Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Link to relevant study records
Reference
Endpoint:
screening for reproductive / developmental toxicity
Remarks:
based on test type (migrated information)
Type of information:
migrated information: read-across from supporting substance (structural analogue or surrogate)
Adequacy of study:
key study
Study period:
12 May - 23 June 2003
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
GLP-Guideline study, tested with the source substance Fatty acids, C18-unsatd., dimers (CAS No. 61788-89-4). According to the ECHA guidance document “Practical guide 6: How to report read-across and categories (March 2010)”, the reliability was changed from RL1 to RL2 to reflect the fact that this study was conducted on a read-across substance.
Reference:
Composition 0
Composition 0
Qualifier:
according to
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Deviations:
no
GLP compliance:
yes
Limit test:
no
Test material information:
Composition 1
Species:
rat
Strain:
other: Sprague-Dawley Rat/IGS (Crl: CD®(SD) IGS BR)
Sex:
male/female
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River UK Ltd., Margate, Kent, UK
- Age at study initiation: ca. 8 weeks
- Weight on arrival: (P) Males: 145 - 165 g; (P) Females: 102 - 138 g
- Housing: Initially animals were housed 2 per polypropylene cage (42 x 72 x 20 cm) with stainless steel grid bottoms and mesh tops. A few days prior to pairing, males were transferred to individual grid-bottomed cages (58 x 38.5 x 20 cm). Mated females were housed individually in solid-bottomed cages (42 x 72 x 20 cm).
- Diet: Rat and Mouse Breeder Diet No. 3 Expanded Ground SQC (Special Diets Services Ltd., Stepfield, Witham, Essex, UK), ad libitum
- Water: domestic quality mains water, ad libitum
- Acclimation period: 13 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20 ± 2
- Humidity (%): 50 ± 15
- Air changes (per hr): 15 - 20
- Photoperiod (hrs dark / hrs light): 12 / 12

IN-LIFE DATES: From: 12 May 2003 To: 23 June 2003
Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
DIET PREPARATION
- Rate of preparation of diet (frequency): Batches of diet were prepared at convenient intervals (weekly or fortnightly) during the study, and used within 12 days of preparation.
- Mixing appropriate amounts with (Type of food): An appropriate quantity of the test item was dissolved in a suitable volume of acetone. This solution was added to a suitable quantity of untreated diet and mixed for ca. 1 h with fan assisted venting to aid removal of the acetone. This dose premix was diluted with untreated diet to give the diet for the intermediate and high dose groups. The low dose diet was prepared by dilution of the intermediate dose diet with untreated diet. The diet premixes were then placed on a Winkworth mixer for ca. 20 min.
A control premix was prepared in the same way as the dose premix by using acetone and untreated diet. By dilution of this control premix with untreated diet the control diet was made, containing the same proportion of premix as the high dose diet.
Details on mating procedure:
- M/F ratio per cage: 1/1
- Length of cohabitation: overnight or up to 16 days
- Proof of pregnancy: copulatory plug and/or sperm in the lavage referred to as Day 0 of pregnancy
- After 9 days of unsuccessful pairing replacement of first male by another male with proven fertility.
- Further matings after two unsuccessful attempts: no
- After successful mating each pregnant female was caged (how): individually
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Analysis of formulated diets were undertaken on 2 occasions during study treatment with regard to concentration and homogeneity. On each occasion triplicate samples of 50 g were withdrawn from each formulated diet (low, mid and high dose diet and control diet). The samples were analysed by the Toxicology Support Laboratory using a method supplied by the sponsor (no details on method reported). A deviation of ± 15% of the nominal concentration indicated an acceptable accuracy of formulation.

Results (mean found) of first analysis (in parenthesis: % difference from nominal):
200 ppm: 176 ppm (- 12%)
2000 ppm: 1770 ppm (- 11.5%)
20000 ppm: 16849 ppm (- 15.8%); reanalysis: 20862 ppm (+ 4.3%)

Results (mean found) of second analysis (in parenthesis: % difference from nominal):
200 ppm: 155 ppm (- 22.5%); reanalysis: 173 ppm (- 13.5%)
2000 ppm: 2109 ppm (+ 5.5%)
20000 ppm: 20609 ppm (+ 3.0%)

