption were noted.

OPHTHALMOSCOPIC EXAMINATION
No effects were noted during the opthamological examination.

HAEMATOLOGY
There were no statistically significant differences in the hematology parameters between the control group and the treatment groups.

CLINICAL CHEMISTRY
The albumin and blood urea nitrogen levels were significantly increased in the males in the high-dose group (see Table 1). As no effects were noted on these parameters in the females of the high-dose group and in the absence of related histopathological findings, these effects are considered to be treatment-related, but not toxicologically relevant.

URINALYSIS
A statistically significant decrease in pH value was noted in males in the mid-dose group and in males and females in the high-dose groups (see Table 2). As there were no other effects on urinary parameters or kidney histopathology, this is considered to be a treatment-related, but not toxicologically relevant effect. The specific gravity was statistically significant increased in mid-dose males, compared to the control group. As the effect was only observed in this group, it is not seen as treatment-related.

NEUROBEHAVIOUR
No treatment-related effects were observed during the neurobehavioral and observational tests.

ORGAN WEIGHTS
The absolute and relative liver weight in high-dose males and females was statistically significantly increased (see Table 3). This is probably an adaptive response to the increased metabolic load due to ingestion of the test substance. As no treatment-related effects were noted on liver enzyme levels or liver histopathology, this is not considered to be a toxicologically relevant effect. The increase in relative gonad weight in mid-dose females is seen as a incidental occurrence, as the effect was only noted at this dose level.

GROSS PATHOLOGY
No treatment-related findings were reported.

HISTOPATHOLOGY: NON-NEOPLASTIC
No treatment-related findings were reported.

OTHER FINDINGS
- Oestrus cycle: There were no statistically significant differences in the mean length of the oestrus cycles and the number of complete cycles between the females in the control group and the treatment groups.
- Sperm parameters: There were no statistically significant differences between the males in the control group and the treatment groups in the mean number and percentage of ultrasound-resistant spermatids, number of motile spermatozoa in the cauda epididymis, and in the percentage of spermatids with malformations.

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: No treatment-related effects observed up to and including the highest dose level

Key result

Critical effects observed:

no

Table 1: Clinical chemistry results

	Group (mg/kg bw/day)
	Males				Females
	Control	100	300	1000	Control	100	300	1000
Albumin (g/L)	30.94 ± 1.04	31.73 ± 0.91	31.74 ± 1.21	32.47 ± 0.99**	34.22 ± 1.10	33.68 ± 3.10	32.93 ± 1.84	33.89 ± 1.19
Blood urea nitrogen (mmol/L)	4.138 ± 0.58	4.260 ± 0.361	3.993 ± 0.430	4.859 ± 0.487**	4.956 ± 0.424	6.921 ± 5.989	4.897 ± 0.717	5.578 ± 1.045

*Statistically significant (p < 0.05)

**Statistically significant (p < 0.01)

 

Table 2: Urinary pH

	Group (mg/kg bw/day)
	Males				Females
	Control	100	300	1000	Control	100	300	1000
pH	6.44 ± 0.22	6.21 ± 0.35	6.05 ± 0.25**	5.76 ± 0.05**	6.15 ± 0.28	6.18 ± 0.24	5.85 ± 0.18	5.78 ± 0.18**

*Statistically significant (p < 0.05)

**Statistically significant (p < 0.01)

Table 3: Liver weights

	Group (mg/kg bw/day)
	Males				Females
	Control	100	300	1000	Control	100	300	1000
Absolute (g)	12.59 ± 1.74	13.02 ± 1.77	13.56 ± 2.03	16.39 ± 2.50**	7.11 ± 0.67	7.93 ± 0.82	8.12 ± 0.85	9.10 ± 0.89**
Relative (g/kg bw)	29.04 ± 2.60	30.06 ± 2.52	30.05 ± 2.04	36.52 ± 2.55**	30.22 ± 2.12	34.45 ± 7.31	33.38 ± 2.52	38.58 ± 2.33**

*Statistically significant (p < 0.05)

**Statistically significant (p < 0.01)

Conclusions:

Based on the lack of treatment-related effect reported for the present 90 d oral toxicity study (OECD 408) in rats the NOAEL was derived at 1000 mg/kg bw/d.

