Octanoic acid, compound with dicyclohexylamine (1:1)

Endpoint summary

Key value for chemical safety assessment

Effects on fertility

Description of key information

Dicyclohexylamine:

In an OECD reproduction/developmental toxicity screening test (OECD TG 421) in rats dicyclohexylamine revealed effects on reproduction only in females at the highest oral dose tested (80 mg/kg bw/day) including slightly reduced gestation index, increase in stillborn pups and decrease in live born pups. The NOAEL (reproductive toxicity) is 80 mg/kg bw/day for males and 40 mg/kg bw/day for females. The NOAEL (offspring) is 40 mg/kg bw/day based on significant reduction in pup weights on day 0 and slight reduction in pup weights on day 4 in offspring of the parents dosed with 80 mg/kg bw/day. These adverse effects on the development of the F1-generation occur only in the presence of severe maternal toxicity.

Octanoic acid:

A casein diet, containing 18.5% MCT (medium chain triglycerides) and 2.5% safflower oil was compared with similar diets containing conventional dietary fats. The MCT contained about 51% octanoic acid and 35% Decanoic arid resulting in an Octanoic acid dietary dose of about 4700 mg/kg bw day and a Decanoic acid dietary dose of about 3200 mg/kg bw day.

The 47-week study showed that the MCT diet supported normal growth and development. The MCT diet supported normal reproduction, as indicated by litter size and number.

Accordingly for Decanoic acid and Octanoic acid as medium chain triglycerides an overall NOAEL of ≥ 8000 mg/kg bw day is apparent in this study.

Since for octanoic acid, naturally present in many types of food, no concern for reproductive toxicity is given, data from reproductive toxicity studies with dicyclohexylamine are used.

For effects on fertility the NOAEL of 40 mg/kg bw for dicyclohexylamine is used as key value for chemical safety assessment. Since the substance to be registered is Octanoic acid, compound with dicyclohexylamine (1:1) which will dissociate to 1 mol octanoic acid and 1 mol dicyclohexylamine, the NOAEL of dicyclohexylamine is calculated for the entire substance considering the molar mass of 325.5 g/mol (55.7% dicyclohexylamine).

Therefore the NOAEL for Octanoic acid, compound with dicyclohexylamine (1:1) is 71.81 mg/kg bw.

Link to relevant study records

Reference

Reference 1

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

1998

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

test procedure in accordance with national standard methods with acceptable restrictions

Qualifier:

equivalent or similar to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Deviations:

not specified

GLP compliance:

yes

Limit test:

no

Species:

rat

Strain:

Crj: CD(SD)

Sex:

male/female

Route of administration:

oral: gavage

Vehicle:

corn oil

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

Males: 49 days
Females: from 14 days before mating to day 3 of lactation

Frequency of treatment:

once daily

Dose / conc.:

20 mg/kg bw/day (nominal)

Dose / conc.:

40 mg/kg bw/day (nominal)

Dose / conc.:

80 mg/kg bw/day (nominal)

No. of animals per sex per dose:

12

Control animals:

yes

Parental animals: Observations and examinations:

clinical signs of toxicity, body weight, mortality, pathology of male organs, number of pairs mated, number of pairs copulated, number of pregnant females, days until copulation, copulation index (no. of pairs with successful copulation / no. of pairs mated) X 100 fertility index (no. of pregnant rats / no. of pairs with successful copulation) X 100duration of gestation, ---gestation index(no. of females with live pups / no. of pregnant females) X 100, ---implantation index (no. of implantations / no. of corpora lutea) X 100

Oestrous cyclicity (parental animals):

estrus cycle length

Sperm parameters (parental animals):

not specified

Litter observations:

live birth index (no. of live pups on day 0 / no. of pups born) X 100, ---delivery index (no of pups born / no. of implantations) X 100, ---sex ratio (no of males /no of females), ---viability index (no of live pups on day 4 / no. of live pups on day 0) X 100, body weight of pups on day 0 and day 4

Postmortem examinations (parental animals):

ORGANS EXAMINED AT NECROPSY (reported organs): --Organ weight (absolute and relative): - male, right and left testes, right and left epididymides

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

unspecific signs of intoxication

Dermal irritation (if dermal study):

not examined

Mortality:

mortality observed, treatment-related

Description (incidence):

In the 80 mg/kg bw/day-group, 1 dam died on day 21 and another dam on day 22 of gestation.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Suppression of body weight gain in both sexes (male: treated rat versus control: 507 g versus 543 g) and low food consumption were observed.

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

effects observed, treatment-related

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

not specified

Reproductive performance:

effects observed, treatment-related

Description (incidence and severity):

80 mg/kg:
Number of stillborn pups was significantly increased (55 versus 11 in controls) and the number of live born pups significantly decreased (72 versus 169 in controls) as well as live born index (58 % versus 94 % in controls), viability index reduced in pups (20.8 % versus 99 % in controls), pup weights on day 0 significantly (m/f: 6.1 g/5.5 g versus 7.3 g/7.0 g) and on day 4 slightly but not statistically significantly reduced (m/f: 9.0 g/8.6 g versus 11.8 g/11.1 g), poor maternal behavior and nursing observed in 7 dams.