The low coefficient of variation (5.6% or less) was indicative of satisfactory homogeneity in all dose groups.
Duration of treatment / exposure:
(P) Males: at least 4 weeks overall, starting from 2 weeks prior to mating until termination
(P) Females: 2 weeks prior to mating, then through mating, gestation and until at least Day 4 of lactation
Frequency of treatment:
daily, 7/days/week (feed)
Remarks:
Doses / Concentrations:
200, 2000 and 20000 ppm
Basis:
nominal in diet
Remarks:
Doses / Concentrations:
14.5, 147 and 1450 mg/kg bw/day (males)
Basis:
other: calculated based on food consumption, nominal dietary concentration and body weight data (group mean achieved dosages of test item; worst-case assumption of doses)
Remarks:
Doses / Concentrations:
16.5, 166 and 1692 mg/kg bw/day (females)
Basis:
other: calculated based on food consumption, nominal dietary concentration and body weight data (group mean achieved dosages of test item; worst-case assumption of doses)
No. of animals per sex per dose:
10
Control animals:
yes, plain diet
Details on study design:
- Dose selection rationale: Existing relevant toxicological data was evaluated for dose selection. Dose levels took into account the maximum tolerable dose in the test animals and other factors such as anticipated exposure.
Parental animals: Observations and examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily
- Cage side observations included: damaged teeth, piloerection, staining on dorsal neck/head, abnormal vocalisation, unkempt coat, body held low, hairloss, scabbing on head/mouth, agitation, hunched posture, rolling gait, pale discoloured skin on the whole body etc.

BODY WEIGHT: Yes
- Time schedule for examinations: All animals: one week prior to the start of treatment; Males: weekly throughout the treatment period until termination; Females: weekly until the start of mating period, then on Day 0 of gestation, followed by Day 7, 14 and 20 of gestation and Day 1 and 4 of lactation.

FOOD CONSUMPTION AND COMPOUND INTAKE: Yes
- Food consumption determined as follows:
All animals: weekly until mating, starting one week prior to start of treatment; Males: weekly measurements continued over the complete treatment period, except during periods of co-habitation with females; Mated females: over the periods Days 0-7, 7-14 and 14-20 of gestation and Days 0-4 of lactation.
The achieved intake of the test item (mg/kg bw/day) was calculated from the following formula: achieved intake = (food consumption x dietary concentration, nominal) / body weight.

WATER CONSUMPTION AND COMPOUND INTAKE: Yes
- Time schedule for examinations: Once weekly throughout the study, the water consumption was monitored by visual inspection of the water bottles.
Estrous cyclicity (parental animals):
Estrous cycle length was evaluated in P females by vaginal smears starting on the first day of cohabitation until mating had occurred.
Sperm parameters (parental animals):
Parameters examined in P male parental generations: testes and epididymides were weighed, and the epididymides, seminal vesicles, coagulating gland, prostate gland and pituitary were fixed in 10% neutral buffered formalin. The testes were fixed in Bouin’s fluid.
A section from each epididymis, and a transverse section from each testis were stained with Haematoxylin and Eosin (H&E) and a further section from each testis was stained with PAS-Haematoxylin. Sections were evaluated histopathologically.
Litter observations:
STANDARDISATION OF LITTERS
- Performed on Day 4 postpartum: no

PARAMETERS EXAMINED
The following parameters were examined in F1 offspring:
number and sex of pups, stillbirths, live births, postnatal mortality, presence of externally visible anomalies, body weight (Day 1 and Day 4 per sex and litter), physical or behavioural abnormalities, presence of milk in the stomach

GROSS EXAMINATION OF DEAD PUPS:
yes, for external abnormalities; possible cause of death was not determined for pups born or found dead.
Postmortem examinations (parental animals):
SACRIFICE
- Male animals: All surviving animals, when mating had been completed and the animals had been dosed for at least 4 weeks.
- Maternal animals: All surviving animals, when all observations had been completed, normally between Day 4 and Day 7 of lactation.

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera.

