Registration Dossier

Administrative data

Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
LOAEL
30 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on fertility: via inhalation route
Endpoint conclusion:
no study available
Effect on fertility: via dermal route
Endpoint conclusion:
no study available
Additional information

A close homologue (CAS-no. 1233873 -37 -4) of the registered substance, which has a branched C12 instead of a branched C9 side chain and lacks a methyl group at the oxime carbon atom, has been tested. Benzaldehyde, dodecylhydroxy-, oxime, branched (solvent-free and dodecylphenol-depleted) was given daily as an oily solution to groups of 10 male and 10 female Wistar rats (F0 animals) by stomach tube at doses of 30, 100 and 300 mg/kg body weight/day (mg/kg bw/d). Control animals (10 male and 10 female Wistar rats) were dosed daily with the vehicle only (corn oil). The study was conducted according to OECD 421 guideline and GLP (BASF, 2014) with some additional examinations. The duration of treatment covered a 2-week premating and mating period in both sexes, about three weeks postmating in males, and the entire gestation period as well as approximately 4 days of the lactation period in females with litters, and 4 weeks of postmating period in non-pregnant females.

 

Observations

After 2 weeks of premating treatment the F0 animals were mated to produce F1 generation pups. Mating pairs were from the same test group. Mating was discontinued as soon as sperm was detected in the vaginal smear. F0 animals were examined for their reproductive performance including determination of the number of implantation sites and the calculation of postimplantation loss for all F0 females.

 

Food consumption of the F0 parents was determined once weekly during premating. In dams food consumption was determined for gestation days 0 - 7, 7 - 14, 14 - 20 and lactation days 1 - 4.

 

Body weights of F0 parents were determined once a week, in males throughout the study and in females during premating. During gestation and lactation period, F0 females were weighed on gestation days (GD) 0, 7, 14 and 20, on the day of parturition (postnatal day [PND] 0) and on PND 4.

 

The pups were sexed and examined for macroscopically evident changes on PND 0. They were weighed on PND 1 and on PND 4. Their viability was recorded. At necropsy on PND 4, all pups were sacrificed with CO2, under isoflurane anesthesia, and examined macroscopically for external and visceral findings.

 

Clinico-chemical and hematological examinations were performed of all animals in each sex and dose-group towards the end of the administration period.

 

Various sperm parameters (motility, sperm head count, morphology) were assessed in the F0 generation males at scheduled sacrifice or after appropriate staining.

 

All F0 parental animals were sacrificed by decapitation,under isoflurane anesthesia, and were assessed by gross pathology. Weights of selected organs were recorded and a histopathological examination was performed.


Results

Analysis

The various analyses:

Demonstrated the stability of the test substance in corn oil over a period of 7 days at room temperature.

- Verified correct concentrations of the test substance preparations.

 

Effects

The following test substance-related adverse effects/findings were noted:

 

300mg/kg bw/d

F0 PARENTAL ANIMALS

CLINICAL EXAMINATIONS/ REPRODUCTIVE PERFORMANCE/CLINICAL PATHOLOGY/ PATHOLOGY

- Decreased food consumption in the males during the whole premating period (up to 24% below control

- Decreased body weights in the males on premating days 7 - 13 (up to 7% below control), during the whole mating period (about 7% below control) and during the whole postmating period (up to 13% below control), reduced body weight gain in accordance

- Indications of regenerative anemia, such as decreased red blood cell (RBC) counts, hemoglobin and hematocrit values, as well as increased relative reticulocyte counts in rats of both sexes

- Prolonged prothrombin time in males

- Decreased mean corpuscular volume (MCV) and increased mean corpuscular hemoglobin concentration (MCHC) in females

- Indications of altered liver cell metabolism such as increased alanine aminotransferase (ALT) activities in rats of both sexes, increased creatinine values and decreased cholesterol values in males, increased triglyceride and total bilirubin values in females

- No copulation in 2/10 pairs, decreased mating index (80 vs. 100% in control)

- No pregnancies at all in females with confirmed copulation (8/10)

- Increased incidences of abnormal sperm and decreased total sperm head counts in the cauda epididymidis

- Decrease in absolute weight of testes (-28%), epididymides (-38%), prostate (-65%) and seminal vesicle (-84%) in male animals

- Decrease in relative weight of the epididymides (-29%), prostate (-60%) and seminal vesicle (-81%) in male animals