Executive summary:

The toxicity of 2 -propylheptyl octanoate (CAS No. 868839 -23 -0), structural analogue, was examined in a sub-chronic (90 day) study in which the test substance was administered to groups of 10 male and 10 female rats each at levels of 0 (control), 100, 300 or 1000 mg/kg bw/d by oral gavage. Observations were made on general appearance and behavior, body weight, food comsumption,food efficiency, water consumption, ophthamoscopy, haematology, clinical biochemistry, urine composition and neurobehaviour. At week 13 all rats were killed and examined grossly for pathological changes. The major organs were weighed and extensive histopathological examinations were carried out.

1/10 females in each of the low-, mid- and high dose groups, respectively, died during the laboratory examinations on the last treatment day after blood withdrawal. These deaths are considered to be caused by the ether narcosis and are therefore not treatment-related. No other mortality was noted during the study. The low-dose female that died during ether narcosis had piloerection on Day 72-78. This is considered to be an incidental occurrence. No other animals showed clinical signs.

No effects of toxicological relevance were found.

It was concluded that the NOAEL of the test itemin the present study was 1000 mg/kg bw/d.

Reference 2

Endpoint:

short-term repeated dose toxicity: oral

Remarks:

combined repeated dose and reproduction / developmental screening

Type of information:

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

Adequacy of study:

weight of evidence

Study period:

01 Nov - 13 Dec 2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

guideline study

Justification for type of information:

REPORTING FORMAT FOR THE ANALOGUE APPROACH
Please refer to cread across justification justification setcion 13.2

1. HYPOTHESIS FOR THE ANALOGUE APPROACH
Please refer to cread across justification justification setcion 13.2

2. SOURCE AND TARGET CHEMICAL(S) (INCLUDING INFORMATION ON PURITY AND IMPURITIES)
Please refer to cread across justification justification setcion 13.2

3. ANALOGUE APPROACH JUSTIFICATION
Please refer to cread across justification justification setcion 13.2

4. DATA MATRIX
Please refer to cread across justification justification setcion 13.2

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

Description (incidence and severity):

statistically significant decrease (-9.4%) in body weight in females during lactation at 1000 mg/kg bw/day

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

In the high dose group (females: gestation/lactation period) a statistically significant reduction in food consumption by 21.7% was noted.

Food efficiency:

not examined

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

no effects observed

Ophthalmological findings:

no effects observed

Haematological findings:

no effects observed

Clinical biochemistry findings:

no effects observed

Urinalysis findings:

not examined

Behaviour (functional findings):

no effects observed

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
Piloerection was seen in 1 female of the high dose group at on day 2-4 of lactation.

BODY WEIGHT AND WEIGHT GAIN
A reduction in body weight (-9.7%) in high dose females during lactation period.

FOOD CONSUMPTION AND COMPOUND INTAKE (if feeding study)
Reduction in food intake (-21.7%) in high dose females during gestation/lactation.

WATER CONSUMPTION AND COMPOUND INTAKE (if drinking water study)
No effects on water consumption in any treatment group were observed.

OPHTHALMOSCOPIC EXAMINATION
No effects were observend in any treatment group.

HAEMATOLOGY
No effects on water consumption in any treatment group were observed.

CLINICAL CHEMISTRY
An decrease of ASAT activity was seen in high dose females on day 15. This effects was considered to be due to the relative low or high value observed for the control group and not to be test item related.

NEUROBEHAVIOUR
No effects observed.