HISTOPATHOLOGY / ORGAN WEIGHTS
Histopathology was conducted on the epididymides, testes and ovaries of all control and high dose animals. Male reproductive organs (epididymides and testes) were weighed individually.
Postmortem examinations (offspring):
SACRIFICE
- The F1 offspring were sacrificed between Day 4 and 7 of lactation.
- These animals were subjected to postmortem examinations (macroscopic) as follows:

GROSS NECROPSY
- Gross necropsy consisted of external examinations.
Statistics:
Body weight and food consumption data in animals prior to mating were subjected to analysis of variance or the Kruskal-Wallis non-parametric analysis as appropriate.
Organ weight data were analysed by analysis of variance and analysis of covariance using the terminal bodyweight as the single covariate.
Histological data were analysed by Fisher’s Exact Probability test.
All statistical tests were two-sided and performed at the 5% significance level. Pairwise comparisons were only performed against the control group.
Reproductive indices:
Fertility index (female) = No. pregnant / No. paired
Fertility index (male) = No. siring a litter / No. paired
Gestation index = No. bearing live pups / No. pregnant
Offspring viability indices:
Birth index = total No. of pups born (live and dead) / No. of implantation scars
Live birth index = No. of pups live on Day 0 of lactation / total No. born (live and dead)
Viability index = No. of pups live on Day 4 of lactation / No. live on Day 0
Clinical signs:
no effects observed
Description (incidence and severity):
No adverse treatment-related effects: 2 premature incidental deaths (females, 2000 ppm); increased piloerection (males and females, control and treatment groups), particularly in high-dose males.
Body weight and weight changes:
no effects observed
Description (incidence and severity):
No adverse treatment-related effects: slight and statistically not significant decrease in body weight (males, 20000 ppm, Week 1 of treatment) and body weight gain (males, 2000 ppm, Week 0-4 of treatment)
Food consumption and compound intake (if feeding study):
no effects observed
Description (incidence and severity):
No adverse treatment-related effects: slight and statistically not significant decrease in body weight (males, 20000 ppm, Week 1 of treatment) and body weight gain (males, 2000 ppm, Week 0-4 of treatment)
Organ weight findings including organ / body weight ratios:
no effects observed
Gross pathological findings:
no effects observed
Histopathological findings: non-neoplastic:
no effects observed
Other effects:
no effects observed
Description (incidence and severity):
Test substance intake: No adverse treatment-related effects: lower (females) or higher achieved concentration (20000 ppm, Week 1 of treatment); slightly decreased concentration throughout gestation period (females, all treatment groups)
Reproductive function: estrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed
CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS)
In the 2000 ppm group, two female rats died prematurely. One animal was found dead after displaying several clinical signs, which included staining, piloerection, rolling gait, subdued behaviour, pale discoloured skin and a swollen/damaged tail. The other animal was killed prematurely due to a prolapse of the vagina. This female rat also showed hunched posture, pale eyes, subdued behaviour and pale discoloured skin on the whole body. These two deaths were considered to be incidental.
In the control groups and at dose levels of 200, 2000 and 20000 ppm, piloerection was noted in 1/10, 5/10, 3/10 and 8/10 males and in 3/10, 2/10, 1/10 and 2/10 females. Due to the distribution of these findings and the lack of any dose relationship, it was not possible to associate them with treatment.
Clinical observations for the other animals were considered to be consistent with those normally observed in rats of this age and strain.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
A slight and statistically non-significant decrease by 5.4% in body weight was noted in males of the high dose group (313 ± 18 g) during the first week of treatment compared to the control males (331 ± 22 g). Body weight gain thereafter was essentially similar to the control group (Table 1). Among females of the high-dose group, mean body weight gain was comparable to the controls throughout the study.
There was a slight reduction by ca. 7% in body weight gain in males at 2000 ppm. This minor difference in body weight performance was considered to reflect the low body weight noted at the start of treatment. There were no obvious effects of treatment in males at 200 ppm or in females at 2000 ppm and 20000 ppm.

FOOD CONSUMPTION (PARENTAL ANIMALS)
Mean food consumption was essentially similar to that of the control in males treated at 20000 ppm (Table 1). At this level, mean food consumption in females was slightly and statistically not significantly increased during Days 0-4 of lactation when compared to controls (29.2 vs. 26.5 g, respectively).
There was a statistically significant increase in food consumption in females of the 2000 ppm group during Week 1 of treatment; thereafter being comparable to controls. Due to the lack of a dose-response relationship, this observation was not considered to be attributable to the test material.
Mean food consumption in the 200 ppm male and female groups was similar to that of the control animals.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
Male and female fertility indices were 100% in all groups. The median number of nights to a positive mating sign was, 2, 2, 4, and 3 nights for 0, 200 ppm, 2000 ppm and 20000 ppm, respectively. There were no animals passing one oestrus to positive mating. No differences in the mean duration of gestation were seen between control and treatment groups. There were thus no treatment-related effects on mating performance, fertility or duration of gestation.

