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Key value for chemical safety assessment

Effects on fertility

Effect on fertility: via oral route
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
Additional information

In a gavage study according to OECD Guideline 422 (GLP standards were fulfilled; acceptable restrictions; Biosafety 1993) twelve male and 12 female Sprague-Dawley rats per dose were gavaged with 0, 100, 300, or 1000 mg/kg bw/day. The exposure period for males was 45 days; females were treated from day 14 before mating to day 3 of lactation. The premating exposure period for males was not clearly stated but presumably ca. 6 weeks. There was no post exposure observation period. Body weight and food consumption was measured in all groups. Estrous cyclicity was determined before mating. Hematology and clinical chemistry was performed in males. The following litter observations were recorded: live pups at birth and at day 4 (termination); sex ratio; litter & pup weight at birth and at day 4; loss of offsprings; abnormal pups. At termination organ weights (absolute and relative) were determined of p generation and necropsy and histopathology performed. The following reproductive/developmental indices were measured: copulation index, fertility index, gestation index, implantation index, delivery index, birth index, and viability index on day 4.

The reproductive performance and the development of the offspring were not affected by oral application of dose levels up to 1000 mg/kg bw/day. Concerning the repeated dose toxicity in females of the parent generation no effects were detected even at the high dose. At 300 mg/kg bw/day no effects of toxicological relevance were recorded in males. At a dose level of 1000 mg/kg bw/day absolute and relative kidney weight was increased in males and the severity in basophilic alteration of the renal tubular epithelium was increased accompanied by an increased incidence in hyaline droplets and protein casts. These effects are considered to be adverse in nature.

Conclusion: Reproductive performance of the parent generation and development of the F1 generation were not affected after oral application of dose levels up to 1000 mg/kg bw/day. Concerning repeated dose toxicity the high dose resulted in no toxic effects in females but in males; the NOAEL for systemic toxicity was 300 mg/kg bw/day.

The available subchronic toxicity study according to OECD 408 (BASF SE, 2013) revealed no test substance-related effects on estrous cycle lenght and the number of cycles and no effects were observed concerning the motility of the sperms and the incidence of abnormal sperms in the cauda epididymidis as well as the sperm head counts in the testis and in the cauda epididymidis up to and including the limit dose of 1000 mg/kg bw. Furthermore, no findings were observed within the histopathological examination of the sexual organs (epididymis, seminal vesicles, testis, ovaries, uterus, vagina).


Short description of key information:
In a gavage study according to OECD Guideline 422 reproductive performance of the parent generation and development of the F1 generation were not affected after oral application of dose levels up to 1000 mg/kg bw/day.

Effects on developmental toxicity

Description of key information
In a gavage study according to OECD Guideline 414 no maternal toxicity and no developmental toxicity were found after oral application of dose levels up to 1000 mg/kg bw/day (limit dose).
Link to relevant study records
Reference
Endpoint:
developmental toxicity
Type of information:
experimental study
Adequacy of study:
key study
Reliability:
1 (reliable without restriction)
Rationale for reliability incl. deficiencies:
other: GLP compliant guideline study
Qualifier:
according to
Guideline:
OECD Guideline 414 (Prenatal Developmental Toxicity Study)
Qualifier:
according to
Guideline:
EPA OPPTS 870.3700 (Prenatal Developmental Toxicity Study)
Qualifier:
according to
Guideline:
other: Commission Regulation(EC) No 440/2008 of 30 May 2008 REACH, Part B: Methods for the determination of toxicity and other health effects: Prenatal Developmental Toxicity Study; Official Journal of the European Union No. L 142
GLP compliance:
yes (incl. certificate)
Remarks:
BASF SE, Experimental Toxicology and Ecology, 67056 Ludwigshafen, Germany
Limit test:
yes
Species:
rat
Strain:
Wistar
Details on test animals and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories, Research Models and Services, Germany GmbH
- Age at study initiation: 10-12 weeks
- Weight at study initiation: 143.7-192.0 g.
- Housing: individually from GD 0-20 in type M III Makrolon cages supplied by BECKER & CO., Castrop-Rauxel, Germany (floor area about 800 cm²).
- Diet: ground Kliba maintenance diet mouse/rat “GLP”, meal, supplied by Provimi Kliba SA, Kaiseraugst, Switzerland, ad libitum
- Water:ad libitum
- Acclimation period: 6 days

ENVIRONMENTAL CONDITIONS
- Temperature (°C): 20-24°C
- Humidity (%): 30-70%.
- Air changes (per hr): 10
- Photoperiod (hrs dark / hrs light): 12/12
Route of administration:
oral: gavage
Vehicle:
water
Details on exposure:
PREPARATION OF DOSING SOLUTIONS:
The aqueous test substance preparations were prepared at the beginning of the administration period and thereafter at maximum intervals of 8 days, which took into account the period of established stability. For the test substance preparation, the specific amount of test substance was weighed,
topped up with drinking water in a volumetric flask and intesely mixed by shaking until it was dissolved.