- Decrease in absolute (-48%) and relative (-46%) ovary weight in female animals

- Increase in absolute adrenal gland weight (+51%) in males and absolute liver weight (+14%) in female animals

- Increase in relative weight of adrenal glands (+75%/+21%), liver (+22%/+29%), and pituitary gland (+32%/+26%) of male and female animals

- Macroscopically reduced size of eight testes and epididymides and nine prostates and seminal vesicles in male animals

- Macroscopically reduced size of nine ovaries in female animals

- Moderate tubular degeneration in two males and slight reduction of tubular size in the left testis in seven males

- Slight to extreme oligospermia in four males and minimal to slight debris in seminiferous tubules in the left epididymis in three males

- Minimal to moderate increase of atretic follicles in eight females, inactivity of interstitial cells in the ovaries in six females, increased number of cyst(s) in nine females, and decreased number of corpora lutea in nine females

F1 PUPS

CLINICAL EXAMINATIONS/ GROSS FINDINGS

- No pregnancies, no pups delivered

 

100 mg/kg bw/d

F0 PARENTAL ANIMALS

CLINICAL EXAMINATIONS/ REPRODUCTIVE PERFORMANCE/CLINICAL PATHOLOGY/ PATHOLOGY

- Decreased total sperm head counts in the cauda epididymidis

- Decrease in absolute weight of the epididymides (-13%), prostate (-35%) and seminal vesicle (-47%) in male animals

- Decrease in relative weight of prostate (-32%) and seminal vesicle (-44%) in male animals

- Increase in relative weight of pituitary gland (+26%) of male animals

- Macroscopically reduced size of two prostates and seminal vesicles in male animals

- Minimal to slight reduction of tubular size in the left testis in six males and minimal debris in seminiferous tubules in the left epididymis in one male

- Moderate increase of atretic follicles and decreased number of corpora lutea in the ovaries in one female

- Decreased number of implantation sites (5.9** [**:p≤0.01] vs. 12.3 implants in control)

- Increased post-implantation loss (46.5% vs. 3.9% in control)

F1 PUPS

CLINICAL EXAMINATIONS/ GROSS FINDINGS

- Decreased mean number of delivered pups (4.1** [**:p≤0.01] vs. 11.8 pups per litter)

- Increased number of dead/cannibalized pups (6 vs. 1 in control), resulting in decreased viability index (about 14% below control)

- Skew of sex ratio towards female sex (33.3% males vs. 66.7% females on PND 0)

 

30 mg/kg bw/d

F0 PARENTAL ANIMALS

CLINICAL EXAMINATIONS/ REPRODUCTIVE PERFORMANCE/CLINICAL PATHOLOGY/ PATHOLOGY

- Decreased total sperm head counts in the cauda epididymidis

- Decrease in absolute and relative weight of the seminal vesicle (-16%/-18%) and increase in relative pituitary gland weight (+17%)

 

 

F1 PUPS

CLINICAL EXAMINATIONS/ GROSS FINDINGS

- No test substance-related adverse findings

 

Conclusion

Under the conditions of this OECD 421 combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in Wistar rats the following NOAEL (no observed adverse effect level) of Benzaldehyde, dodecylhydroxy-, oxime, branched (solvent-free and dodecylphenol-depleted) were determined:

 

TheNOAEL for general, systemic toxicity was 100 mg/kg bw/d for the F0 males and females based on anemia and altered liver cell metabolism at 300 mg/kg bw/d.

 

No NOAEL for fertility was determined for the F0 parental males because a dose-dependent decrease in the number of sperm in the cauda epididymidis as well as a change in relative organ weights of seminal vesicles and pituitary glands were noted at all tested dose levels of 30 mg/kg bw/d and above. Fertility and reproductive performance of F0 parental females were unaffected at 30 mg/kg bw/d. Fertility and reproductive performance were distinctly impaired at 100 mg/kg bw/d, while outright infertility was the result of the exposure to 300 mg/kg bw/d.

 

The NOAEL for developmental toxicity in the F1 offspring was 30 mg/kg bw/d, based on fetal and pup mortality at 100 mg/kg bw/d.