ORGAN WEIGHTS (PARENTAL ANIMALS)
The weights of testes and epididymides were essentially similar in all groups (Table 1).

GROSS PATHOLOGY (PARENTAL ANIMALS)
The female rat of the 2000 ppm group found dead showed autolysis of all tissues and enlarged left horn of the uterus. The other female of the same group killed prematurely due to a prolapse of the vagina also presented a small thymus.
Other findings included pelvic dilation in the right kidney in one female of the 200 ppm group and distended urinary bladder in one male of the 200 ppm group. This findings were considered not to be treatment-related.
There were no further necropsy findings in any of the remaining treatment groups.

HISTOPATHOLOGY (PARENTAL ANIMALS)
There were no abnormalities at microscopical examination of ovaries in the control and 20000 ppm females.
Minimal seminiferous epithelial degeneration (bilateral) was noted in 1 male of the 20000 group. There were no abnormalities in testes in control rats. At the examination of the epididymis in the 20000 ppm and control group, chronic inflammatory cell infiltration was noted in 3 treated animals and in 1 control animal, respectively. Another control animal showed chronic inflammation (focal, adnexal) of the epididymis. Minimal cellular debris (luminal, bilateral) was observed in 1 of the high-dose group. However, these findings in testes and epididymis were considered not to be treatment-related.

OTHER FINDINGS (PARENTAL ANIMALS): ACHIEVED DIETARY INTAKE
The achieved dietary intake for females in the high dose group was lower in the Week 1 of treatment (1886 mg/kg bw/day) than in Week 2 (2190 mg/kg bw/day). Males treated with 20000 ppm showed a higher mean dietary intake during the Week 1 (1889 mg/kg bw/day) than in the following weeks (Week 2: 1875 mg/kg bw/day; Week 4: 1450 mg/kg bw/day).
Furthermore, there was a decreased concentration in females throughout the gestation period in all treatment groups (Table 1). During this period, the achieved concentrations at all levels were slightly less than proportional to the diet concentrations.
At other times, the achieved concentration was essentially proportional to the diet concentrations.
Dose descriptor:
NOAEL
Effect level:
>= 1 450 mg/kg bw/day
Based on:
test mat.
Remarks:
achieved intake equivalent to 20000 ppm (worst-case assumption)
Sex:
male
Basis for effect level:
other: no adverse effects on clinical signs; mortality; body weight; food consumption and compound intake; gross pathology; organ weights; histopathology; fertility index
Dose descriptor:
NOAEL
Effect level:
>= 1 692 mg/kg bw/day
Based on:
test mat.
Remarks:
achieved intake equivalent to 20000 ppm (worst-case assumption)
Sex:
female
Basis for effect level:
other: see 'Remark'
Clinical signs:
not examined
Mortality / viability:
no mortality observed
Body weight and weight changes:
no effects observed
Sexual maturation:
not examined
Organ weight findings including organ / body weight ratios:
not examined
Gross pathological findings:
not examined
Histopathological findings:
not examined
VIABILITY (OFFSPRING)
A higher mean number of implants per pregnancy was observed in all treatment groups compared to control (Table 2). Comparison with historical data showed, however, that these findings in the treatment groups were within the background ranges for rats of this strain and age in similar studies conducted at the testing facility. It was most likely considered that the control value was at the lower end of the background range and therefore these findings were not related to treatment with the test item.
No obvious treatment-related effects were observed on litter size or litter survival at any dose level (Table 2).

BODY WEIGHT (OFFSPRING)
No obvious treatment-related effects were observed on litter or pup weights at any dose level (Table 2).

OTHER FINDINGS (OFFSPRING)
No external abnormalities were observed among pups.
According the authors, findings considered to reflect maternal care or pup survival were observed, but not reported.
Dose descriptor:
NOAEL
Remarks:
developmental toxicity
Generation:
F1
Effect level:
>= 1 692 mg/kg bw/day
Based on:
test mat.
Remarks:
achieved intake equivalent to 20000 ppm (worst-case assumption)
Sex:
male/female
Basis for effect level:
other: no adverse effects on birth index; live birth index; litter size; litter weight; pup weight; viability index; grossly visible abnormalities
Reproductive effects observed:
not specified

Table 1. Reproductive / developmental toxicity screening test: Parental examinations

 

