Alcohols, C6-8, ethoxylated

Toxicity to reproduction

Administrative data

Endpoint:

screening for reproductive / developmental toxicity

Type of information:

experimental study

Adequacy of study:

key study

Study period:

2012

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Guideline and GLP compliant study with Klimisch rating 1

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:

Alcohols, C6-C8-(even numbered, linear)-ethoxylated (<2,5 EO)

EC Number:

800-182-9

Cas Number:

1426148-68-6

Molecular formula:

R-O-R' , whereas R=C6-8-(even numbered, linear, saturated)-alkyl and R'=H or xEO wheras x=1-12, mean=2,3

IUPAC Name:

Alcohols, C6-C8-(even numbered, linear)-ethoxylated (<2,5 EO)

Test material form:

other: liquid

Test animals

Species:

rat

Strain:

Wistar

Sex:

male/female

Details on test animals or test system and environmental conditions:

TEST ANIMALS
- Source: Charles River, Sulzfeld, Germany
- Age at study initiation: 10 - 11 weeks (males), 10 - 11 weeks (females)
- Weight at study initiation: 280 - 329 (males), 176 - 216 (females)
- Fasting period before study: overnight
- Housing: individually (except during mating) in IVC cages, type III H
- Use of restrainers for preventing ingestion (if dermal): no
- Diet (e.g. ad libitum): ad libitum
- Water (e.g. ad libitum): ad libitum
- Acclimation period: at least 5 days

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

Administration / exposure

Route of administration:

oral: gavage

Vehicle:

water

Details on mating procedure:

After 14 days of treatment animals were mated (1:1) for a maximum of 14 days.

Analytical verification of doses or concentrations:

yes

Duration of treatment / exposure:

Animals were dosed for a treatment period of 54 days, i.e. during 14 days of pre-mating and maximum 14 days 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 was completed.

Frequency of treatment:

single daily doses

Doses / concentrations

Doses / concentrations 1

Dose / conc.:

40 mg/kg bw/day

Doses / concentrations 2

Dose / conc.:

200 mg/kg bw/day

Doses / concentrations 3

Dose / conc.:

750 mg/kg bw/day

Remarks:

Due to significant general toxicity including mortality at the highest dose of 1000 mg/kg body weight, the dosage was reduced to 750 mg/kg body weight in the high dose group from day 5 of treatment onwards.

Doses / concentrations 4

Dose / conc.:

1 000 mg/kg bw/day

Remarks:

Due to significant general toxicity including mortality at the highest dose of 1000 mg/kg body weight, the dosage was reduced to 750 mg/kg body weight in the high dose group from day 5 of treatment onwards.

No. of animals per sex per dose:

10

Control animals:

yes, concurrent vehicle

Details on study design:

Due to significant general toxicity including mortality at the highest dose of 1000 mg/kg body weight, the dosage was reduced to 750 mg/kg body weight in the high dose group from day 5 of treatment onwards.

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: weekly

Litter observations:

number and sex of pubs, stillbirths, live births, runts, presence of gross abnormalities

Postmortem examinations (parental animals):

SACRIFICE
- Male animals: All surviving animals at terminal sacrifice, i.e. minimum of 28 days
- Maternal animals: All surviving animals at terminal sacrifice, i.e. PND 4

GROSS NECROPSY
- Gross necropsy consisted of external and internal examinations including the cervical, thoracic, and abdominal viscera. Special attention was given to the organs of the reproductive system.

HISTOPATHOLOGY / ORGAN WEIGHTS
Full histopathology of lung, urinary bladder, lymph nodes (mesenteric and axillary), trachea, kidneys, adrenal glands and heart of all animals which died during the study. For the surviving animals the organs were preserved for histopathology if needed.

Full histopathology in all animals of the organs of the reproductive system [i.e. testes, epididymides, ovaries, uterus with cervix, vagina and accessory sex organs (prostate, seminal vesicle with coagulating gland)

Detailed qualitative examination of the testes taking into account the tubular stages of the spermatogenic cycle

Postmortem examinations (offspring):

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

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:

effects observed, treatment-related

Description (incidence and severity):

General unspecific signs of toxicity and mortality in high dose animals only

Body weight and weight changes:

no effects observed

Food consumption and compound intake (if feeding study):

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Histopathological findings: non-neoplastic:

no effects observed

Other effects:

not examined

Description (incidence and severity):

Test substance intake: No feeding study

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)
General unspecific clinical signs and mortality in high dose animals. Based on clinical signs and pathological observations, the premature death was considered to be due to a combination of direct test item-related general toxicity and gastric and/or pulmonary lesions indicative of a strong local irritant effect of the test item at the highest dose tested.

BODY WEIGHT AND FOOD CONSUMPTION (PARENTAL ANIMALS)
There were no adverse treatment related changes noted for body weight, body weight change and food consumption of male and female treated groups when compared to corresponding control

REPRODUCTIVE FUNCTION: ESTROUS CYCLE (PARENTAL ANIMALS)
No treatment related changes noted.

