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Diss Factsheets

Toxicological information

Toxicity to reproduction

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Administrative data

Endpoint:
screening for reproductive / developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
guideline study

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
2013
Report date:
2013

Materials and methods

Test guidelineopen allclose all
Qualifier:
according to guideline
Guideline:
OECD Guideline 422 (Combined Repeated Dose Toxicity Study with the Reproduction / Developmental Toxicity Screening Test)
Qualifier:
according to guideline
Guideline:
OECD Guideline 421 (Reproduction / Developmental Toxicity Screening Test)
Qualifier:
according to guideline
Guideline:
other: OECD Guideline 407
Qualifier:
according to guideline
Guideline:
other: EU Method B.7
GLP compliance:
yes (incl. QA statement)

Test material

Constituent 1
Reference substance name:
Amines, C11-14-branched alkyl, monohexyl and dihexyl phosphates
EC Number:
279-632-6
EC Name:
Amines, C11-14-branched alkyl, monohexyl and dihexyl phosphates
Cas Number:
80939-62-4
Molecular formula:
na (UVCB)
IUPAC Name:
Amines, C11-14-branched alkyl, monohexyl and dihexyl phosphates
Test material form:
liquid: viscous

Test animals

Species:
rat
Strain:
Wistar
Sex:
male/female

Administration / exposure

Route of administration:
oral: gavage
Details on exposure:
After acclimatization, four groups of ten male and ten female Wistar Han rats were exposed by oral gavage to the test substance at 0, 10, 30 and 100 mg/kg/day. Males were exposed for 29 days, i.e. 2 weeks prior to mating, during mating, and up to termination. Females were exposed for 41 - 54 days, i.e. during 2 weeks prior to mating, during mating, during post-coitum, and during at least 4 days of lactation.
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
Accuracy, homogeneity and stability of formulations were demonstrated by analyses.
Duration of treatment / exposure:
Males were exposed for 29 d and females were exposed for 41-54 days.
Frequency of treatment:
Daily once
Doses / concentrationsopen allclose all
Dose / conc.:
10 mg/kg bw/day (actual dose received)
Dose / conc.:
30 mg/kg bw/day (actual dose received)
Dose / conc.:
100 mg/kg bw/day (actual dose received)
No. of animals per sex per dose:
10
Control animals:
yes, concurrent vehicle

Examinations

Parental animals: Observations and examinations:
The following observations and examinations were evaluated: mortality / viability, clinical signs (daily), functional observations and locomotor activity (Week 4 (males); end of lactation (females)), body weight and food consumption (at least at weekly intervals), clinical pathology (Week 4 (males); end of lactation (females)), macroscopy at termination, organ weights and histopathology on a selection of tissues. Reproductive parameters were mating, fertility and conception, indices, precoital time, number of corpora lutea and implantation sites, gestation index and duration, parturition, maternal care, sex ratio.
Postmortem examinations (offspring):
Early postnatal pup development (mortality, clinical signs, body weights and macroscopy).

Results and discussion

Results: P0 (first parental generation)

General toxicity (P0)

Clinical signs:
no effects observed
Mortality:
no mortality observed
Body weight and weight changes:
no effects observed
Food consumption and compound intake (if feeding study):
no effects observed
Haematological findings:
effects observed, treatment-related
Clinical biochemistry findings:
no effects observed
Organ weight findings including organ / body weight ratios:
effects observed, treatment-related
Histopathological findings: non-neoplastic:
effects observed, treatment-related

Reproductive function / performance (P0)

Reproductive function: oestrous cycle:
no effects observed
Reproductive function: sperm measures:
no effects observed
Reproductive performance:
no effects observed

Effect levels (P0)

Key result
Dose descriptor:
LOAEL
Effect level:
10 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
haematology
organ weights and organ / body weight ratios
gross pathology
histopathology: non-neoplastic

Target system / organ toxicity (P0)