Control group

200 ppm

2000 ppm

20000 ppm

Body weight gain (g)

Males

Week 0

288 ± 18

284 ± 14

277 ± 11

282 ± 15

Males

Week 1

331 ± 22

323 ± 12

320 ± 17

313 ± 18

Males

Week 2

370 ± 29

374 ± 18

358 ± 22

361 ± 24

Males

Week 3

404 ± 36

409 ± 19

387 ± 26

394 ± 29

Males

Week 4

432 ± 37

437 ± 23

411 ± 29

417 ± 39

Males

(week 0 – 4)

144 ± 22

153 ± 13

134 ± 21

135 ± 25

Females

(week 0 – 2)

41 ± 12

43 ± 8

38 ± 7

37 ± 7

Females

Day 0 – 20 of gestation

139

143

140

146

Females

Day 4 of lactation

287 ± 18

290 ± 12

294 ± 20

293 ± 22

Food consumption (g)

Females

Week 0

21.0 ± 1.2

18.0 ± 3.9

18.2 ± 2.0

18.2 ± 2.1

Females

Week 1

18.1 ± 2.8

17.9 ± 0.5

20.2 ± 0.6 *

19.1 ± 0.8

Females

Week 2

24.3 ± 3.2

21.5 ± 2.2

22.3 ± 1.9

24.2 ± 0.9

Females

Day 0 - 4 of lactation

26.5

22.7

27.9

29.2

Group mean achieved dosages of test item (mg/kg bw/day)

Males

Week 1

-

18.6

201

1889

Males

Week 2

-

18.4

177

1875

Males

Week 4

-

14.5**

147**

1450**

Females

Week 1

-

18.4

202

1886

Females

Week 2

-

19.9

204

2190

Females

Day 0-7 of gestation

-

19.4

189

1980

Females

Day 7-14 of gestation

-

18.6

184

1836

Females

Day 14-20 of gestation

-

16.5**

166**

1692**

Females

Day 1-4 of Lactation

-

16.6

199

2097

Absolute epididymides weights (g)

Males

1.1258 ± 0.0809

1.1205 ± 0.0548

1.0607 ± 0.0611

1.0555 ± 0.1157

Absolute testes weights (g)

Males

3.39 ± 0.16

3.48 ± 0.32

3.36 ± 0.24

3.38 ± 0.35

 

 

* significantly different from control P < 0.01

** These values represent the “worst-case” achieved intakes taken into account for hazard assessment.

 

Table 1. Reproductive / developmental toxicity screening test: Offspring examinations

 

Control group

200 ppm

2000 ppm

20000 ppm

Mean duration of gestation and overall litter performance values

Mean number pregnant

10

10

10

10

Mean duration of gestation (days)

21.7

21.8

21.6

21.7

Number of females producing a liver litter

10

10

9

10

Gestation index (%)

100

100

90

100

Mean number of implant sites* per pregnancy

12.9 ± 2.3

15.6 ± 0.8

14.7 ± 2.6

15.2 ± 1.9

Mean total number of pups* born per litter

11.8 ± 2.0

14.1 ± 1.6

13.0 ± 1.8

14.1 ± 1.6

Mean number of live pups per litter

Day 0 of lactation

11.8 ± 2.0

14.1 ± 1.6

12.9 ± 2.0

13.7 ± 1.8

Mean number of live pups per litter

Day 4 of lactation

11.6 ± 2.0

12.1 ± 3.4

12.6 ± 2.1

12.0 ± 3.9

Group mean F1 survival indices

Birth index (%)

91

91

91**

92

Live birth index (%)

99

100

99**

93

Viability Index Days 0-4(%)

79

87

86**

82

Group mean litter and pup weight*

Litter

Day 1 of lactation (g)

78 ± 10

73 ± 22

79 ± 12

82 ± 11

Litter

Day 4 of lactation (g)

112 ± 13

105 ± 30

116 ± 18

111 ± 35

Males

Day 1 of lactation (g)

7.0 ± 0.8

6.0 ± 0.9

6.5 ± 0.6

6.4 ± 0.9

Males

Day 4 of lactation (g)

10.0 ± 1.3

8.9 ± 1.1

9.5 ± 0.9

9.0 ± 1.1

Females

Day 1 of lactation (g)

6.5 ± 0.8

5.6 ± 0.9

6.2 ± 0.5

6.1 ± 1.0

Females

Day 4 of lactation (g)