That this read across is justified was confirmed by a 14 day test study in rats:

Ethanone, 1-(2-hydroxy-5-nonylphenyl)-, oxime, branched was administered daily for 14 days as an oily solution to groups of 5 male and 5 female Wistar rats orally by gavage at doses of 0, 150, 450 and 750 mg/kg body weight/day (mg/kg bw/d). Due to clinical findings (i.e. piloerection, smeared fur at anogenital region) and body weight loss in animals of the high-dose group, the dose level of 750 mg/kg bw/d was reduced to 600 mg/kg bw/d from study day 3 onwards.Control animals (5 male and 5 female Wistar rats) were dosed daily with the vehicle only (corn oil)over a period of 14 days.

 

The present study does not have a GLP-status. The protocol and the experimental procedure were not checked by the QAU.

 

Observations

The animals were examined for signs of toxicity or mortality before the administration as well as within 2 hours and within 5 hours after the administration.

 

Water consumption, food consumption and body weight were determined on days 0, 3, 7, 10 and 14.

 

Clinico-chemical and hematological examinations were performed of all animals in each sex and dose-group towards the end of the administration period.

 

Various sperm parameters (motility, sperm head count, morphology) were assessed in all males at scheduled sacrifice or after appropriate staining.

 

On day 15 all animals were sacrificed by decapitation,under isoflurane anesthesia, and were assessed by gross pathology. Weights of selected organs were recorded and a histopathological examination was performed.

Results

The following test substance-related adverse effects/findings were noted:

 

Test group 3: 750/600 mg/kg bw/d

 

Clinical Examinations:

·        Reduced testes size in 3/5 males

·        Piloerection in 5/5 males and 5/5 females

·        Fur smeared in the anogenital region in 5/5 males and 2/5 females

·        Increased water consumption in males and females during the whole study (up to 67% and 91%, respectively)

·        Decreased food consumption in males during study days 0 - 14 (about 25%)

·        Decreased food consumption in females during study days 0 - 7 (up to 53%)

·        Decreased body weights in males (up to 12%)

·       Body weight loss in males (days 0 - 14; -9.5 g vs. 35.1 g in control)

 

Clinical Pathology:

·       Decreased hemoglobin and hematocrit values in both sexes

·       Decreased red blood cell counts in females

·       Decreased relative reticulocyte counts in males

·       Increased globulin values in females

·       Increased creatinine values in males

·       Decreased motility, decreased sperm head counts in the testis and the cauda epididymidis and increased relative abnormal sperm counts in two of five males

 

Pathology:

·       Increased relative weight of livers (+24)% in male animals and increased absolute (+49%) and relative (+54%) weights of livers in female animals

·       Slight to moderate centrilobular hypertrophy in livers of male and female animals

·       Decreased absolute (-27%) and relative (-16%) weights of testes

·       Slight to moderate degeneration of testicular tubules in 4/5 animals

·       Vacuolization of Sertoli cells in 4/5 animals

·       Decreased absolute (-42%) and relative (-32%) weights of epididymides

·       Minimal to severe oligospermia in the epididymis in 3/5 animals

·       Cellular debris in the epididymis in 4/5 animals

·       Decreased absolute (-64%) and relative (-59%) prostate weights

·       Decreased absolute (-85%) and relative (-83%) weights of seminal vesicles

·       Changes of interstitial glands (ovaries) in 5/5 females


Test group 2: 450 mg/kg bw/d

 

Clinical Examinations:

·        Reduced testes size in 1/5 males

·        Piloerection in 1/5 females

·        Fur smeared in the anogenital region in 2/5 males

·        Increased water consumption in males during study days 0 - 14 (about 30%)

·        Increased water consumption in females during study days 0 - 14 (about 64%)

·        Decreased food consumption in males and females during study days 0 - 3 (about 25% and 30%, respectively)

·       Decreased body weight gain in males during study days 0 - 14 (12.1 g vs. 35.1 g in control)

 

Clinical Pathology:

·       Decreased hemoglobin, hematocrit values and RBC counts in females

·       Increased globulin values in females

·       Decreased sperm head counts in the cauda epididymidis and increased relative abnormal sperm counts in one of five males

 

Pathology:

·       Increased relative weight of livers (+27)% in male animals and increased absolute (+41%) and relative (+43%) weights of livers in female animals

·       Minimal to slight centrilobular hypertrophy in livers of male and female animals

·       Minimal degeneration of testicular tubules in 3/5 animals

·       Decreased absolute (-17%) weight of epididymides

·       Cellular debris in the epididymis in 2/5 animals

·       Decreased absolute (-43%) and relative (-38%) prostate weights

·       Decreased absolute (-64%) and relative (-61%) weights of seminal vesicles

·       Changes of interstitial glands (ovaries) in 5/5 females

 

 

Test group 1: 150 mg/kg bw/d

 

Clinical Examinations, Clinical Pathology:

·       No treatment-related, adverse effects were measured regarding clinical examinations and clinical pathology parameters.