VEHICLE
- Amount of vehicle (if gavage): 10 ml/kg
Analytical verification of doses or concentrations:
yes
Details on analytical verification of doses or concentrations:
The analyses of the test substance preparations were carried out at the Analytical Chemistry Laboratory of Experimental Toxicology and Ecology of BASF SE, Ludwigshafen, Germany. Analytical verifications of the stability of the test substance in drinking water over a period of a maximum of 8 day at ambient temperature were carried out prior to the study (Project No.: 01Y0030/10Y058).
Samples of the test substance preparations were sent to the analytical laboratory at the beginning of administration for verification of the concentrations.

Details on mating procedure:
The animals were paired by the breeder (“time-mated”); the day of evidence of mating (= de-tection of vaginal plug/sperm) was referred to as GD 0. The animals arrived on the same day (GD 0) at the experimental laboratory. The following day was designated as “GD 1”. The animals were
acclimated to the laboratory conditions between start of the study (beginning of the experimental phase) and first administration (GD 6).
Duration of treatment / exposure:
The test substance preparations were administered to the animals once a day orally by gavage, from implantation to one day prior to the expected day of parturition (GD 6 to GD 19), always at approximately the same time in the morning. The animals of the control group were treated with the vehicle (drinking water) in the same way. The volume administered each day was 10 ml/kg body weight. The calculation of the administration
volume was based on the most recent individual body weight.


Frequency of treatment:
daily
Duration of test:
GD0 - GD20
On GD 20, the females were sacrificed in a randomized order and examined macroscopically. The fetuses were removed from the uterus and
investigated.
Remarks:
Doses / Concentrations:
100, 300, 1000 mg/kg
Basis:
actual ingested
No. of animals per sex per dose:
25 mated females
Control animals:
yes, concurrent vehicle
Maternal examinations:
CAGE SIDE OBSERVATIONS: Yes
- Time schedule: A check was made twice a day on working days or once a day on Saturdays, Sundays or on public holidays (GD 0-20).

DETAILED CLINICAL OBSERVATIONS: Yes
- Time schedule: A cage-side examination was conducted at least once daily for any signs of morbidity, pertinent behavioral changes and signs of
overt toxicity. If such signs occurred, the animals were examined several times daily (GD 0-20).

BODY WEIGHT: Yes
- Time schedule for examinations: All animals were weighed on GD 0, 1, 3, 6, 8, 10, 13, 15, 17, 19 and 20. The body weight change of the animals was calculated based on the obtained results. Furthermore, the corrected body weight gain was calculated after terminal sacrifice (terminal
body weight on GD 20 minus weight of the unopened uterus minus body weight on GD 6).

FOOD CONSUMPTION Yes
The consumption of food was recorded for the intervals GD 0-1, 1-3, 3-6, 6-8, 8-10, 10-13, 13-15, 15-17, 17-19 and 19-20.

POST-MORTEM EXAMINATIONS: Yes
- Sacrifice on gestation day 20
- Organs examined: uteri and ovaries.
Ovaries and uterine content:
The ovaries and uterine content was examined after termination: Yes
Examinations included:
- Gravid uterus weight: Yes
- Number of corpora lutea: Yes
- Number of implantations: Yes
- Number of early resorptions: Yes
- Number of late resorptions: Yes
- Other: Furthermore, calculations of conception rate and pre- and postimplantation losses were carried out.
Dead fetuses (hypoxemic fetuses which did not breathe spontaneously after the uterus had been opened)

Fetal examinations:
- External examinations: Yes: all per litter
- Soft tissue examinations: Yes: half per litter
- Skeletal examinations: Yes: half per litter
Furthermore, the viability of the fetuses and the condition of placentae, umbilical cords, fetal membranes, and fluids were examined. Individual
placental weights were recorded.
Statistics:
- Simultaneous comparison of all dose groups with the control group using the DUNNETT- test (two-sided) for the hypothesis of equal means for the following parameters: Food consumption, body weight, body weight change, corrected body weight gain (net maternal body weight change), carcass weight, weight of unopened uterus, number of corpora lutea, number of implantations, number of resorptions, number of live fetuses, proportions of pre¬implantation loss, proportions of postimplantation loss, proportions of resorptions, proportion of live fetuses in each litter, litter mean fetal body weight, litter mean placental weight
- Pairwise comparison of each dose group with the control group using FISHER'S EXACT test (one-sided) for the hypothesis of equal proportions for the following parameters: Female mortality, females pregnant at terminal sacrifice, number of litters with fetal findings.
- Pairwise comparison of each dose group with the control group using the WILCOXON-test (onesided) for the hypothesis of equal medians for the following parameters: Proportions of fetuses with malformations, variations and/or unclassified observations in each litter.
For the parameter food consumption the "mean of means" was calculated and can be found in the relevant summary tables. The "mean of means" values allow a rough estimation of the total food consumption during different time intervals (pretreatment (days 0-6), treatment (days 6-19) and entire study (days 0-20)); they are not exactly precise values, because the size of the intervals taken for calculation differs. For the "mean of means" values no statistical analysis was performed.