9.5 ± 1.3

8.5 ± 1.2

9.1 ± 0.7

8.8 ± 1.3

* excludes littes where all pups died

** based on 8 litters (litters of animal found dead and of animal killed prematurely were not considered)

Effect on fertility: via oral route
Endpoint conclusion:
no adverse effect observed
Quality of whole database:
The available information comprises an adequate and reliable study (Klimisch score 2 due to read-across) from a reference substance with similar structure and intrinsic properties. Read-across is justified based on structural similarity as a result of common origin and production process line (refer to endpoint discussion for further details).
The selected study is thus sufficient to fulfil the standard information requirements set out in Annex VIII, 8.7.1, and IX, 8.7.3, in accordance with Annex XI, 1.5, of Regulation (EC) No 1907/2006.
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

Justification for grouping of substances and read-across

There are no data available on the reproductive toxicity of Fatty acids, C18-unsaturated, trimers, hydrogenated. In order to fulfil the standard information requirements set out in Annex VIII, Section 8.7.1, in accordance with Annex XI, Section 1.5 of Regulation (EC) No 1907/2006, read-across from a structurally similar substance is conducted.

In accordance with Article 13 (1) of Regulation (EC) No 1907/2006, "information on intrinsic properties of substances may be generated by means other than tests, provided that the conditions set out in Annex XI are met.” In particular for human toxicity, information shall be generated whenever possible by means other than vertebrate animal tests, which includes the use of information from structurally related substances (grouping or read-across).

Having regard to the general rules for grouping of substances and read-across approach laid down in Annex XI, Item 1.5, of Regulation (EC) No 1907/2006, whereby physicochemical, toxicological and ecotoxicological properties may be predicted from data for reference substance(s) by interpolation to other substances on the basis of structural similarity, Fatty acids, C18-unsatd., dimers (CAS 61788-89-4) is selected as reference substances for assessment of reproductive toxicity.

The read-across is based on structural similarity as a result of common origin and production process line. Shortly, the source and target substances are derived from catalytically di- and trimerised long-chain fatty acids; dimers and trimers are separated by distillation and unsaturated alkyl chains are hydrogenated as specifically required. A detailed analogue approach justification is provided in the technical dossier (see IUCLID Section 13).

Overview of reproductive toxicity

 

Target substance

Source substance

CAS No.

1373883-45-4

61788-89-4

Chemical name

Fatty acids, C18-unsaturated, trimers, hydrogenated

Fatty acids, C18-unsatd., dimers

Screening for reproductive/developmental toxicity

RA: CAS 61788-89-4

Experimental result:

NOAEL (m) ≥ 1450 mg/kg bw/day

NOAEL (f) ≥ 1692 mg/kg bw/day

(OECD 421)

Effects on reproductive organs (90-day study)

RA: CAS 61788-89-4

Experimental result:

NOAEL (rat, m) = ca. 3590 mg/kg bw/day

NOAEL (rat, f) = ca. 4085 mg/kg bw/day

(similar to OECD 408)

 

Screening for reproductive/developmental toxicity

CAS 61788-89-4

A Reproduction/Developmental Toxicity Screening Test was conducted with Fatty acids, C18-unsatd., dimers following OECD guideline 421 and under GLP conditions (Clubb and Sutherland, 2004). Four groups of 10 rats per sex and dose were fed the test material at 200, 2000 and 20000 ppm in diet. Based on body weight and food consumption monitoring data, the minimum exposure levels during the study period were 14.5, 147 and 1450 mg/kg bw/day and 16.5, 166, 1692 mg/kg bw/day for males and females, respectively. Control animals were fed plain diet. Male animals were treated for 2 weeks prior to mating, through until necropsy after 4 weeks of treatment. Female animals were treated for 2 weeks prior to mating, through mating, gestation and until termination on at least Day 4 of lactation.

The observed effects were limited to a slight and statistically not significant decrease in body weight of males of the 20000 ppm group during the first week of treatment, and an increase in the incidence of piloerection in all male treatment groups. However, body weight gain for males of the 20000 ppm group was essentially similar to control animals for the rest of the study on Weeks 2-4 and the incidence of piloerection showed no dose-relationship. No effects on testes, epididymides and ovaries and on the examined reproductive parameters were observed between control and test P and F1 animals.