 

Pathology:

·       Decreased absolute weight (-30%) of seminal vesicles

Conclusion

The two week oral administration of Ethanone 1-(2-hydroxy-5-nonylphenyl)-, oxime, branched to male and female Wistar rats revealed test substance-related, adverse signs of toxicity with regard to erythrocytes, liver, adrenal glands, male reproductive organs and ovaries at a dose of 450 mg/kg bw/d and above

 

Therefore, under the conditions of the present study the no observed adverse effect level (NOAEL) for general, systemic toxicity for the females was 150 mg/kg bw/d based on anemia, centrilobular hypertrophy in liver cells and changes of the interstitial glands in the ovaries at 450 mg/kg bw/d and above.

The NOAEL for the males was lower than 150 mg/kg bw/d because a dose-dependent decrease in absolute organ weights of the seminal vesicles were noted at all tested dose levels of 150 mg/kg bw/d and above, together with other findings in the male reproductive organs, anemia and centrilobular hypertrophy in liver cells in the two higher dose levels.


Short description of key information:
Based on the available data from the OECD 421 study with a close homologue (CAS-no. 1233873 -37 -4) of the registered substance, which has a branched C12 instead of a branched C9 side chain and lacks a methyl group at the oxime carbon atom, fertility and reproductive performance of the parental animals were adversely affected by treatment with the test substance. In addition, also developmental toxicity was evident in the offspring.

Effects on developmental toxicity

Description of key information
Based on the available data from the OECD 421 study with a close homologue (CAS-no. 1233873 -37 -4) of the registered substance, which has a branched C12 instead of a branched C9 side chain and lacks a methyl group at the oxime nitrogen, fertility and reproductive performance of the parental animals were adversely affected by treatment with the test substance. In addition, also developmental toxicity was evident in the offspring.
Effect on developmental toxicity: via oral route
Endpoint conclusion:
adverse effect observed
Dose descriptor:
NOAEL
30 mg/kg bw/day
Study duration:
subacute
Species:
rat
Effect on developmental toxicity: via inhalation route
Endpoint conclusion:
no study available
Effect on developmental toxicity: via dermal route
Endpoint conclusion:
no study available
Additional information

A close homologue (CAS-no. 1233873 -37 -4) of the registered substance, which has a branched C12 instead of a branched C9 side chain and lacks a methyl group at the oxime nitrogen, has been tested.

Under the conditions of the OECD 421 combined repeated dose toxicity study with the reproduction/developmental toxicity screening test in Wistar rats the following NOAEL (no observed adverse effect level) of Benzaldehyde, dodecylhydroxy-, oxime, branched (solvent-free and dodecylphenol-depleted) were determined:

 

TheNOAEL for general, systemic toxicity was 100 mg/kg bw/d for the F0 males and females based on anemia and altered liver cell metabolism at 300 mg/kg bw/d.

 

No NOAEL for fertility was determined for the F0 parental males because a dose-dependent decrease in the number of sperm in the cauda epididymidis as well as a change in relative organ weights of seminal vesicles and pituitary glands were noted at all tested dose levels of 30 mg/kg bw/d and above. Fertility and reproductive performance of F0 parental females were unaffected at 30 mg/kg bw/d. Fertility and reproductive performance were distinctly impaired at 100 mg/kg bw/d, while outright infertility was the result of the exposure to 300 mg/kg bw/d.

 

The NOAEL for developmental toxicity in the F1 offspring was 30 mg/kg bw/d, based on fetal and pup mortality at 100 mg/kg bw/d.

As similar effects on the reproductive organs were observed with Ethanone, 1-(2-hydroxy-5-nonylphenyl)-, oxime, branched in a 14 day test study it can be assumed that Ethanone, 1-(2-hydroxy-5-nonylphenyl)-, oxime, branched will also cause similar developmental effects in rat pups.

Justification for classification or non-classification

Based on the available data, a classification with R60 (May impair fertility, Cat. 2) and R61 (May cause harm to the unborn child, Cat. 2) according to DSD-DPD and a classification as toxic to reproduction with Cat. 1B Fertility and Development (H360) according to CLP is warranted.