Key result
Critical effects observed:
yes
Lowest effective dose / conc.:
10 mg/kg bw/day (actual dose received)
System:
haematopoietic
Organ:
adrenal glands
mesenteric lymph node
spleen
Treatment related:
yes
Dose response relationship:
yes

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:
no effects observed
Other effects:
no effects observed

Developmental neurotoxicity (F1)

Behaviour (functional findings):
no effects observed

Effect levels (F1)

Key result
Dose descriptor:
NOAEL
Generation:
F1
Effect level:
100 mg/kg bw/day (actual dose received)
Based on:
test mat.
Sex:
male/female
Basis for effect level:
other: No treatment-related changes were noted in any of the reproductive and developmental parameters investigated in this study.

Target system / organ toxicity (F1)

Key result
Critical effects observed:
no

Overall reproductive toxicity

Key result
Reproductive effects observed:
no

Applicant's summary and conclusion

Conclusions:
Under the study conditions, no NOAEL could be determined for parental systemic toxicity and hence the LOAEL for systemic toxicity was determined to be 10 mg/kg bw/day. A reproduction and developmental toxicity NOAEL of 100 mg/kg bw/day was derived.
Executive summary:

A study was conducted to determine the reproductive-developmental toxicity potential of the substance according to OECD Guideline 422, 421 and 407 and EU Method B.7, under GLP conditions. Four groups of ten male and ten female Wistar Han rats were exposed by oral gavage to the test substance at 0, 10, 30 and 100 mg/kg bw/day. Males were exposed for 29 d, i.e. 2 weeks prior to mating, during mating, and up to termination. Females were exposed for 41 - 54 d, i.e. during 2 weeks prior to mating, during mating, during post-coitum, and during at least 4 d of lactation. The following observations and examinations were evaluated: mortality / viability, clinical signs (daily), functional observations and locomotor activity (Week 4 (males); end of lactation (females)), body weight and food consumption (at least at weekly intervals), clinical pathology (Week 4 (males); end of lactation (females)), macroscopy at termination, organ weights and histopathology on a selection of tissues, and reproduction/developmental parameters, consisting of mating, fertility and conception indices, precoital time, number of corpora lutea and implantation sites, gestation index and duration, parturition, maternal care, sex ratio and early postnatal pup development (mortality, clinical signs, body weights and macroscopy). Formulations were analyzed once during the study to assess accuracy, homogeneity and stability. No clinical signs of toxicity were observed in the parental animals. Body weight development and food consumption were not affected by administration of the test substance. Hematological examinations revealed slightly increased leucocyte counts in males and females at 100 mg/kg bw/day, primarily due to increased neutrophil counts. Increased leucocyte counts were also present in females at the mid dose and the percentage of neutrophils was increased in both sexes at this dose. No toxicologically relevant changes were observed by clinical chemistry examinations. Enlarged spleen with increased weight was observed at the high dose only. Histopathological findings were confined to lesions in the mesenteric lymph nodes (foamy macrophages with/without fibrosis, sinus ectasia, focal necrosis within the aggregates of foamy macrophages with/without fibrosis and macrophage foci) and adrenal gland cortex (inflammatory lymphocytic cells). The higher neutrophil counts (and white blood cell counts) at 30 and 100 mg/kg bw/day were considered to be due to these inflammatory histopathological changes. No treatment-related changes were noted in any of the reproductive parameters investigated in this study. Histopathologically, the assessment of the integrity of the spermatogenetic cycle did not provide any evidence of impaired spermatogenesis, and no abnormalities were seen in the reproductive organs of the animal that failed to deliver healthy offspring. Finally, no treatment-related changes were noted in any of the developmental parameters investigated in this study. Under the study conditions, no NOAEL could be determined for parental systemic toxicity and hence the LOAEL for systemic toxicity was determined to be 10 mg/kg bw/day. A reproduction and developmental toxicity NOAEL of 100 mg/kg bw/day was derived (van Otterdijk, 2013).