Based on the lack of toxicologically relevant effects up to the highest dose level tested, a NOAEL for systemic/reproductive toxicity and offspring development ≥ 1450 mg/kg bw/day and ≥ 1692 mg/kg bw/day for males and females was determined, respectively.

Effects on reproductive organs

CAS 61788-89-4

In a previous subchronic oral toxicity study, Fatty acids, C18-unsaturated, dimers were tested in rats according to a method similar to OECD guideline 408 and under GLP conditions (Spurgeon and Hepburn, 1993). Groups of 20 Sprague-Dawley rats per sex and dose were fed the test item at 0.1, 1.0 and 5.0% in diet for 13 weeks. The corresponding dose levels (averaged over the 13-week study period) were ca. 74.1, 740.9, 3591.2 mg/kg bw/day for males and ca. 90.5, 854.9, 4085.5 mg/kg bw/day for females, based on the reported body weight and food intake data.

Histopathological examinations included the analysis of testes, epididymides, seminal vesicles, prostate, uterus, vagina, mammary glands, ovaries and fallopian tubes.

No changes were found after histopathological examination of male and female reproductive organs up to the highest dose tested (ca. 3590 and 4085 mg/kg bw/day for males and females, respectively).

Two-generation reproductive toxicity study

In accordance with Column 1 of Annex IX, Section 8.7.3 of Regulation (EC) No 1907/2006, a two-generation reproductive toxicity study is required if the 28-day or 90-day study indicates adverse effects on reproductive organs or tissues.

As indicated above, hazard assessment is conducted by means of read-across from the structurally similar substance Fatty acids, C18-unsatd., dimers (CAS No. 61788-89-4).

Fatty acids, C18-unsatd., dimers were tested in a 90-day repeated dose oral toxicity study and in a reproduction/developmental toxicity screening study (Spurgeon and Hepburn, 1993; Clubb and Sutherland, 2004). In the subchronic study, no changes were found after histopathological examination of male and female reproductive organs up to the highest dose level tested (ca. 3590 and 4085 mg/kg bw/day for males and females, respectively). In the screening study, no effects were observed in reproductive organs and in any of the reproductive parameters examined. The NOAEL was determined to be ≥ 1450 and ≥ 1692 mg/kg bw/day for males and females, respectively (highest dose level tested).

Based on read-across, the available data does not indicate adverse effects on reproductive organs or tissues. Therefore, a two-generation reproductive toxicity study is not required.

Conclusions for reproductive toxicity

There is no information available on reproductive toxicity. Therefore, in order to fulfil the standard information requirements set out in Annex IX, Section 8.7.1, in accordance with Annex XI, Section 1.5 of Regulation (EC) No 1907/2006, read-across from a structurally similar substance is conducted.

The substance Fatty acids, C18-unsatd., dimers (CAS 61788-89-4) has been tested in a reproduction/developmental toxicity screening study. No toxicologically relevant effects were observed in any of the reproductive parameters examined up to and including the highest dose level tested. Therefore, the NOAEL was determined to be ≥ 1450 and ≥ 1692 mg/kg bw/day for males and females, respectively.

In a 90-day repeated dose oral toxicity study with Fatty acids, C18-unsatd., dimers, no changes were found after histopathological examination of male and female reproductive organs up to the highest dose level tested, corresponding to ca. 3590 and 4085 mg/kg bw/day for males and females, respectively.

Based on the available data, the substance Fatty acids, C18-unsaturated, trimers, hydrogenated is considered to be not toxic to reproduction.


Short description of key information:
Based on read-across from Fatty acids, C18-unsaturated, dimers (CAS No. 61788-89-4):
NOAEL systemic/reproductive/developmental toxicity (rat, m/f) ≥ 1450 (m) and 1692 (f) mg/kg /bw/day (OECD 421, GLP)

Justification for selection of Effect on fertility via oral route:
Hazard assessment is conducted by means of read-across from a structural analogue. The selected study is the most adequate and reliable study based on the identified similarities in structure and intrinsic properties between source and target substance and overall assessment of quality, duration and dose descriptor level (refer to the endpoint discussion for further details).

Effects on developmental toxicity

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available

Justification for classification or non-classification

Based on read-across from a structurally similar substance following an analogue approach, the available data on the reproductive toxicity of the substance do not meet the classification criteria according to Regulation (EC) 1272/2008 or Directive 67/548/EEC, and are therefore conclusive but not sufficient for classification.

Data are lacking for (pre-natal) developmental toxicity and effects via lactation.