Indices:
conception rate, preimplantation loss, postimplantation loss
Details on maternal toxic effects:
Details on maternal toxic effects:
There were no test substance-related or spontaneous mortalities in any of the groups. No test substance-related clinical signs or any disturbances
of the general behavior were observed in any dam during the entire study period.
The mean food consumption of the dams in test groups 1-3 (100, 300 or 1000 mg/kg bw/d) was comparable to the concurrent control throughout the entire study period. The statistically significantly increased food consumption value of the high-dose females during GD 19-20 was considered to be incidental.
The mean body weight and mean body weight gain of all substance-treated dams in test groups 1-3 (100, 300 or 1000 mg/kg bw/d) were in general comparable to the controls throughout the entire study period. The statistically significantly increased body weight gain of the low-dose females during GD 19-20 was judged to be incidental.

The mean gravid uterus weights of the animals of test group 1-3 (100, 300 and 1000 mg/kg bw/d) were not influenced by the test substance. The differences between these groups and the control group revealed no dose-dependency and were assessed to be without biological relevance
No test substance-related or spontaneous findings occurred at necropsy in any dam.
The conception rate reached 96% in the control and the low-dose group (0 and 100 mg/kg bw/d) and 100% in the mid- and high-dose groups (300 and 1000 mg/kg bw/d). With these rates, a sufficient number of pregnant females were available for the purpose of the study (according to the test guidelines listed in chapter 2.3.).
There were no test substance related and/or biologically relevant differences between test groups 0, 1, 2 and 3 (0, 100, 300 and 1000 mg/kg bw/d) in conception rate, in the mean number of corpora lutea and implantation sites or in the values calculated for the pre- and the postimplantation losses, the number of resorptions and viable fetuses. All observed differences are considered to reflect the normal range of fluctuations for animals of
this strain and age.




Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: maternal toxicity
Details on embryotoxic / teratogenic effects:
Details on embryotoxic / teratogenic effects:
The sex distribution of the fetuses in test groups 1-3 (100, 300 and 1000 mg/kg bw/d) was comparable to the control fetuses. Observable differences were without biological relevance.
The mean placental weights were comparable between the dosed groups (100; 300 and 1000 mg/kg bw/d) and the corresponding control group.
The mean fetal weights were nearly similar in all test groups (0, 100, 300 or 1000 mg/kg bw/d and did not show any biologically differences.
External malformations were recorded for two fetuses in the high-dose group (1000 mg/kg bw/d). Both fetuses had more than one malformation
affecting the head. The total incidence of external malformations in treated animals did not differ significantly from the control group and was
comparable to the historical control data . No fetal external variations were recorded.One external unclassified observation, i.e. placentae fused, was recorded for one mid-dose fetus This finding was considered to be spontaneous in nature.

One soft tissue malformation was observed in one high-dose litter (1000 mg/kg bw/d). It can be found in the historical control data at a comparable frequency. Furthermore, the overall incidences of soft tissue malformations were comparable to those found in the historical control data.

Three soft tissue variations, i.e. short innominate, dilated renal pelvis and dilated ureter, were detected in all test groups including the controls. The incidences of these variations were neither statistically significantly nor dose-dependently increased in the treated groups. Therefore, all differences were not considered biologically relevant. No unclassified soft tissue observations were recorded.

Skeletal malformations were noted in single fetuses of test groups 2 (300 mg/kg bw/d and 3 (1000 mg/kg bw/d) . These findings affected individual fetuses in three mid-dose and three high-dose litters each. Although the individual malformations appeared without dose relation, the overall incidences of skeletal malformations were statistically significantly increased in the respective test groups. However, the overall incidences of skeletal malformations were clearly within the historical control range (mean value: 1.2%; range per study: 0.0 – 4.8%). For all test groups, skeletal variations of different bone structures were observed, with or without effects on corresponding cartilages. The observed skeletal variations were related to several parts of fetal skeleton and appeared without a relation to dosing. The overall incidences of skeletal variations were comparable to the historical control data. Additionally, some isolated cartilage findings without impact on the respective bony structures, which were designated as unclassified cartilage observations, occurred in all test groups. The observed unclassified cartilage findings were related to the skull, cervical vertebrae, ribs and sternum and did not show any relation to dosing.