ORGAN WEIGHTS
All effects observed (slight increase in absolute and relative liver weight in males) were still within the historical control data of the laboratory and thus not of toxicological relevance.

GROSS PATHOLOGY
No effects observed.

HISTOPATHOLOGY:
No effects observed.

OTHER FINDINGS
The qualitative sperm staging revealed no test item-related specific spermatogenic changes in the male animals from the high dose group (1000 mg/kg b.w./day).

Key result

Dose descriptor:

NOAEL

Effect level:

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

Based on:

test mat.

Sex:

female

Basis for effect level:

other: adverse effects on body weight and body weight gain and food consumption

Key result

Dose descriptor:

NOAEL

Effect level:

1 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: no adverse affects observed

Key result

Critical effects observed:

no

Individual body weights of females during the pre-mating and lactation period.

Control group	Day(s) relative to start
	1	8	15
11	196	209	212
12	217	228	243
13	210	220	213
14	217	234	244
15	3211	215	232
16	195	208	197
17	205	224	239
18	212	238	233
19	224	236	259
20	200	218	214
Mean	209	223	229
SD	9	10	19

1000 mg/kg bw	Day(s) relative to start
	1	8	15
71	200	210	225
72	210	231	234
73	206	234	247
74	210	222	235
75	194	219	218
76	218	243	223
77	214	230	227
78	222	225	210
79	198	200	201
80	203	223	231
Mean	207	224	225
SD	9	12	13

Control group	Day(s) relative to littering
	1	4
11	286	309
12	323	330
13	325	311
14	331	327
15	311	322
16	282	302
17	309	327
18	312	328
19	315	331
20	300	329
Mean	309	322
SD	16	10

1000 mg/kg bw	Day(s) relative to littering
	1	4
71	270	281
72	339	301
73	289	309
75	289	317
77	253	247
78	280	271
79	290	296
80	293	308
Mean	288	291
SD	24	23

Relative food consumption of females between day 1 and 4 of lactation

Control group		1000 mg/kg bw
11	122	71	115
12	91	72	96
13	105	73	63
14	107	75	110
15	106	77	30
16	121	78	63
17	114	79	98
18	100	80	110
19	101
20	126
Mean	109	Mean	86
SD	11	SD	30

Conclusions:

Based on the results of this study, the NOAEL was 1000 mg/kg bw/d for males and 300 mg/kg bw/d for females (reduced food consumption and body weight gain during lactation).

Executive summary:

8 -Methylnonyl octadec-9-enoate (CAS No 59231-34-4), a structural analogue, was evaluated for possible adverse effects following repeated oral dosing to males and to females in an subacute oral toxicity study according to OECD 422.

Piloerection was seen in 1 female of the high dose group at on day 2-4 of lactation and a reduction in body weight (-9.7%) in high dose females during lactation. Furthermore, reduced food intake in high dose females during gestation and lactation was reported. No additional toxicological relavant effects were observed.

Based on the results discussed, the No Observed Adverse Effect Level (NOAEL) of the test item was found to be 1000 mg/kg bw/d in males and 300 mg/kg bw/d in females under the experimental conditions employed in this study.

Endpoint conclusion

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

300 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Releibale without restrictions

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

Mode of Action Analysis / Human Relevance Framework

In the absence of any evidence for species specific effects or modes of action the effects observed in animals are regarded as relevant for humans.

Additional information

In the absence of any studies performed with the registration substance, fatty acids, C18 unsaturated, C12-14 (even numbered) alkyl esters, EC No 952-655-5, read across to other members of the long-chain aliphatic ester category members was conducted.

For a detailed category description and justification please refer to IUCLID section 13.2

Justification for classification or non-classification

Due to the NOAEL of 300 mg/kg bw/day in an OECD 422 repeated dose toxicity study in rats the substance does not have to be classified for STOT (RE) regarding systemic and target organ toxicity after repeated exposure according to the criteria laid down in the Regulation (EC) No 1272/2008.