C16-18-(even numbered, C18-unsaturated)-alkylamines acetates

Toxicity to reproduction

Administrative data

Endpoint:

one-generation reproductive toxicity

Remarks:

based on generations indicated in Effect levels (migrated information)

Type of information:

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

Adequacy of study:

key study

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline study according to GLP

Data source

Reference

Reference Type:

study report

Title:

Unnamed

Year:

2013

Report date:

2013

Materials and methods

Test guideline

Qualifier:

according to guideline

Guideline:

OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Limit test:

no

Test material

Test material information

Constituent 1

Reference substance name:

C16-18-(even numbered)-alkylamines acetates

EC Number:

800-526-8

Cas Number:

1273322-45-4

Molecular formula:

R-NH2xHOOCCH3 R = alkyl, mainly C16-18-(even numbered)

IUPAC Name:

C16-18-(even numbered)-alkylamines acetates

Test material form:

other: solid

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River
- Age at study initiation: males 11-12 weeks, females 11-12 weeks
- Weight at study initiation: males 302-348g, females 184-217g
- Fasting period before study: overnight
- Housing: individually in IVC cages, type III H
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: 5 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 22 +/- 3°C
- Humidity (%): 55 +/- 10%
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

other: sesame oil

Details on exposure:

VEHICLE
- Justification for use and choice of vehicle (if other than water): sesame oil is a recommended vehicle and was chosen on the basis of solubility tests.

Details on mating procedure:

Mating was performed using a ratio of 1:1 (male to female). The vaginal smear of the females was checked every morning after the start of the mating period to confirm the pregnancy. The day of the vaginal plug and/or sperm was considered as day 0 of gestation. Females with unsuccessful mating will be allowed to mate with other male of the same group.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

The animals were treated with the test item formulation or vehicle on 7 days per week for a period of 54 days, i.e. during 14 days of pre-mating and 14 days of mating in both males and females, during the gestation period and up to post-natal day 3 in females. Males were dosed after the mating period until the minimum total dosing period of 28 days were completed.

Frequency of treatment:

once daily

Doses / concentrations

Remarks:

Doses / Concentrations:
0, 12, 30, 75 mg/kg body weight per day
Basis:
nominal conc.

No. of animals per sex per dose:

10 males and 10 females per group (in total 80 animals)

Control animals:

yes, concurrent vehicle

Positive control:

no

Examinations

Parental animals: Observations and examinations:

CAGE SIDE OBSERVATIONS: Yes
- Time schedule: daily

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: daily

BODY WEIGHT: Yes
- Time schedule for examinations: before start of study and weekly thereafter

Sperm parameters (parental animals):

For the testes, a detailed qualitative examination was made; taking into account the tubular stages of the spermatogenic cycle at evaluation of additional hematoxylin-PAS (Periodic Acid Schiff) stained slides.

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

only high dose animals

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

mid and high dose animals

Food consumption and compound intake (if feeding study):

effects observed, treatment-related

Description (incidence and severity):

mid and high dose animals

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

not examined

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:

no effects observed

Reproductive function: sperm measures:

no effects observed

Reproductive performance:

no effects observed

Details on results (P0)

CLINICAL SIGNS AND MORTALITY (PARENTAL ANIMALS): Unspecific clinical symptoms in high dose animals but no mortality

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS): Decrease in body weight in male and female animals of mid- and high dose group.

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS): No significant effects noted

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS): No significant effects noted

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS): No significant effects noted

ORGAN WEIGHTS (PARENTAL ANIMALS): No substance related effects noted

GROSS PATHOLOGY (PARENTAL ANIMALS): No substance related effects noted

HISTOPATHOLOGY (PARENTAL ANIMALS): No significant changes noted.

Effect levels (P0)

1

Dose descriptor:

NOAEL

Effect level:

12 mg/kg bw/day

Based on:

test mat.

Sex:

female

Basis for effect level:

other: overall effects

2

Dose descriptor:

NOAEL

Effect level:

12 mg/kg bw/day

Based on:

test mat.

Sex:

male

Basis for effect level:

other: overall effects

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

mortality observed, treatment-related

Description (incidence and severity):

Total number of pubs born at PND 0 was significantly decreased in high dose animals. Additionally, number of living pubs was significantly decreased at PND 4 in high dose group.

Body weight and weight changes:

effects observed, treatment-related

Description (incidence and severity):

Decreased total litter weight in high dose group at PND 0

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

not examined

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Details on results (F1)

VIABILITY (OFFSPRING): The total number of pubs born at PND 0, the number of living pubs at PND 0 and the number of living pubs at PND 4 was decreased in high dose group.

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

12 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: overall effects

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Based on the results of this study the NOAEL for male and female parental animals was 12 mg/kg body weight per day. Likewise, the NOAEL for the pubs was 12 mg/kg body weight per day.

Executive summary:

Possible effects of C16-18-(even numbered)-alkylamines acetates on male and female fertility and embryofetal development after repeated dose administration in Wistar rats were investigated in an OECD 421 screening assay according to GLP. The test item was administered daily in graduated doses of 12, 30 and 75 mg/kg body weight per day to 3 groups of 10 test animals (5 male, 5 female), one dose level per group for a treatment period of 54 days, i.e. during 14 days of pre-mating and 14 days of mating in both males and females, during the gestation period and up to post-natal day 3 in females. Males were dosed after the mating period until the minimum total dosing period of 28 days were completed. Animals of an additional control group were treated identically but received only the vehicle sesame oil. During the period of administration, the animals were observed each day for signs of toxicity. Body weight and food consumption were measured weekly. Animals that died were examined macroscopically and at the conclusion of the test, surviving animals were sacrificed and observed macroscopically. After 14 days of treatment to both male and female, animals were mated (1:1) for a maximum of 14 days. The males were sacrificed after completion of the mating period on treatment days 29 and 30 and the females along with their pups were sacrificed on post natal day 4.

For male animals, moderate clinical symptoms and a significantly decreased body weight development was found at 75 mg/kg body weight. At 30 mg/kg body weight a significantly attenuated body weight gain was found during specific intervals, too. Hence, the observed adverse effect level (NOAEL) for male animals is assumed to be 12 mg/kg body weight.

In female animals, moderate clinical symptoms and a significantly reduced body weight development during specific intervals were observed at 75 mg/kg body weight. An attenuated body weight gain (not statistical significant) was also mentioned at 30 mg/kg body weight. Hence, the observed adverse effect level (NOAEL) for female animals is assumed to be 12 mg/kg body weight.

At a dose level of 75 mg/kg body weight, the total number of pubs born was significantly reduced at PND 0 and the number of living pubs as well as total litter weight was significantly reduced at PND 0 and PND 4, too. In addition, number of implantation sites was significantly decreased in the high dose group. 2 female dams exhibited mortalities of pubs. At 30 mg/kg a tendency towards a decreased number of born pubs was observed. Furthermore, a decrease in the number of implantation sites could be recorded. Both findings at 30 mg/kg body weight are not statistical significant. However, they confirm the findings in the high dose group and hence are assumed to be the starting point of toxicological relevance which may be attributable to the maternal toxic effects seen at these higher doses. Therefore the no observed adverse effect level (NOAEL) for toxicity of the pubs is conservatively assumed to be 12 mg/kg body weight.