Dose descriptor:
NOAEL
Effect level:
1 000 mg/kg bw/day
Based on:
test mat.
Basis for effect level:
other: teratogenicity
Abnormalities:
not specified
Developmental effects observed:
not specified

The stability of the test substance preparations over a period of 8 days was demonstrated. Given that the test substance is completely miscible with drinking water, solutions were considered to be homogenous without further analysis.

The results of the analysis of the test substance solutions in drinking water confirmed the correctness of the prepared concentrations. The measured concentrations of the samples corresponded to the expected values within the limits of the analytical method, i.e. were always above 90% and below 110% of the nominal concentrations.

 

Conclusions:
Under the conditions of this prenatal developmental toxicity study, the oral administration of Neopentylglycol to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) at a dose of 1000 mg/kg bw/d caused no evidence of maternal and developmental toxicity.
In conclusion, the no observed adverse effect level (NOAEL) for maternal and prenatal developmental toxicity is 1000 mg/kg bw/d.
Executive summary:

In a prenatal developmental toxicity study the test compound Neopentylglycol was administered to pregnant Wistar rats daily by gavage from implantation to one day prior to the expected day of parturition (GD 6-19) to evaluate its potential maternal and prenatal developmental toxicity. Analyses confirmed the correctness of the prepared concentrations and the stability of the test substance in the vehicle. Generally, clinical observations revealed no toxicologically relevant difference between the dams receiving 100, 300 or 1000 mg/kg bw/ d Neopentylglycol and controls. No differences of toxicological relevance were noted between the control and the treatment groups (100, 300 or 1000 mg/kg bw/d) for any reproductive parameters. This included conception rate, mean number of corpora lutea, mean number of implantations and pre- and postimplantation loss. Similarly, no influence of the test compound on fetal weights and sex distribution was noted at any dose. Overall, there was no evidence for toxicologically relevant adverse effects of the test substance on fetal morphology at any dose.

Under the conditions of this prenatal developmental toxicity study, the oral administration of Neopentylglycol to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) at a dose of 1000 mg/kg bw/d caused no evidence of maternal and developmental toxicity.

Effect on developmental toxicity: via oral route
Endpoint conclusion:
no adverse effect observed
Dose descriptor:
NOAEL
1 000 mg/kg bw/day
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

In a prenatal developmental toxicity study according to OECD 414 (key, BASF SE, 2013) the test compound Neopentylglycol was administered to pregnant Wistar rats daily by gavage from implantation to one day prior to the expected day of parturition (GD 6-19). Analyses confirmed the correctness of the prepared concentrations and the stability of the test substance in the vehicle. Generally, clinical observations revealed no toxicologically relevant difference between the dams receiving 100, 300 or 1000 mg/kg bw/ d Neopentylglycol and controls. No differences of toxicological relevance were noted between the control and the treatment groups (100, 300 or 1000 mg/kg bw/d) for any reproductive parameters. This included conception rate, mean number of corpora lutea, mean number of implantations and pre- and postimplantation loss. Similarly, no influence of the test compound on fetal weights and sex distribution was noted at any dose. Overall, there was no evidence for toxicologically relevant adverse effects of the test substance on fetal morphology at any dose. Under the conditions of this study, the oral administration of Neopentylglycol to pregnant Wistar rats from implantation to one day prior to the expected day of parturition (GD 6-19) at a dose of 1000 mg/kg bw/d caused no evidence of maternal and developmental toxicity.

In a supporting study according to OECD Guideline 422 and GLP standards twelve female Sprague-Dawley rats per dose were gavaged with 0, 100, 300, or 1000 mg/kg bw/day from day 14 before mating to day 3 of lactation (Biosafety, 1993). The following litter observations were recorded: live pups at birth and at day 4 (termination); sex ratio; litter & pup weight at birth and at day 4; loss of offsprings; abnormal pups (external examinations). At termination organ weights (absolute and relative) of dams were determined and necropsy and histopathology performed. The following reproductive/developmental indices were measured: copulation index, fertility index, gestation index, implantation index, delivery index, birth index, and viability index on day 4. The reproductive performance and the development of the offspring were not affected by oral application of dose levels up to 1000 mg/kg bw/day. No maternal toxicity was detected at this dose level.

Conclusion: No maternal toxicity and no developmental toxicity were found after oral application of dose levels up to 1000 mg/kg bw/day (limit dose).


Justification for selection of Effect on developmental toxicity: via oral route:
GLP guideline study

Justification for classification or non-classification

Classification is not warranted since the criteria of EU Directive 67/548/EEC and EU Classification, Labelling and Packaging of Substances and Mixtures (CLP) Regulation (EC) No. 1272/2008 are not met.