Key result

Dose descriptor:

NOAEL

Effect level:

40 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

female

Basis for effect level:

mortality

body weight and weight gain

food consumption and compound intake

Key result

Dose descriptor:

NOAEL

Effect level:

80 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male

Basis for effect level:

other: no effects

Clinical signs:

not specified

Dermal irritation (if dermal study):

not specified

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

Offsprings of the 80 mg/kg bw/day-dosed animals:number of stillborn pups significantly increased (55 versus 11 in controls),number of live born pups significantly decreased (72 versus 169 in controls) as well as live born index (58 % versus 94 % in controls), viability index reduced in pups of the 80 mg/kg bw/day group (20.8 % versus 99 % in controls) and pup weights on day 0 significantly (m/f: 6.1 g/5.5 g versus 7.3 g/7.0 g) and on day 4 slightly but not statistically

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Pup weights on day 0 significantly (m/f: 6.1 g/5.5 g versus 7.3 g/7.0 g) and on day 4 slightly but not statistically
significantly reduced (m/f: 9.0 g/8.6 g versus 11.8 g/11.1 g)

Food consumption and compound intake (if feeding study):

not examined

Food efficiency:

not examined

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

not examined

Ophthalmological findings:

not examined

Haematological findings:

not examined

Clinical biochemistry findings:

not examined

Urinalysis findings:

not examined

Sexual maturation:

not examined

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

not examined

Histopathological findings:

not examined

Other effects:

not specified

Behaviour (functional findings):

not examined

Developmental immunotoxicity:

not examined

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

40 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

body weight and weight gain

Key result

Critical effects observed:

not specified

Key result

Reproductive effects observed:

no

Conclusions:

In an OECD reproduction/developmental toxicity screening test (OECD TG 421) in rats dicyclohexylamine revealed effects on reproduction only in females at the highest oral dose tested (80 mg/kg bw/day) including slightly reduced gestation index, increase in stillborn pups and decrease in live born pups. The NOAEL (reproductive toxicity) is 80 mg/kg bw/day for males and 40 mg/kg bw/day for females. The NOAEL (offspring) is 40 mg/kg bw/day based on significant reduction in pup weights on day 0 and slight reduction in pup weights on day 4 in offspring of the parents dosed with 80 mg/kg bw/day. These adverse effects on the development of the F1-generation occur only in the presence of severe maternal toxicity.

Executive summary:

In an OECD reproduction/developmental toxicity screening test (OECD TG 421) in rats dicyclohexylamine revealed effects on reproduction only in females at the highest oral dose tested (80 mg/kg bw/day) including slightly reduced gestation index, increase in stillborn pups and decrease in live born pups. The NOAEL (reproductive toxicity) is 80 mg/kg bw/day for males and 40 mg/kg bw/day for females. The NOAEL (offspring) is 40 mg/kg bw/day based on significant reduction in pup weights on day 0 and slight reduction in pup weights on day 4 in offspring of the parents dosed with 80 mg/kg bw/day. These adverse effects on the development of the F1-generation occur only in the presence of severe maternal toxicity.

Reference 2

Endpoint:

multi-generation reproductive toxicity

Type of information:

experimental study

Adequacy of study:

supporting study

Study period:

1968

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

study well documented, meets generally accepted scientific principles, acceptable for assessment

Qualifier:

no guideline followed

Principles of method if other than guideline:

47 weeks reproduction/developmental study

GLP compliance:

not specified

Species:

rat

Strain:

other: Mc Collum Wisconsin

Sex:

male/female

Route of administration:

oral: feed

Vehicle:

unchanged (no vehicle)

Analytical verification of doses or concentrations:

not specified

Duration of treatment / exposure:

47 weeks

Frequency of treatment:

ad libitum

Dose / conc.:

4 700 mg/kg bw/day (nominal)

Remarks:

40% of daily
calories in food
supplied by MCT

No. of animals per sex per dose:

not specified

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Behaviour (functional findings):

not specified

Immunological findings:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Histopathological findings: non-neoplastic:

not specified

Histopathological findings: neoplastic:

not specified

Other effects:

not specified

Reproductive function: oestrous cycle:

not specified

Reproductive function: sperm measures:

not specified

Reproductive performance:

no effects observed

Key result

Dose descriptor:

NOAEL

Effect level:

>= 8 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects observed

Key result

Critical effects observed:

no

Immunological findings:

not specified

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Key result

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

>= 8 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects observed

Key result

Critical effects observed:

no

Clinical signs:

no effects observed

Dermal irritation (if dermal study):

not specified

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Food efficiency:

not specified

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

not specified

Ophthalmological findings:

not specified

Haematological findings:

not specified

Clinical biochemistry findings:

not specified

Urinalysis findings:

not specified

Sexual maturation:

not specified

Organ weight findings including organ / body weight ratios:

not specified

Gross pathological findings:

not specified

Histopathological findings:

not specified

Other effects:

not specified

Behaviour (functional findings):

not specified

Developmental immunotoxicity:

not specified

Key result

Dose descriptor:

NOAEL

Generation:

F2

Effect level:

>= 8 000 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: no effects observed

Key result

Critical effects observed:

no

Key result

Reproductive effects observed:

no

Conclusions:

A casein diet, containing 18.5% MCT (medium chain triglycerides) and 2.5% safflower oil was compared with similar diets containing conventional dietary fats. The MCT contained about 51% octanoic acid and 35% Decanoic arid resulting in an Octanoic acid dietary dose of about 4700 mg/kg bw day and a Decanoic acid dietary dose of about 3200 mg/kg bw day.
The 47-week study showed that the MCT diet supported normal growth and development. The MCT diet supported normal reproduction, as indicated by litter size and number.
Accordingly for Decanoic acid and Octanoic acid as medium chain triglycerides an overall
NOAEL of ≥ 8000 mg/kg bw day is apparent in this study.

Executive summary:

A casein diet, containing 18.5% MCT (medium chain triglycerides) and 2.5% safflower oil was compared with similar diets containing conventional dietary fats. The MCT contained about 51% octanoic acid and 35% Decanoic arid resulting in an Octanoic acid dietary dose of about 4700 mg/kg bw day and a Decanoic acid dietary dose of about 3200 mg/kg bw day.

The 47-week study showed that the MCT diet supported normal growth and development. The MCT diet supported normal reproduction, as indicated by litter size and number.

Accordingly for Decanoic acid and Octanoic acid as medium chain triglycerides an overall NOAEL of ≥ 8000 mg/kg bw day is apparent in this study.

Reference 3

Endpoint:

screening for reproductive / developmental toxicity

Data waiving:

study scientifically not necessary / other information available

Justification for data waiving:

other:

Justification for type of information:

According to REACH Annex XI, section 1, the standard testing regime may be adapted if testing does not appear scientifically necessary.
In aqueous systems Octanoic acid, compound with dicyclohexylamine (1:1) will rapidly dissociate to octanoic acid and dicyclohexylamine.
Octanoic acid is a linear saturated fatty acid and is ubiquitous in nature.
According to Umweltbundesamt GmbH on behalf of Federal Ministry of Agriculture, Forestry, Environment and Water Management octanoic acid is not genotoxic (citation):
“Data obtained in a 47-week study showed that the MCT diet supported normal growth and development. The MCT diet supported normal reproduction, as indicated by litter size and number. However weight gain of F1 rats was highest with the oleo oil diet, lower with the MCT diet but lowest with the low-fat diet. Accordingly for Decanoic acid and Octanoic acid as medium chain triglycerides an overall NOAEL of ≥ 8000 mg/kg bw day is apparent in this study. Taking furthermore into consideration the arguments listed in chapter 4.7 (bullet points) there is no concern for reproductive toxicity.”
“Data for potential effects on fertility are available with medium chain fatty acid triglycerids. Data for potential effects on the development are available for octanoic acid and for nonanoic acid. None of these data indicate a concern for reproductive toxicity. However this is also not to be expected given the knowledge on metabolism in humans and daily exposure to fat as nutrient.”

Effect on fertility: via oral route

Endpoint conclusion:

adverse effect observed

Dose descriptor:

NOAEL

71.81 mg/kg bw/day

Study duration:

subacute

Species:

rat

Quality of whole database:

Guideline study available

Effect on fertility: via inhalation route

Endpoint conclusion:

no study available

Effect on fertility: via dermal route

Endpoint conclusion:

no study available

Effects on developmental toxicity

Effect on developmental toxicity: via oral route

Endpoint conclusion:

no study available

Quality of whole database:

no study required

Justification for classification or non-classification

DCHA:

Dicyclohexylamine revealed effects on reproduction only in females at the highest oral dose tested (80 mg/kg bw/day). Since at these dose level mortality was observed, the effects on reproductive performance is considered only as secondary to massive maternal toxicity.

 

Octanoic acid:

Since for octanoic acid, naturally present in many types of food, no concern for reproductive toxicity is given.

 

Since the substance to be registered is Octanoic acid, compound with N-cyclohexylcyclohexanamine (1:1) which will dissociate to 1 mol octanoic acid and 1 mol dicyclohexylamine, data from the respective dissociation products dicyclohexylamine and octanoic acid are used for classification and labelling purposes.

Since the observed adverse effects of dicyclohexylamine on the development of the F1-generation occur only in the presence of severe maternal toxicity and octanoic acid is devoid of any reproductive toxicity, no classification of Octanoic acid, compound with N-cyclohexylcyclohexanamine (1:1) for reproductive toxicity is required.