REPRODUCTIVE FUNCTION: SPERM MEASURES (PARENTAL ANIMALS)
No treatment related changes noted.

REPRODUCTIVE PERFORMANCE (PARENTAL ANIMALS)
No treatment related changes noted.

ORGAN WEIGHTS (PARENTAL ANIMALS)
No treatment related changes of toxicological significance.

GROSS PATHOLOGY (PARENTAL ANIMALS)
Gastric and/or lung lesions indicative of strong local irritant effects in high dose animals only.

HISTOPATHOLOGY (PARENTAL ANIMALS)
No treatment related effects of toxicological significance noted.

Effect levels (P0)

Dose descriptor:

NOAEL

Effect level:

200 mg/kg bw/day (nominal)

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: Mortalities due to general toxicity and gastric lesions indicative of strong local irritant effects at highest dose

Results: F1 generation

General toxicity (F1)

Clinical signs:

no effects observed

Mortality / viability:

no mortality observed

Body weight and weight changes:

no effects observed

Sexual maturation:

no effects observed

Organ weight findings including organ / body weight ratios:

no effects observed

Gross pathological findings:

no effects observed

Histopathological findings:

not examined

Details on results (F1)

VIABILITY (OFFSPRING)
No treatment related effects noted.

CLINICAL SIGNS (OFFSPRING)
No treatment related effects noted.

BODY WEIGHT (OFFSPRING)
No treatment related effects noted.

SEXUAL MATURATION (OFFSPRING)
No treatment related effects noted.

ORGAN WEIGHTS (OFFSPRING)
No treatment related effects noted.

GROSS PATHOLOGY (OFFSPRING)
No treatment related effects noted.

HISTOPATHOLOGY (OFFSPRING)
Not examined

Effect levels (F1)

Dose descriptor:

NOAEL

Generation:

F1

Effect level:

750 mg/kg bw/day

Based on:

test mat.

Sex:

male/female

Basis for effect level:

other: There were no toxicologically relevant findings noted for reproductive and developmental paramaters in any of the pubs at any dose level.

Overall reproductive toxicity

Reproductive effects observed:

not specified

Applicant's summary and conclusion

Conclusions:

Based on the data generated from this “Reproduction/ Developmental Toxicity Screening Test with Alcohols, C6-8-alkyl-(even,linear), ethoxylated (<2.5 EO), the no observed adverse effect level (NOAEL) for general and maternal toxicity is considered to be 200 mg/kg body weight and for reproductive and developmental toxicity 750 mg/kg body weight.

Executive summary:

The registration substance was investigated for reproductive / developmental toxicity in an OECD 421 screening study according to GLP. Repeated dose administration of the Alcohols, C6-8-alkyl-(even,linear), ethoxylated (<2.5 EO) to groups of 10 male (for 28 days) and 10 female (for a maximum 54 days) Wistar rats at dosages of 40, 200 and 1000 (for 4 days) / 750 (from the 5th day) mg/kg body weight revealed mortalities in male and female animals at the highest dose. Based hereupon, the starting dose of 1000 mg/kg body weight was reduced to 750 mg/kg body weight. The mortalities were mostly in animals treated at 1000 mg/ kg body weight. Premature mortalities were also noted in animals treated only at 750 mg/ kg body weight. There were prominent lung lesions seen histologically and were considered indicative of (per)acute damage to the airways by a local irritant effect of the test item when accidentally reaching the lung. There were also predominant organ lesions seen in the stomach. Therefore, pulmonary and gastric lesions noted histopathologically were interpreted as contributory factors to death.

There were very few clinical signs recorded in the animals of LD or MD groups, which were transient in nature. There were clinical signs namely abnormal breathing, nasal discharge, piloerection, moving the bedding, prone position, catalepsy, salivation, reduced spontaneous activity, comatose, ataxia, lethargic, dehydration recorded in males or females of HD group.

There were no adverse treatment related changes noted for body weight, body weight change and food consumption of male and female treated groups when compared to corresponding control. No treatment related changes were noted for absolute and relative organ weights and no test item-related histological findings were observed in reproductive organs in the males and in surviving females in this study.

There were no toxicologically relevant findings noted for reproductive and developmental parameters in any dose group. No treatment related changes were noted for total number of pups born, number of male and female pups, sex ratio, live pups on PND 0 and PND 4. There were no treatment related changes noted for litter mean weight, total litter weight, male litter weight and female litter weight on PND 0 and 4. No changes for the duration of precoital interval and gestation were noted as well as for the number of corpora lutea, number of implantation sites, number of live pups born on PND 0, percentage of pre and post implantation loss in treated groups when compared to corresponding control group. Additionally, no treatment related changes were noted for copulation, fertility, delivery, viability indices and survival of the pubs from PND 0 to PND 4 in treated groups when compared to the control. No treatment related gross external findings were observed in the treated groups.

Based on the findings of this study, the no observed adverse effect level (NOAEL) for general maternal toxicity is considered to be 200 mg/kg body weight and for reproductive and developmental toxicity 750 mg/kg body weight.